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Osteosarcoma and Metastasis

Gaohong Sheng, Yuan Gao, Yong Yang and 1 more

Frontiers in Oncology · 2021 · Review · CC BY

doi:10.3389/fonc.2021.780264

Abstract

Osteosarcoma is the most common primary bone malignancy in adolescents. Its high propensity to metastasize is the leading cause for treatment failure and poor prognosis. Although the research of osteosarcoma has greatly expanded in the past decades, the knowledge and new therapy strategies targeting metastatic progression remain sparse. The prognosis of patients with metastasis is still unsatisfactory. There is resonating urgency for a thorough and deeper understanding of molecular mechanisms underlying osteosarcoma to develop innovative therapies targeting metastasis. Toward the goal of elaborating the characteristics and biological behavior of metastatic osteosarcoma, it is essential to combine the diverse investigations that are performed at molecular, cellular, and animal levels from basic research to clinical translation spanning chemical, physical sciences, and biology. This review focuses on the metastatic process, regulatory networks involving key molecules and signaling pathways, the role of microenvironment, osteoclast, angiogenesis, metabolism, immunity, and noncoding RNAs in osteosarcoma metastasis. The aim of this review is to provide an overview of current research advances, with the hope to discovery druggable targets and promising therapy strategies for osteosarcoma metastasis and thus to overcome this clinical impasse.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents and characterized by mesenchymal cells or osteogenic progenitor cells producing osteoid and immature bone. The estimated incidence rate of OS is 2–4/million/year worldwide, with first peak at age of 15–19 years (incidence: 8–11/million/year) and second minor peak at age of >60 years. OS most commonly occurs in the metaphysis of long extremity bone, such as distal femur, proximal tibia, proximal femur, and proximal humerus, while it rarely arise in axial skeleton and other sites. The 5-year survival rate has reached a plateau in OS patients with localized disease ranging from 60%–70% since the introduction of systematic chemotherapy. However, the survival rate of around 20% is still dismal in patients with metastasis. More importantly, almost all patients are presumed to have subclinical micrometastatic lesions at diagnosis, whereas only 15%–20% of newly diagnosed OS are successfully detected with metastasis.

The OS cells show a high propensity to disseminate to develop metastasis, which appears to be the most important intrinsic factor for poor outcome of OS patients. OS can virtually metastasize to any sites or organs, mostly to lungs and occasionally to bone or lymph nodes. The metastatic OS cells from the primary tumor undergo a series of critical steps to colonize and grow in the second site and finally progress into clinically detectable lesions. The biological behavior of metastasis is quite different from primary tumor with respect to cell cycle, differentiation, karyotype, metabolism and surrounding microenvironment, which is caused by differentially expressed genes, shift of molecule profiles, and interaction with microenvironment. In the last few decades, a lot of research has been carried out to uncover potential mechanisms underlying OS metastasis and has made encouraging progress. Under the unremitting efforts, more and more biomarkers that are involved in metastasis and prognosis have been discovered. Functional experiments in cells and animal models further validate some remarkable genes and signaling pathways as well as their regulatory patterns responsible for metastasis. Based on these basic and preclinical studies, many clinical trials have also been initiated to identify novel therapeutic strategies against metastasis. Early diagnosis of metastasis especially micrometastasis will significantly innovate therapeutic modality and doubtlessly improve the prognosis of patients.

In this review, we performed a thorough literature search on OS metastasis and mainly discussed those studies that have been validated in vivo. Our focus was primarily on the biological behavior and underlying mechanisms of metastasis. We illustrated the panorama of OS metastasis from various perspectives, such as microenvironment, osteoclast, angiogenesis, metabolism, and immunity. Also, the role of noncoding RNAs in OS metastasis was also discussed, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). The aim of our study is to provide an overall insight into the cross-talk regulatory network in metastasis and to identify core nodes as potential targets for the development of novel therapies. Only breakthroughs in the diagnosis and treatment of metastatic OS can further improve the survival of patients.

Process of Metastasis

The dissemination of cancer cells from the primary tumor to a secondary site requires a set of multiple steps, and these metastatic cells exhibit completely distinct characteristics from primary tumor. The pulmonary metastasis process can be divided into three stages, including escape of cancer cells from primary tumor, transit within circulation system, and colonization and establishment of metastatic lesions in lung. Although a large number of tumor cells may gain the potential to enter this metastatic cascade, there are only a few cells that can survive to successfully form metastasis due to the limited efficiency in each step of metastatic cascade. Schematic diagram of OS metastasis to the lung is shown in Figure 1.

Stage 1: Dissemination From the Primary Tumor

At the first stage of metastasis, OS cells with an invasive phenotype migrate away from primary tumor and then invade into surrounding tissues. Such process of cancer invasion is critically dependent on the destruction and degradation of basement membrane and extracellular matrix (ECM), which is catalyzed by pericellular and extracellular proteases, mainly by the matrix metalloprotease (MMP) family. Remarkably, a series of studies have suggested that many proteins and microRNAs can promote OS metastasis via upregulating various MMPs, including MMP-9, MMP-13, membrane-associated MT1-MMP (also called MMP14), and MMP-16. Cathepsin is another proteolytic enzyme to be involved in OS metastasis. Furthermore, some inhibitors targeting MMPs have been explored to suppress OS aggressive behavior by blocking this stage, such as tissue inhibitor of metalloproteinases (TIMPs) and Nobiletin. In addition, the interactions between tumor cells and microenvironment such as endothelial cells and mesenchymal stem cells (MSCs) may promote tumorigenicity, whereas interactions with primed dendritic cells and natural killer (NK) cells (33) have antitumor effects. For instance, MSCs promote OS metastasis by the interaction of CCL5 from MSCs and SDF-1 from OS cells via autocrine/paracrine communication. Tumor lysate-pulsed dendritic cells have been studied in combination with other candidate strategies, such as agonist antiglucocorticoid-induced tumor necrosis factor receptor (anti-GITR) antibody, anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibody, and antitransforming growth factor-β (anti-TGF-β) antibody, to further improve OS treatment via enhancing antitumor immunity. In addition, NK cells can kill OS cells, including tumor-initiating cells, through the interaction between natural killer group 2 member D (NKG2D) receptor and its ligand (NKG2DL). The significance of osteoclast-mediated bone destruction and resorption has been revealed throughout the OS development and progression. Nevertheless, the exact role of osteoclast in OS metastasis remains controversial and subject to further clarification. A more detailed discussion would be presented in the subsequent part of osteoclasts and metastasis in this review. Figure 1 A depicts the processes of OS cell invasion and migration at primary site.

Stage 2: Transit Within Circulation System

Firstly, OS cells need to intravasate into microvasculature such as blood vasculature by crossing endothelial cells and basement membrane and then travel within blood flow. The circulating tumor cells arrest and eventually extravasate out from blood into the target secondary organ. Several studies have investigated the interactions between tumor cells and endothelia cells and identified a few related molecules, including runt-related transcription factor 2 (RUNX2), osteopontin (OPN), urokinase-type plasminogen activator (uPAR), and formyl peptide receptor type 1 (FPR1), all of which are further shown to facilitate metastasis in vivo. In order to survive in blood vessels, OS cells must acquire anoikis resistance property, which is regulated by many genes such as FASN and ID1. Additionally, tumor cells also encounter with various physical hemodynamic forces (e.g., fluid shear stress) during transit. The time and intensity of circulating tumor cells exposure to fluids will affect their fates either survival or apoptosis. The development of bone adapts to mechanical load, suggesting that OS cells might be sensitive to their surround physical stimuli. Moreover, the changes in physical stimuli could not only affect biological behaviors of OS cells but also influence their response to chemotherapy and radiation therapy. The transfer of OS cells within vasculature is shown in Figure 1 B.

Stage 3: Colonization and Establishment of Metastasis in Lung

Under a poorly defined mechanism, the majority of circulating tumor cells arrive and arrest in lung microvasculature and subsequently extravasate into lung tissues, whereas only a minority of tumor cells can survive and eventually generate detectable metastasis. Compared with primary site, the microenvironment at the secondary site presents a lot of differences, including oxygen tension, nutrition supply, and other physiochemical features. Lung is a foreign microenvironment, where tumor cells will undergo many challenges and face various fates, including apoptosis or death (e.g., immune clearance), dormancy, and proliferation into micrometastasis. In terms of micrometastases, they also have several fates either entering into angiogenic dormancy, or regression, or proliferation to form vascularized macrometastatic lesions.

A few studies have attempted to elucidate the potential mechanisms by which OS cells conquer the selective pressures to successfully survive and proliferate in lungs. The response of OS cells to different stresses encountered in lungs is diverse. Endoplasmic reticulum (ER) stress can alter environment in ER lumen and disturb protein folding. The unfolded protein response (UPR) and UPR-related signaling pathways are also identified to dysregulated in OS. Compared with low metastatic counterparts, OS cells with high metastatic potential express a higher level of ER chaperone protein HSPA5, whose inhibition can reduce lung metastasis. The ER stress may even partly account for the resistance of chemotherapy in OS. Moreover, the mechanism remains poorly understood by which OS cells preferentially metastasize to lungs. Based on current research, the mechanical restriction of circulating tumor cells within lung microvasculature might play a crucial role in lung tropism. Another possible explanation of lung tropism is the notion of premetastatic niche. Extracellular vesicles, specifically exosomes released from cancer and stromal cells provide a favorable scenario for initiating organ-directed metastasis in several cancers, including melanoma, gastric cancer, pancreatic cancer, and cervical squamous cell carcinoma. A few reviews have discussed the role of exosomes in metastatic organotropism, among which one publication focused on bone sarcomas. Moreover, Hoshino et al. revealed that tumor-derived exosomes could be uptaken by organ-specific cells to prepare the premetastatic niche, which is mediated by different exosomal integrins depending on the metastatic organs. Although their results were mainly from breast cancer, they also profiled the proteome of OS-derived exosome. Recently, several research groups have demonstrated that OS-derived exosomes enhance OS lung metastasis and some circulating plasma exosomal biomarkers are detected to be dysregulated in metastatic OS. Another study further confirmed the preferential seeding of OS-secreted EVs in lung tissue by fluorescence microscopy with lifetime imaging in vivo. Thus, we speculate that exosomes derived from metastatic OS cells may preferentially retain in lung to create a premetastatic niche by interacting with resident cells, and thus attract OS cells to migrate to lung and support their survival. More studies are needed to investigate the biodistribution of OS-secreted exosomes and whether molecules within exosomes direct OS cells to lung. A brief description of OS lung metastasis is presented in Figure 1 C.

Molecular Mechanisms and Promising Targets

As mentioned above, each step of metastatic cascade is rate limited and therefore the key nodes in these steps can serve as potential targets for drug design. Some druggable targets have been summarized in other reviews based on which step the drug acts on. Considering the clinical scenario that the majority of patients already have micrometastasis, novel therapy focusing on the later step of metastasis may be more effective. Herein, we provide an overview of biology behavior and regulatory networks of metastasis from various perspectives and summarize current research advances and explore potential targets. The data are extracted from articles, where the results have been validated in animal experiments. Based on the relevance and similarity among these data, we list the core genes and involved signaling pathways or events in Table 1. These genes serve as nodes to weave a biological regulatory network of OS metastasis through related pathways, which will continue to be extended and improved with further research. Promising therapy targeting such hub genes or pathways may open a new avenue to treat OS metastasis.

Microenvironment and Metastasis

Bone is a type of connective tissue with complex components, including various cells, soluble factors, and extracellular matrix (ECM). These components interact and influence with each other, by which the bone tissue maintains homeostasis in physiological conditions. The appropriate balance between bone formation and destruction determines normal structure of bone. Indeed, OS occurrence and metastatic initiation arise in such a complex bone environment. Additionally, metastatic cells also interact with surrounding microenvironment in each step of metastatic process, primarily in lung. Therefore, study on the interactions between microenvironment and metastatic cells will expand our understanding of OS biology. Increasing evidence has indicated that metastatic cells elicit and receive signals to and from microenvironment, which lead to metastasis inhibition or promotion. Figure 2 provides a brief overview of the interactions between metastatic OS cells and microenvironment.

TP63 is a member of the well-known tumor suppressor gene p53 family, and its splice variant ΔNTP63 is characterized by the lack of N-terminal transactivation domain. Bid and colleagues have shown that ΔNTP63 overexpression in OS cells increases phosphorylation of signal transducer and activator of transcription 3 (STAT3) by enhancing interleukin-6 (IL-6) and interleukin-8 (IL-8) secretion. In addition, phosphorylation of STAT3 can stabilize hypoxia-inducible factor 1-alpha (HIF1-α) and induce vascular endothelial growth factor (VEGF) secretion. Combined with clinical data, these results reveal a prometastatic role of ΔNTP63 in OS. Furthermore, the suppression of above cytokine/chemokine signaling pathways can reduce OS metastasis. In a mouse model, the inhibitions of IL-6 and C–X–C motif chemokine 8 (CXCL8, also called IL-8) significantly prolong survival by decreasing their deaths from metastasis. Moreover, the combination of inhibitors against IL-6 and CXCL8 achieves an intensive antimetastatic efficiency whereas each inhibitor alone only shows a modest effect. Another laboratory has reported that the metastatic OS cells expressing ΔNTP63α disseminate in a transforming growth factor beta (TGFβ)-rich microenvironment by upregulation of Smad4 and TβRII via suppressing miRNA-527/665. In addition, TGF-β expression on the surface of extracellular vesicles (EVs), derived from OS cells, can induce the IL-6 secretion from mesenchymal stem cells (MSCs), which in turn facilitated proliferation of metastatic cells by activating STAT3. The administration of anti-IL-6 antibody disturbs this cross-talk signaling to reduce metastasis in mice. A research group recently has reported that myofibroblastic reprogramming of OS cells contribute to the formation of lung metastasis. This fibrotic reprogramming could be initiated by the activation of fibroblast growth factor (FGF) signaling and sustained by the resultant fibronectin (FN) deposition. They also demonstrated the efficacy of nintedanib in disrupting lung metastasis, but not in primary bone lesion, by blocking fibrotic reprogramming through inhibiting pan FGFR-FN axis.

Kleinerman and colleagues have indicated a noteworthy connection between OS cells and resident cells within lung, that is, the metastatic cells expressing Fas will be eliminated by binding to ligand (FasL), which is consistently expressed in lung. Under such selective pressure, only those Fas-negative OS cells or cells with nonfunctional Fas signaling can evade this defense mechanism and survive in lung. Thus, it is feasible to find agents that can induce Fas expression on OS cells as an alternative therapeutic approach against lung metastasis. This research group has identified two agents, chemotherapeutic agent gemcitabine and histone deacetylase inhibitor entinostat, both of which induce the regression of lung metastasis in wild-type mice by upregulating Fas expression. However, such therapeutic efficacy was not observed in FasL-deficient mice since a FasL+ lung microenvironment is a prerequisite for this treatment. Moreover, another study confirmed this result again in a canine model with lung metastasis. These findings suggest that incorporating lung microenvironment as part of the therapy strategy may benefit patients with established lung metastasis. As an important factor in microenvironment, EVs like tumor-derived exosomes contain various components (e.g., proteins and nucleic acids) and play an essential role in intercellular communication and metastatic progression in a variety of cancers. Notably, the expression profiles of EVs from OS samples with low metastatic potential are significantly distinguished from that in high metastatic potential samples by transcriptome analysis. A study further indicated that culture medium supplemented with exosomes would change secretome of OS cells and affect their aggressive properties. Interestingly, proteomic analysis of the EVs derived from highly metastatic OS cells shows the enrichment of metastasis-related proteins. The EVs from highly metastatic clonal variants of OS can even be internalized into low metastatic cells and thereby endow them with metastatic ability through horizontal phenotypic transfer. Also, an in vivo metastatic model further confirmed the potential of OS-derived EVs to promote metastasis. The exosomes released by OS cells, carrying programmed death-ligand 1 (PD-L1) and N-cadherin, could also stimulate pulmonary metastasis, and a recent study found that the plasma exosomal sentrin SUMO-specific protease 1 (SENP1) level is closely related to pulmonary metastasis in OS patients. As such, OS cells preferentially migrate and localize to lung directed by the EVs they have secreted, which may partly account for lung tropism of metastasis. The role of cancer-derived exosomes in cancer development and progression was systematically discussed in a review by Kok et al., mainly elaborating on the trafficking of enriched genetic signals carried by exosomal cargo in fostering cancer progression in several tumor types, including OS. In addition to exosomes derived from the tumor itself, exosomes from other cells such as bone marrow mesenchymal stem cells, adipose-derived mesenchymal stem cells and tumor-associated macrophages can also affect metastasis of osteosarcoma. OS cells and non-OS cells in tumor microenvironment could influence themselves or each other by releasing EVs through autocrine/paracrine pathways, shaping tumor microenvironment, modulating cell biological behaviors, especially the aggressiveness of OS cells. The secreted CXCLs within microenvironment selectively recruit different types of cells through binding to their transmembrane receptors. Tumor cells and leukocytes expressing CXCRs migrate following CXCL gradient. The CXCL/CXCR axis plays an essential role in leukocyte trafficking, immune homeostasis maintenance like T-cell homing, directional migration of tumor cells. It is well documented that the binding of CXCL12 (also known as SDF-1) to its receptor like CXCR4 or CXCR7 remarkably promotes tumor progression including OS. In primary bone site, OS epigenetically downregulates CXCL12 expression by DNMT1, impairs cytotoxic T-cell homing to the tumor site and this chemokine gradient of CXCL12 drives the metastasis of OS cells to the lung ( Figure 3 A ), where CXCL12 is highly expressed. The constitutive expression of CXCL12 in lung may largely determine lung as the main site of OS metastasis ( Figure 3 B ). In addition to CXCR4, CXCR7 is another receptor for CXCL12 and also participate in OS lung metastasis. The coexpression of CXCR7 and CXCR4 on OS cells could enhance their metastatic ability, since a chemokine gradient of CXCL12 between bone and lung is produced through CXCR7-mediated CXCL12 scavenging in primary bone site.Moreover, osteoprotegerin could induce SDF-1 secretion from endothelial cells, which further promotes OS development by increasing neovascularization via SDF-1/CXCR4 axis. Nigris et al. indicated that transcriptional repressor Yin Yang 1 protein (YY1) enhances metastatic potential of OS cells by activating VEGF/CXCR4 axis. Another study also suggested that VEGF secreted from MSCs promotes CXCR4-mediated metastasis. In addition, IL-8 produced by MSCs increases anoikis resistance and metastasis of OS cells by regulating CXCR1/Akt signaling pathway. Gozo and colleagues has demonstrated that forkhead box protein C2 (FOXC2) maintains OS cells in a stem-like state and promotes metastasis by increasing CXCR4. More importantly, the inhibition of CXCR4 by its antibody or inhibitor (like AMD300) can successfully reduce metastasis. Due to the prominent role of CXCL/CXCR axis in metastasis and its close association with angiogenesis, anoikis, and immune response, novel therapy targeting this axis might be promising for treating metastasis.

Osteoclasts and Metastasis

The progression of bone tumor leads to osteolysis, which in turn promotes the dissemination of tumor cells and thus forms by a vicious cycle. Breaking this vicious cycle between osteoclasts and tumor cells may be one of the promising ways to treat OS metastasis. Several studies have used RANK-Fc to perturb TNFRSF11A/TNFSF11 (also called RANK/RANKL) axis and successfully reduced metastasis by inducing anoikis and apoptosis of OS cells. In addition, other agents that can restrict bone resorption are also expected to become potential candidates to inhibit metastasis, such as inhibitors against transcription factor Sp7, TNFSF10 and TGF-β/Smad signaling. Anti-osteoclast drug like zoledronic acid could be synergistically used to enhance the therapy efficacy for OS progression. One publication has discussed the prospects of novel therapeutic strategy targeting osteoclast activity for OS. However, Munoz et al. suggested the tendency of mutual restrain between metastatic OS cells and osteoclasts and that metastasis-competent OS cells induce the loss of ACP5+ osteoclasts, which in turn facilitate metastasis. Notably, EVs derived from OS could suppress osteoclastogenesis and further enhance its metastasis. An in vitro study was performed to directly explore the reciprocal modulation between OS and osteoclastic cells by a co-culture system. More studies are needed to further clarify the exact role of osteoclast in OS metastasis. The interaction between osteoclasts and OS cells was displayed in Figure 3 C.

Angiogenesis and Metastasis

Angiogenesis is an essential component for tumor growth and progression by supplying adequate blood and nutrients. Additionally, these new blood vessels provide the principal route by which cancer cells exit the primary site and enter circulation. Angiogenesis is also required for tumor colonization at the site of metastasis. In OS metastasis, intensive investigation has explored the role of angiogenesis and interaction between proangiogenic and antiangiogenic factors, in order to develop potential optimum targets for antiangiogenic therapy ( Figure 3 A ). A meta-analysis including nine articles revealed that VEGF is positively associated with tumor metastasis and a higher tumor grade. Two publications also suggested that angiopoietin-like protein 2 and YY1 accelerate metastasis via VEGF-mediated angiogenesis. Furthermore, VEGF knockdown restricts OS metastasis. Also, the blockade of VEGF receptor 2 (VEGFR2) by anlotinib, a tyrosine kinase inhibitor, results in metastasis suppression in a preclinical study. In contrast to VEGF-related angiogenesis, pigment epithelium-derived factor (PEDF) or PEDF-derived synthetic peptides both exhibited antimetastasis activity by inhibiting angiogenesis. Antiangiogenesis therapy seems to be an appealing and attractive alternative strategy to manage OS metastasis. However, the safety and efficacy of antiangiogenic therapy has not been confirmed in clinical trials, more work is needed to achieve clinical transformation of this treatment. Current research progress and application limitation in antiangiogenesis therapy for OS can refer to other reviews.

Metabolism and Metastasis

The metabolic program of primary tumor cells is quite different from that of metastatic cells in many ways such as nutritional availability, energy demand, oxygenation level, metabolites, and metabolic pathways, all of which participate in tumor metastasis. An advanced metabolomics has shed light on the study of biochemical status and reprogrammed metabolism during metastasis. Metabolomics covers a wide range of metabolites, mainly including sugars, amino acids, and fatty acids. Giang et al. have observed the Warburg effect in several human OS cell lines, a common phenomenon of aerobic glycolysis in cancer cells that means pyruvate is transformed into lactic acid even in the presence of oxygen. Further study in mice by Hua and colleagues found the dynamic metabolic reprogramming throughout tumor occurrence and progression. They identified a number of differentially expressed metabolic biomarkers in serum prior and postmetastasis. Their results suggested the metabolic reprogramming in OS metastasis, characterized by lowered carbohydrate and amino acid metabolism, while an elevated lipid metabolism. Moreover, the serum metabolic profile of lung metastasis is distinct from that of primary tumor. Mice developing lung metastasis have a higher level of lipid metabolites in serum compared with mice without metastasis. Consistently, a global analysis of lipidomic reveals the alteration of lipid profiles in metastatic OS cells. Previous studies using synvinolin (inhibitor of de novo cholesterol synthesis) observed metastasis reduction, which further supported a critical role of lipid metabolism in tumor metastasis. The inositol pathway is significantly downregulated in highly metastatic OS cells. Functional study both in ex vivo lung culture and in vivo mouse model has indicated that the administration of inositol hexaphosphate, which will be converted to inositol once entering cells, can reduce lung metastasis by suppressing MAPK and PI3K signaling pathways.

HIF1-α expression is positively associated with metastasis while negatively with survival. Naggar et al. has shown that Y-box-binding protein 1 (YB-1) facilitates metastasis by direct translational activation of epithelial-to-mesenchymal transition (EMT) and HIF1-α, which then induces CXCR4 expression. Functionally, HIF1-α enhances invasion of OS cells in hypoxia via increasing VEGF-A. Another pathway, HIF1-α/CXCR4 is also proven to facilitate metastasis in vitro and in vivo. Additionally, HIF-1α binds to AP-1-binding motif within Cyr61 (also called CCN1) promoter and induces Cyr61 expression, which plays a prometastatic role in human melanoma cells under hypoxia. Hypoxia is one of the prominent features of many malignant tumors and also provides an opportunity to develop agents that target hypoxic region. For instance, hypoxia-activated prodrug TH-302 can reduce OS metastasis as a single agent or in combination with chemotherapy. The high expression of Cyr61 indicates poor survival in OS patients and promotes metastasis via activating PI-3K/Akt/GSK3β, IGF1/IGFR signaling pathways, facilitating angiogenesis characterized by an increase in VEGF, FGF2, PECAM, and a decrease in TSP-1 and SPARC and promoting EMT-like process. Of note, WW domain containing oxidoreductase (WWOX) as tumor suppressor has been revealed to maintain mitochondrial respiration and attenuate Warburg effect by inhibiting HIF1-α and c-Jun by physical interaction with them. Recently, a research group further found that WWOX inhibits OS metastasis in vitro and in vivo through downregulation of RUNX2. The suppression of c-Jun activity can inhibit metastasis by increasing apoptosis and chemosensitivity in OS cells. Tang and colleagues demonstrated that cadherin-4 (CDH4) overexpression would activate c-Jun via the JNK pathway. In addition to c-Jun, proteins from several families like c-Fos, ATF, and MAF, can form transcriptional complex AP-1, and their activation may be one of the mechanisms underlying metastasis. Leaner et al. have shown a higher activity of AP-1 in highly metastatic OS cells, compared with low metastatic counterparts. In terms of OS, AP-1 promotes metastasis by upregulating podoplanin and TGF-β. Another study also reported that FGFR1 silence, a downstream target of c-Fos/AP-1 complex, could significantly reduce lung metastasis. The growth and progression of malignant tumors largely rely on glycolysis for energy, resulting in an acidic tumor microenvironment, which may in turn affect the biological behaviors of tumor cells. Several studies have investigated how OS cells adapt to acidic microenvironment. Brief exposure of OS cells to acidic condition results in cell death, whereas prolonged exposure reverses cell death, and even fosters tumor invasiveness. The adaption of OS cells to acidosis leads to a metabolic reprogramming with epigenetic stability. The underlying mechanism has been further explored, by which acid microenvironment activates a stress-regulated switch to support cell survive. Studies found that cIAP proteins and NF-κB pathway are activated in OS cells in response to acid tumor microenvironment. Metabolism-related regulatory networks are shown in Figure 4.

As mentioned above, redox stress is a metabolic challenge in lung microenvironment for tumor cells. Studies shown that the excess reactive oxidative species and reactive nitrogen species, both impair mitochondrial function. In order to overcome such oxidative pressures, metastatic OS cells trigger their antioxidant response by upregulating redox-related enzymes or glutathione-related metabolic pathways. However, the previous mentioned study by Hua et al. reported the contradictory result that glutathione pathway is suppressed at the metastasis phase. More studies are urgently needed to further elucidate the exact role of metabolism especially glucose metabolism in tumor cells during dynamic metastatic process. Thereby, the exploration of metabolism reprogramming and metabolic vulnerability may provide novel targets for treating metastasis.

Immunity and Metastasis

It is well known that immune system both innate and adaptive immunity plays a key role in tumorigenesis and progression, and even to a large extent determines the fate of tumor cells. With the advance in basic and preclinical research, increasing immune-based therapies are being approved for clinical use in various cancers, which yield encouraging outcomes in those patients who are resistant to conventional treatment. Nevertheless, the application of immunotherapy in metastatic OS is far from satisfactory to date. Recently, a series of studies identified several immune cells, including innate immunocytes (e.g., macrophages and dendritic cells) and adaptive immunocytes (e.g., T lymphocytes), all of which putatively participate in immune response during OS metastatic progression ( Figure 5 ). The number, function, state of immune cells, and their interactions with each other collectively determine whether they promote or inhibit metastasis. Researchers have also recognized some immunocytes as diagnostic or prognostic biomarkers. For instance, the increase of M2-polarized tumor-associated macrophages (TAMs) maintains OS stemness and metastatic property. In addition, TAMs activated by mifamurtide or M2-type macrophages suppressed by all-trans retinoic acid (ATRA) both can inhibit tumorigenicity and progression of OS cells. However, the inconsistent results among studies are available, which require more research to further elucidate the dynamic and complex role of TAMs in OS. In addition to TAMs, tumor-infiltrating lymphocytes (TILs) within OS microenvironment also affect OS progression. The increased CD8+ TILs as well as the high ratio of CD8+/FOXP3+ TILs both predict a better prognosis in OS patients. However, the higher density of TILs is found to be within metastatic sites compared with primary tumor, which constitutes a special immune niche. It should be noted that the interaction between PD-L1 (expressed in metastatic OS cells) and PD-1 (expressed in tumor-infiltrating cytotoxic T lymphocytes) limits antitumor function of T cells and thus promotes OS metastasis by evading immune surveillance. The dynamic and intricate regulation of immune system seems to be decisive for metastasis with respect to synthesis of immune factors, spatiotemporal expression of surface markers and phenotypic transition of immunocytes, and their interactions with surrounding compositions. With increasing understanding of immunomodulatory mechanism underlying OS metastasis, researchers are constantly exploring the key immune checkpoints to develop potential immunotherapy strategies for OS with the aim of improving prognosis. A recent review has discussed the mechanisms and status of immunotherapy for OS.

Noncoding RNA

Noncoding RNAs are a large group of RNAs characterized by the lack of ability to encode proteins, which can be divided into regulatory and housekeeping noncoding RNAs. Here, we focused on the role of the former in OS metastasis, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). We further outlined the biological function of these noncoding RNAs in OS metastasis and the underlying molecular mechanism. Table 2 summarizes the noncoding RNAs that have been validated in vivo.

MicroRNA

MiRNAs contain 18–25 bases and most of them fell within 21–23 bases. Typically, miRNAs bind to 3′untranslated region (3′UTR) of mRNAs by complementarily pairing to destabilize mRNAs or block translation and thus reduce their expressions. A single miRNA can target multiple mRNAs and vice versa, one mRNA can be regulated by various miRNAs. Thereby, miRNAs may indirectly affect various biological processes such as proliferation, differentiation, apoptosis, and angiogenesis. The unique signatures of miRNA expression profile have been studied in OS metastasis as diagnostic and/or prognostic biomarkers. More importantly, an enormous growing body of studies have explored potential mechanisms, by which miRNAs participate in OS metastasis.

A minority of the miRNAs that we retrieved from literature have been demonstrated for their effects on OS metastasis in vivo. Also, only few miRNAs show prometastatic activity in OS, while the majority of miRNAs inhibit metastasis. A study reported that miR-195 suppressed metastatic potential by targeting FASN. However, other studies found a high level of miR-195 in serum from OS patients. Thus, a single miRNA might play a dual role in different stages of OS progression or the seemingly contradictory results are probably caused by small number of participants. Further studies are needed to confirm the exact function of such miRNAs like miR-195. Whether miRNAs promote or inhibit metastasis depends on proteins they target. Intriguingly, miR-27a* is the first passenger miRNA strand and shows prometastatic activity in OS cells, which is encoded by MIR27 and directly connects with CBFA2T3, the same as miR-27a. Furthermore, the injection of OS cells expressing miR-27a to mice can generate metastatic nodules within lung and bone in vivo. In turn, miRNAs are also regulated by metastasis-associated genes such as MYC, TP53, and TGFB1. The epigenetic modulation affects the miRNA expression as well. One research team found that apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) participated in multiple biological processes of OS by shifting miRNA expression profiles. Some drugs used to treat OS-like epirubicin and diallyltrisulfide can also alter miRNA expression profiles.

Unfortunately, miRNA-mediated therapy still remains the first phase of clinical trial at best despite so much basic and preclinical research. The main issue needed to be solved is how to deliver miRNAs efficiently and precisely to the sites of interest. Current methods generally show the following deficiencies, including low transfection efficiency, rapid degradation, and abnormal accumulation in nonspecific tissues and organs. Using hyaluronic acid-associated liposomes as carrier may accelerate the entry of miRNAs into cells and prevent them from degradation. An alternative approach is to apply viral vectors with hairpin molecules that will be processed into mature miRNAs.

Long Noncoding RNA

LncRNAs are a large group of noncoding RNAs with more than 200 nucleotides and emerging evidence demonstrates its crucial role in multiple biological processes, particularly in tumorigenesis. Briefly, lncRNAs in nucleus can regulate gene expression both at genetic and epigenetic levels by affecting transcription factors and chromatin-modifying complexes to bind specific gene loci. In cytoplasm, lncRNAs modulate the stability and translation activity of mRNAs either directly or indirectly. The majority of lncRNAs included in our study compete with miRNAs to bind target mRNAs as sponges. Recently, lncRNAs have engaged much attention in the field of tumor aggressiveness, including migration, invasion, and metastasis. Unlike miRNAs, most of lncRNAs involved in OS are positively associated with metastatic property. We outlined those lncRNAs that have been widely studied in OS metastasis and confirmed in vivo.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), also named noncoding nuclear-enriched abundant transcript 2 (NEAT2), is located in chromosome 11q13 with a length of 8.7kb. The MALAT1 overexpression is closely correlated with advanced clinical stage and distant metastasis in OS patients. Furthermore, a meta-analysis confirmed the predictive value of MALAT1 for metastasis and poor prognosis in six different types of cancer, including OS. Consistent with this result, another meta-analysis only including OS also showed MALAT1 as a valuable biomarker for prognosis. MALAT1 knockdown inhibits OS metastasis in vitro and in vivo by affecting various downstream pathways, such as downregulation of PI3K/Akt/MMP-9 signaling pathway and upregulation of E-cadherin and several miRNAs. Also, high dose of 17β-estradiol inhibits metastatic potential of OS cells by suppressing MALAT1 while low dose presents the opposite effect. It is noteworthy that the most widely studied lncRNAs is the large family of small nucleolar RNA host gene (SNHG), of which all members are considered to promote OS progression and metastasis by sponging various miRNAs. SNHG1, for example, activates Nin one binding protein (NOB1) by sponging miRNA-326 and thus promotes migration/invasion in OS cells and metastasis in murine models. Consistently, additional research further shows that SNHG1 is positively related to advanced clinical stage, distant metastasis, and poor survival of OS patients. In addition, SNHG1 facilitates cell proliferation, migration, and invasion via activating PI3K/AKT and Wnt/β-catenin pathways by sequestrating various miRNAs. Besides, SNHG12 promotes metastasis by increasing angiomotin, Notch2 and IGF1R through sponging miRNA-195-5p. There are two research groups that independently demonstrated the role of lncRNA DANCR in OS progression and possible underlying mechanisms. As a competitive endogenous lncRNA, DANCR either increases rho-associated protein kinase 1 (ROCK1) through decoying miRNA-335-5p and miRNA-1972, or enhances AXL/PI3K/Akt signaling pathway by sponging miRNA-33a-5p, and thereby promotes OS metastasis.

Circular RNA

CircRNAs are a newly identified class of endogenous noncoding RNAs characterized by closed-loop structures. Unlike typical linear RNA, circRNAs do not contain 5′-3′ polarity or polyadenylated tail and is thus resistant to enzyme degradation. Similar to lncRNAs, circRNAs can competitively bind miRNAs as sponges to indirectly regulate gene expression. Currently, increasing evidence indicates that circRNAs have an important role in many biological behaviors and diseases, particularly in tumorigenesis and tumor progression. The dysregulation of some circRNAs has also been identified in OS metastatic process. Almost all circRNAs, like lncRNAs, act as sponges of miRNAs to disinhibit specific prometastatic pathways that normally are inhibited by miRNAs in OS. However, it is not always the case. It has been reported that low expression of circ-HIPK3 is observed in OS cell lines, tissues, and plasm and associated with lung metastasis. Overexpression of circ-HIPK3 can inhibit proliferation, migration, and invasion in OS cells. These findings indicate that circ-HIPK3 may have great value in clinical practice as a tumor suppressor. Intriguingly, circ-HIPK3 plays the opposite role in tumor occurrence and progression in other tumors, which strongly suggests that whether a single circRNA acts as an oncogene or a tumor suppressor gene depends on tumor types and which miRNA it sponges. In addition, circRNAs hsa_circ_0002052 and circ-ITCH are also found to be downregulated in OS cell lines and tissues. Functional studies further confirm that their overexpression can suppress OS cell progressiveness by inhibiting Wnt/β-catenin pathway via targeting miRNA-1205/APC2 axis, and by suppressing PTEN/PI3K/AKT and Sp1 pathways via sponging miRNA-22, respectively. So far, the knowledge and research on circRNAs in OS metastasis are much less than that of miRNAs or lncRNAs. Nevertheless, the special annular structure gives circRNAs unique advantages with stronger stability and higher abundance.

In addition to tumor tissues, collecting noncoding RNAs from blood is convenient in clinical practice. Notably, a number of studies have reported that exosomes could carry noncoding RNAs and even transport them into OS cells, thus foster OS metastasis. With the deeper understanding of the relationship between noncoding RNAs and clinicalpathological characteristics, noncoding RNAs will help early diagnosis of metastasis, monitoring of treatment, and prediction of prognosis in OS patients. Although there is no therapy targeting noncoding RNAs used for OS yet, further research will make significant progress to develop novel therapeutic strategies and improve outcomes for OS patients with metastasis.

Discussion

In conclusion, metastasis is the most important factor resulting in treatment failure and the leading cause of death in OS patients. The 5-year survival rate for patients with metastasis remains only about 20% despite the use of aggressive surgery and intensive chemotherapy. Approximately 20% of patients present detectable metastasis at their first visit to hospital. However, almost all patients with localized disease are assumed to have micrometastasis already and nearly half of them will progress to clinical metastasis.

Although there have been great advances in the research of OS metastasis in the past few decades, the underlying mechanism is not yet clearly elucidated. Generally, the formation of new blood vessels by endothelial cells is a prerequisite for both primary and metastatic tumor growth. For OS, publications suggested that OS cell could facilitate endothelial cell proliferation and several reagents have been tested to suppress angiogenesis of endothelial cells by directly acting on OS cells. Although seemingly inconsistent with tumor angiogenesis, OS cells induce contact-dependent endothelial apoptosis, which may contribute to tumor invasion across vascular barrier during metastasis. Therefore, the role of endothelial cells and the interaction between them and OS cells are complex, perhaps playing a dual role, or changing dynamically with the stage and site of OS metastasis.

Lung is the most common site of OS metastasis; however, the underlying mechanism of this apparent organotropism remains to be elucidated. Recently, research found that secreted extracellular vesicles, specifically exosomes, would prepopulate in a particular organ, making it more suitable for tumor metastasis. Metastatic organotropism is one of the prominent characteristics of OS, and more investigations are necessary to reveal the potential mechanisms. In addition, novel therapy targeting those molecules that direct OS cells to lung may yield encouraging outcomes in OS patients. Also, immunotherapy has occupied an important position in the field of tumor therapy. However, no immunotherapy has made a breakthrough in metastatic osteosarcoma so far. The role of immune system in OS development and progression may differ from other tumors. Efforts should be made to explore the unique immune niche of OS metastasis, supporting performance of clinical transformation. In addition to external environmental and genetic factors, physical stimuli and modulation significantly influence OS metastatic process. The interaction of metastatic OS cells with their microenvironment, where they encounter dynamic mechanical forces, definitely affects OS cell invasiveness and to some extent determines the preferred metastatic site. However, it is not fully understood how OS cells specifically respond and adapt to their mechanical surroundings. Besides, the substrate stiffness and fluid flow shear stress may also modify the response of OS to therapy. Thus, the research on the fluid flow and/or substrate pressure can provide a novel consideration for developing anti-metastasis therapy.

Herein, we summarize the key regulatory molecules, signaling pathways, and dysregulated noncoding RNAs during metastatic process and hope to reveal potential druggable targets. The innovative technologies have ushered OS metastasis research into new era, such as multi-omics, liquid biopsy, tissue engineering, bioluminescent imaging, and so on. The OS research community should create biological banks and online databases to store and share precious specimens and relevant research results. Bioinformatics is an effective approach to reanalyze the raw data and explore the most valuable information. Moreover, there is a complex regulatory network between microenvironment, angiogenesis, osteoclast, metabolism, immunity, drug resistance, and OS metastasis. Based on emerging technologies and methods, it is expected to depict this network and expand our understanding of metastasis biology.

The standard drug development platform and evaluation system are necessary for clinical translation of promising drugs specifically in rare diseases like OS. As such, it is essential to establish various cell lines and biological models including animal models and bioengineering models that will facilitate research on metastasis. The models especially canine model that faithfully recapitulate metastasis development as in humans are prerequisites for clinical trials of candidate drugs. In addition, we should pay more attention to the effect of drugs on micrometastasis since some drugs uniquely reduce subclinical lesions. The novel drug delivery strategy and routes may allow conventional drugs to achieve unexpected efficiency while decreasing systemic toxicity.

The early diagnosis of metastasis and detection of circulating OS cells or micrometastasis will be the hotspots of future research and lead to breakthrough in improving survival of metastatic patients. A sensitive immunomagnetic detection assay has been successfully used to detect micrometastases from bone marrow and peripheral blood. Molecular imaging with specific molecular probes are also attempted to track OS cells, such as CXCR4-targeted near-infrared fluorescence imaging and ssDNA aptamer LP-16 targeting metastatic OS cells, which both allow detection of OS microlesions.

Drug therapy may be the only option to completely eliminate micrometastasis or inoperable lesions. The increasing studies have identified more and more biomarkers that are of predictive value for metastasis and prognosis in OS patients. However, individualized comprehensive molecular profiling of OS patients has not significantly changed the therapeutic prospects of advanced osteosarcoma. Therefore, more work is needed to better classify patients and further propel personalized management for specific patients. In short, only overcoming metastasis can effectively improve the survival of patients with osteosarcoma.

Author Contributions

The manuscript was drafted by GS. YG created the diagrams. YY was the guarantor of the entire manuscript for designing and supervising the entire study. HW checked and approved it. All authors contributed to the article and approved the submitted version.

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 51537004).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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    Ren L Hong SH Cassavaugh J Osborne T Chou AJ Kim SY. The Actin-Cytoskeleton Linker Protein Ezrin is Regulated During Osteosarcoma Metastasis by PKC. Oncogene (2009 ) 28(6):792–802

    Not in our library10.1038/onc.2008.437

  75. 75.

    Folkman J. Role of Angiogenesis in Tumor Growth and Metastasis. Semin Oncol (2002 ) 29(6 Suppl 16):15–8

    Not in our library10.1053/sonc.2002.37263

  76. 76.

    Lafleur EA Koshkina NV Stewart J Jia SF Worth LL Duan X. Increased Fas Expression Reduces the Metastatic Potential of Human Osteosarcoma Cells. Clin Cancer Res (2004 ) 10(23):8114–9

    Not in our library10.1158/1078-0432.ccr-04-0353

  77. 77.

    Ek ET Dass CR Contreras KG Choong PF. Pigment Epithelium-Derived Factor Overexpression Inhibits Orthotopic Osteosarcoma Growth, Angiogenesis and Metastasis. Cancer Gene Ther (2007 ) 14(7):616–26

    Not in our library10.1038/sj.cgt.7701044

  78. 78.

    Gordon N Kleinerman ES. Aerosol Therapy for the Treatment of Osteosarcoma Lung Metastases: Targeting the Fas/FasL Pathway and Rationale for the Use of Gemcitabine. J Aerosol Med Pulm Drug Deliv (2010 ) 23(4):189–96

    Not in our library10.1089/jamp.2009.0812

  79. 79.

    Ek ET Dass CR Contreras KG Choong PF. Inhibition of Orthotopic Osteosarcoma Growth and Metastasis by Multitargeted Antitumor Activities of Pigment Epithelium-Derived Factor. Clin Exp Metastasis (2007 ) 24(2):93–106

    Not in our library10.1007/s10585-007-9062-1

  80. 80.
    Anti‐PD‐1 therapy redirects macrophages from an M2 to an M1 phenotype inducing regression of OS lung metastases · 2018
    No notice
  81. 81.

    Ek ET Dass CR Contreras KG Choong PF. PEDF-Derived Synthetic Peptides Exhibit Antitumor Activity in an Orthotopic Model of Human Osteosarcoma. J Orthop Res (2007 ) 25(12):1671–80

    Not in our library10.1002/jor.20434

  82. 82.

    Lussier DM O'Neill L Nieves LM McAfee MS Holechek SA Collins AW. Enhanced T-Cell Immunity to Osteosarcoma Through Antibody Blockade of PD-1/PD-L1 Interactions. J Immunother (2015 ) 38(3):96–106

    Not in our library10.1097/cji.0000000000000065

  83. 83.

    Tang Q Lu J Zou C Shao Y Chen Y Narala S. CDH4 is a Novel Determinant of Osteosarcoma Tumorigenesis and Metastasis. Oncogene (2018 ) 37(27):3617–30

    Not in our library10.1038/s41388-018-0231-2

  84. 84.

    Gvozdenovic A Arlt MJ Campanile C Brennecke P Husmann K Li Y. CD44 Enhances Tumor Formation and Lung Metastasis in Experimental Osteosarcoma and is an Additional Predictor for Poor Patient Outcome. J Bone Miner Res (2013 ) 28(4):838–47

    Not in our library10.1002/jbmr.1817

  85. 85.

    Dass CR Khachigian LM Choong PF. C-Jun Is Critical for the Progression of Osteosarcoma: Proof in an Orthotopic Spontaneously Metastasizing Model. Mol Cancer Res (2008 ) 6(8):1289–92

    Not in our library10.1158/1541-7786.mcr-08-0036

  86. 86.

    Gvozdenovic A Arlt MJ Campanile C Brennecke P Husmann K Born W. Silencing of CD44 Gene Expression in Human 143-B Osteosarcoma Cells Promotes Metastasis of Intratibial Tumors in SCID Mice. PloS One (2013 ) 8(4):e60329

    Not in our library10.1371/journal.pone.0060329

  87. 87.

    Dass CR Khachigian LM Choong PF. C-Jun Knockdown Sensitizes Osteosarcoma to Doxorubicin. Mol Cancer Ther (2008 ) 7(7):1909–12

    Not in our library10.1158/1535-7163.mct-08-0086

  88. 88.

    Xu JF Pan XH Zhang SJ Zhao C Qiu BS Gu HF. CD47 Blockade Inhibits Tumor Progression Human Osteosarcoma in Xenograft Models. Oncotarget (2015 ) 6(27):23662–70

    Not in our library10.18632/oncotarget.4282

  89. 89.

    Dass CR Friedhuber AM Khachigian LM Dunstan DE Choong PF. Downregulation of C-Jun Results in Apoptosis-Mediated Anti-Osteosarcoma Activity in an Orthotopic Model. Cancer Biol Ther (2008 ) 7(7):1033–6

    Not in our library10.4161/cbt.7.7.6037

  90. 90.

    Manara MC Bernard G Lollini PL Nanni P Zuntini M Landuzzi L. CD99 Acts as an Oncosuppressor in Osteosarcoma. Mol Biol Cell (2006 ) 17(4):1910–21

    Not in our library10.1091/mbc.e05-10-0971

  91. 91.

    Sabile AA Arlt MJ Muff R Bode B Langsam B Bertz J. Cyr61 Expression in Osteosarcoma Indicates Poor Prognosis and Promotes Intratibial Growth and Lung Metastasis in Mice. J Bone Miner Res (2012 ) 27(1):58–67

    Not in our library10.1002/jbmr.535

  92. 92.

    Adhikari AS Agarwal N Wood BM Porretta C Ruiz B Pochampally RR. CD117 and Stro-1 Identify Osteosarcoma Tumor-Initiating Cells Associated With Metastasis and Drug Resistance. Cancer Res (2010 ) 70(11):4602–12

    Not in our library10.1158/0008-5472.can-09-3463

  93. 93.

    Habel N Vilalta M Bawa O Opolon P Blanco J Fromigue O. Cyr61 Silencing Reduces Vascularization and Dissemination of Osteosarcoma Tumors. Oncogene (2015 ) 34(24):3207–13

    Not in our library10.1038/onc.2014.232

  94. 94.

    He A Yang X Huang Y Feng T Wang Y Sun Y. CD133(+) CD44(+) Cells Mediate in the Lung Metastasis of Osteosarcoma. J Cell Biochem (2015 ) 116(8):1719–29

    Not in our library10.1002/jcb.25131

  95. 95.

    Habel N Stefanovska B Carene D Patino-Garcia A Lecanda F Fromigue O. CYR61 Triggers Osteosarcoma Metastatic Spreading via an IGF1Rbeta-Dependent EMT-Like Process. BMC Cancer (2019 ) 19(1):62

    Not in our library10.1186/s12885-019-5282-4

  96. 96.

    Zhang Y Ma Q Liu T Guan G Zhang K Chen J. Interleukin-6 Suppression Reduces Tumour Self-Seeding by Circulating Tumour Cells in a Human Osteosarcoma Nude Mouse Model. Oncotarget (2016 ) 7(1):446–58

    Not in our library10.18632/oncotarget.6371

  97. 97.

    Tu B Du L Fan QM Tang Z Tang TT. STAT3 Activation by IL-6 From Mesenchymal Stem Cells Promotes the Proliferation and Metastasis of Osteosarcoma. Cancer Lett (2012 ) 325(1):80–8

    Not in our library10.1016/j.canlet.2012.06.006

  98. 98.

    Kularatne SA Deshmukh V Ma J Tardif V Lim RK Pugh HM. A CXCR4-Targeted Site-Specific Antibody-Drug Conjugate. Angew Chem Int Ed Engl (2014 ) 53(44):11863–7

    Not in our library10.1002/anie.201408103

  99. 99.

    Zhang Z Wang F Li Q Zhang H Cui Y Ma C. CD151 Knockdown Inhibits Osteosarcoma Metastasis Through the GSK-3beta/Beta-Catenin/MMP9 Pathway. Oncol Rep (2016 ) 35(3):1764–70

    Not in our library10.3892/or.2015.4517

  100. 100.

    Neklyudova O Arlt MJ Brennecke P Thelen M Gvozdenovic A Kuzmanov A. Altered CXCL12 Expression Reveals a Dual Role of CXCR4 in Osteosarcoma Primary Tumor Growth and Metastasis. J Cancer Res Clin Oncol (2016 ) 142(8):1739–50

    Not in our library10.1007/s00432-016-2185-5

  101. 101.

    Itoh H Kadomatsu T Tanoue H Yugami M Miyata K Endo M. TET2-Dependent IL-6 Induction Mediated by the Tumor Microenvironment Promotes Tumor Metastasis in Osteosarcoma. Oncogene (2018 ) 37(22):2903–20

    Not in our library10.1038/s41388-018-0160-0

  102. 102.

    Dang H Wu W Wang B Cui C Niu J Chen J. CXCL5 Plays a Promoting Role in Osteosarcoma Cell Migration and Invasion in Autocrine- and Paracrine-Dependent Manners. Oncol Res (2017 ) 25(2):177–86

    Not in our library10.3727/096504016x14732772150343

  103. 103.

    Wang M Wang L Ren T Xu L Wen Z. IL-17a/IL-17RA Interaction Promoted Metastasis of Osteosarcoma Cells. Cancer Biol Ther (2013 ) 14(2):155–63

    Not in our library10.4161/cbt.22955

  104. 104.

    Du L Han XG Tu B Wang MQ Qiao H Zhang SH. CXCR1/Akt Signaling Activation Induced by Mesenchymal Stem Cell-Derived IL-8 Promotes Osteosarcoma Cell Anoikis Resistance and Pulmonary Metastasis. Cell Death Dis (2018 ) 9(7):714

    Not in our library10.1038/s41419-018-0745-0

  105. 105.

    Segaliny AI Mohamadi A Dizier B Lokajczyk A Brion R Lanel R. Interleukin-34 Promotes Tumor Progression and Metastatic Process in Osteosarcoma Through Induction of Angiogenesis and Macrophage Recruitment. Int J Cancer (2015 ) 137(1):73–85

    Not in our library10.1002/ijc.29376

  106. 106.

    Brennecke P Arlt MJ Campanile C Husmann K Gvozdenovic A Apuzzo T. CXCR4 Antibody Treatment Suppresses Metastatic Spread to the Lung of Intratibial Human Osteosarcoma Xenografts in Mice. Clin Exp Metastasis (2014 ) 31(3):339–49

    Not in our library10.1007/s10585-013-9632-3

  107. 107.

    Akiyama T Choong PF Dass CR. RANK-Fc Inhibits Malignancy via Inhibiting ERK Activation and Evoking Caspase-3-Mediated Anoikis in Human Osteosarcoma Cells. Clin Exp Metastasis (2010 ) 27(4):207–15

    Not in our library10.1007/s10585-010-9319-y

  108. 108.

    Zhang P Dong L Yan K Long H Yang TT Dong MQ. CXCR4-Mediated Osteosarcoma Growth and Pulmonary Metastasis is Promoted by Mesenchymal Stem Cells Through VEGF. Oncol Rep (2013 ) 30(4):1753–61

    Not in our library10.3892/or.2013.2619

  109. 109.

    Akiyama T Dass CR Shinoda Y Kawano H Tanaka S Choong PF. Systemic RANK-Fc Protein Therapy is Efficacious Against Primary Osteosarcoma Growth in a Murine Model via Activity Against Osteoclasts. J Pharm Pharmacol (2010 ) 62(4):470–6

    Not in our library10.1211/jpp.62.04.0009

  110. 110.

    Goguet-Surmenian E Richard-Fiardo P Guillemot E Benchetrit M Gomez-Brouchet A Buzzo P. CXCR7-Mediated Progression of Osteosarcoma in the Lungs. Br J Cancer (2013 ) 109(6):1579–85

    Not in our library10.1038/bjc.2013.482

  111. 111.

    Lamoureux F Picarda G Rousseau J Gourden C Battaglia S Charrier C. Therapeutic Efficacy of Soluble Receptor Activator of Nuclear Factor-Kappa B-Fc Delivered by Nonviral Gene Transfer in a Mouse Model of Osteolytic Osteosarcoma. Mol Cancer Ther (2008 ) 7(10):3389–98

    Not in our library10.1158/1535-7163.mct-08-0497

  112. 112.

    de Nigris F Rossiello R Schiano C Arra C Williams-Ignarro S Barbieri A. Deletion of Yin Yang 1 Protein in Osteosarcoma Cells on Cell Invasion and CXCR4/angiogenesis and Metastasis. Cancer Res (2008 ) 68(6):1797–808

    Not in our library10.1158/0008-5472.can-07-5582

  113. 113.

    Picarda G Lamoureux F Geffroy L Delepine P Montier T Laud K. Preclinical Evidence That Use of TRAIL in Ewing's Sarcoma and Osteosarcoma Therapy Inhibits Tumor Growth, Prevents Osteolysis, and Increases Animal Survival. Clin Cancer Res (2010 ) 16(8):2363–74

    Not in our library10.1158/1078-0432.ccr-09-1779

  114. 114.

    Gozo MC Jia D Aspuria PJ Cheon DJ Miura N Walts AE. FOXC2 Augments Tumor Propagation and Metastasis in Osteosarcoma. Oncotarget (2016 ) 7(42):68792–802

    Not in our library10.18632/oncotarget.11990

  115. 115.

    Cao Y Zhou Z de Crombrugghe B Nakashima K Guan H Duan X. Osterix, a Transcription Factor for Osteoblast Differentiation, Mediates Antitumor Activity in Murine Osteosarcoma. Cancer Res (2005 ) 65(4):1124–8

    Not in our library10.1158/0008-5472.can-04-2128

  116. 116.

    Brennecke P Arlt MJ Muff R Campanile C Gvozdenovic A Husmann K. Expression of the Chemokine Receptor CXCR7 in CXCR4-Expressing Human 143B Osteosarcoma Cells Enhances Lung Metastasis of Intratibial Xenografts in SCID Mice. PloS One (2013 ) 8(9):e74045

    Not in our library10.1371/journal.pone.0074045

  117. 117.

    Lamora A Talbot J Bougras G Amiaud J Leduc M Chesneau J. Overexpression of Smad7 Blocks Primary Tumor Growth and Lung Metastasis Development in Osteosarcoma. Clin Cancer Res (2014 ) 20(19):5097–112

    Not in our library10.1158/1078-0432.ccr-13-3191

  118. 118.

    Perissinotto E Cavalloni G Leone F Fonsato V Mitola S Grignani G. Involvement of Chemokine Receptor 4/Stromal Cell-Derived Factor 1 System During Osteosarcoma Tumor Progression. Clin Cancer Res (2005 ) 11(2 Pt 1):490–7.

    Not in our library

  119. 119.

    Endo-Munoz L Cumming A Rickwood D Wilson D Cueva C Ng C. Loss of Osteoclasts Contributes to Development of Osteosarcoma Pulmonary Metastases. Cancer Res (2010 ) 70(18):7063–72

    Not in our library10.1158/0008-5472.can-09-4291

  120. 120.

    Rodriguez Calleja L Jacques C Lamoureux F Baud'huin M Tellez Gabriel M Quillard T. DeltaNp63alpha Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGFbeta-Induced Metastasis. Cancer Res (2016 ) 76(11):3236–51

    Not in our library10.1158/0008-5472.can-15-2317

  121. 121.

    Gross AC Cam H Phelps DA Saraf AJ Bid HK Cam M. IL-6 and CXCL8 Mediate Osteosarcoma-Lung Interactions Critical to Metastasis. JCI Insight 3(16):e99791

    Not in our library10.1172/jci.insight.99791

  122. 122.

    Gvozdenovic A Boro A Meier D Bode-Lesniewska B Born W Muff R. Targeting Alphavbeta3 and Alphavbeta5 Integrins Inhibits Pulmonary Metastasis in an Intratibial Xenograft Osteosarcoma Mouse Model. Oncotarget (2016 ) 7(34):55141–54

    Not in our library10.18632/oncotarget.10461

  123. 123.

    Bid HK Roberts RD Cam M Audino A Kurmasheva RT Lin J. DeltaNp63 Promotes Pediatric Neuroblastoma and Osteosarcoma by Regulating Tumor Angiogenesis. Cancer Res (2014 ) 74(1):320–9

    Not in our library10.1158/0008-5472.can-13-0894

  124. 124.

    Li R Shi Y Zhao S Shi T Zhang G. NF-kappaB Signaling and Integrin-Beta1 Inhibition Attenuates Osteosarcoma Metastasis via Increased Cell Apoptosis. Int J Biol Macromol (2019 ) 123:1035–43

    Not in our library10.1016/j.ijbiomac.2018.11.003

  125. 125.

    Li Y Liao Q Li K Zhong D Weng X Mi M. Knockdown of Endothelin A Receptor Expression Inhibits Osteosarcoma Pulmonary Metastasis in an Orthotopic Xenograft Mouse Model. Mol Med Rep (2012 ) 5(6):1391–5

    Not in our library10.3892/mmr.2012.842

  126. 126.

    Pourebrahim R Zhang Y Liu B Gao R Xiong S Lin PP. Integrative Genome Analysis of Somatic P53 Mutant Osteosarcomas Identifies Ets2-Dependent Regulation of Small Nucleolar RNAs by Mutant P53 Protein. Genes Dev (2017 ) 31(18):1847–57

    Not in our library10.1101/gad.304972.117

  127. 127.

    Zhang D Jiang F Wang X Li G. Knockdown of SALL4 Inhibits Proliferation, Migration, and Invasion in Osteosarcoma Cells. Oncol Res (2017 ) 25(5):763–71

    Not in our library10.3727/096504016x14772402056137

  128. 128.
    ONZIN Upregulation by Mutant p53 Contributes to Osteosarcoma Metastasis Through the CXCL5-MAPK Signaling Pathway · 2018
    Not checked
  129. 129.
    LDOC1 regulates Wnt5a expression and osteosarcoma cell metastasis and is correlated with the survival of osteosarcoma patients · 2017
    Not checked
  130. 130.

    Luther GA Lamplot J Chen X Rames R Wagner ER Liu X. IGFBP5 Domains Exert Distinct Inhibitory Effects on the Tumorigenicity and Metastasis of Human Osteosarcoma. Cancer Lett (2013 ) 336(1):222–30

    Not in our library10.1016/j.canlet.2013.05.002

  131. 131.

    Wang J Ni J Song D Ding M Huang J Li W. MAT1 Facilitates the Lung Metastasis of Osteosarcoma Through Upregulation of AKT1 Expression. Life Sci (2019 ) 234:116771

    Not in our library10.1016/j.lfs.2019.116771

  132. 132.

    Su Y Wagner ER Luo Q Huang J Chen L He BC. Insulin-Like Growth Factor Binding Protein 5 Suppresses Tumor Growth and Metastasis of Human Osteosarcoma. Oncogene (2011 ) 30(37):3907–17

    Not in our library10.1038/onc.2011.97

  133. 133.

    Zeng H Zhang JM Du Y Wang J Ren Y Li M. Crosstalk Between ATF4 and MTA1/HDAC1 Promotes Osteosarcoma Progression. Oncotarget (2016 ) 7(6):7329–42

    Not in our library10.18632/oncotarget.6940

  134. 134.

    Wang S Zhang D Han S Gao P Liu C Li J. Fibulin-3 Promotes Osteosarcoma Invasion and Metastasis by Inducing Epithelial to Mesenchymal Transition and Activating the Wnt/beta-Catenin Signaling Pathway. Sci Rep (2017 ) 7(1):6215

    Not in our library10.1038/s41598-017-06353-2

  135. 135.

    Lu J Song G Tang Q Zou C Han F Zhao Z. IRX1 Hypomethylation Promotes Osteosarcoma Metastasis via Induction of CXCL14/NF-kappaB Signaling. J Clin Invest (2015 ) 125(5):1839–56

    Not in our library10.1172/jci78437

  136. 136.

    Zhang D Wang S Chen J Liu H Lu J Jiang H. Fibulin-4 Promotes Osteosarcoma Invasion and Metastasis by Inducing Epithelial to Mesenchymal Transition via the PI3K/Akt/mTOR Pathway. Int J Oncol (2017 ) 50(5):1513–30

    Not in our library10.3892/ijo.2017.3921

  137. 137.

    Manara MC Baldini N Serra M Lollini PL De Giovanni C Vaccari M. Reversal of Malignant Phenotype in Human Osteosarcoma Cells Transduced With the Alkaline Phosphatase Gene. Bone (2000 ) 26(3):215–20

    Not in our library10.1016/s8756-3282(99)00266-5

  138. 138.

    Zhang G Li M Jin J Bai Y Yang C. Knockdown of S100A4 Decreases Tumorigenesis and Metastasis in Osteosarcoma Cells by Repression of Matrix Metalloproteinase-9. Asian Pac J Cancer Prev (2011 ) 12(8):2075–80.

    Not in our library

  139. 139.

    Li YJ Dong BK Fan M Jiang WX. BTG2 Inhibits the Proliferation and Metastasis of Osteosarcoma Cells by Suppressing the PI3K/AKT Pathway. Int J Clin Exp Pathol (2015 ) 8(10):12410–8.

    Not in our library

  140. 140.

    Fujiwara M Kashima TG Kunita A Kii I Komura D Grigoriadis AE. Stable Knockdown of S100A4 Suppresses Cell Migration and Metastasis of Osteosarcoma. Tumour Biol (2011 ) 32(3):611–22

    Not in our library10.1007/s13277-011-0160-y

  141. 141.

    Chen MW Wu XJ. SLC25A22 Promotes Proliferation and Metastasis of Osteosarcoma Cells via the PTEN Signaling Pathway. Technol Cancer Res Treat (2018 ) 17:1533033818811143

    Not in our library10.1177/1533033818811143

  142. 142.

    Qin Y Ye J Zhao F Hu S Wang S. TRIM2 Regulates the Development and Metastasis of Tumorous Cells of Osteosarcoma. Int J Oncol (2018 ) 53(4):1643–56

    Not in our library10.3892/ijo.2018.4494

  143. 143.

    Chien MH Lee WJ Yang YC Tan P Pan KF Liu YC. N-Alpha-Acetyltransferase 10 Protein Promotes Metastasis by Stabilizing Matrix Metalloproteinase-2 Protein in Human Osteosarcomas. Cancer Lett (2018 ) 433:86–98

    Not in our library10.1016/j.canlet.2018.06.033

  144. 144.

    Chen Y Guo Y Yang H Shi G Xu G Shi J. TRIM66 Overexpresssion Contributes to Osteosarcoma Carcinogenesis and Indicates Poor Survival Outcome. Oncotarget (2015 ) 6(27):23708–19

    Not in our library10.18632/oncotarget.4291

  145. 145.

    Li Y Nakka M Kelly AJ Lau CC Krailo M Barkauskas DA. P27 Is a Candidate Prognostic Biomarker and Metastatic Promoter in Osteosarcoma. Cancer Res (2016 ) 76(13):4002–11

    Not in our library10.1158/0008-5472.can-15-3189

  146. 146.

    Cao J Wang Y Dong R Lin G Zhang N Wang J. Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells. Cancer Res (2015 ) 75(22):4839–51

    Not in our library10.1158/0008-5472.can-15-0711

  147. 147.

    Endo-Munoz L Cai N Cumming A Macklin R Merida de Long L Topkas E. Progression of Osteosarcoma From a Non-Metastatic to a Metastatic Phenotype Is Causally Associated With Activation of an Autocrine and Paracrine uPA Axis. PloS One (2015 ) 10(8):e0133592

    Not in our library10.1371/journal.pone.0133592

  148. 148.

    Fukaya Y Ishiguro N Senga T Ichigotani Y Sohara Y Tsutsui M. A Role for PI3K-Akt Signaling in Pulmonary Metastatic Nodule Formation of the Osteosarcoma Cell Line, LM8. Oncol Rep (2005 ) 14(4):847–52

    Not in our library10.3892/or.14.4.847

  149. 149.

    Shi QM Luo J Wu K Yin M Gu YR Cheng XG. High Level of alphaB-Crystallin Contributes to the Progression of Osteosarcoma. Oncotarget (2016 ) 7(8):9007–16

    Not in our library10.18632/oncotarget.6928

  150. 150.

    Liu JF Tsao YT Hou CH. Amphiregulin Enhances Intercellular Adhesion Molecule-1 Expression and Promotes Tumor Metastasis in Human Osteosarcoma. Oncotarget (2015 ) 6(38):40880–95

    Not in our library10.18632/oncotarget.5679

  151. 151.

    Lv YF Yan GN Meng G Zhang X Guo QN. Enhancer of Zeste Homolog 2 Silencing Inhibits Tumor Growth and Lung Metastasis in Osteosarcoma. Sci Rep (2015 ) 5:12999

    Not in our library10.1038/srep12999

  152. 152.

    Guo YS Zhao R Ma J Cui W Sun Z Gao B. Betaig-H3 Promotes Human Osteosarcoma Cells Metastasis by Interacting With Integrin Alpha2beta1 and Activating PI3K Signaling Pathway. PloS One (2014 ) 9(3):e90220

    Not in our library10.1371/journal.pone.0090220

  153. 153.

    Baglio SR Lagerweij T Perez-Lanzon M Ho XD Leveille N Melo SA. Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression. Clin Cancer Res (2017 ) 23(14):3721–33

    Not in our library10.1158/1078-0432.ccr-16-2726

  154. 154.

    Ren K Zhang J Gu X Wu S Shi X Ni Y. Migration-Inducing Gene-7 Independently Predicts Poor Prognosis of Human Osteosarcoma and Is Associated With Vasculogenic Mimicry. Exp Cell Res (2018 ) 369(1):80–9

    Not in our library10.1016/j.yexcr.2018.05.008

  155. 155.

    Liu J Luo B Zhao M. Bmi1targeting Suppresses Osteosarcoma Aggressiveness Through the NFkappaB Signaling Pathway. Mol Med Rep (2017 ) 16(6):7949–58

    Not in our library10.3892/mmr.2017.7660

  156. 156.

    Han W Liu J. Epigenetic Silencing of the Wnt Antagonist APCDD1 by Promoter DNA Hyper-Methylation Contributes to Osteosarcoma Cell Invasion and Metastasis. Biochem Biophys Res Commun (2017 ) 491(1):91–7

    Not in our library10.1016/j.bbrc.2017.07.049

  157. 157.

    El-Naggar AM Clarkson PW Negri GL Turgu B Zhang F Anglesio MS. HACE1 is a Potential Tumor Suppressor in Osteosarcoma. Cell Death Dis (2019 ) 10(1):21

    Not in our library10.1038/s41419-018-1276-4

  158. 158.

    Yue B Ren QX Su T Wang LN Zhang L. ERK5 Silencing Inhibits Invasion of Human Osteosarcoma Cell via Modulating the Slug/MMP-9 Pathway. Eur Rev Med Pharmacol Sci (2014 ) 18(18):2640–7.

    Not in our library

  159. 159.

    Sun W Wang W Lei J Li H Wu Y. Actin-Like Protein 6A is a Novel Prognostic Indicator Promoting Invasion and Metastasis in Osteosarcoma. Oncol Rep (2017 ) 37(4):2405–17

    Not in our library10.3892/or.2017.5473

  160. 160.

    Contaldo C Myers TJ Zucchini C Manara MC Chiodoni C Colombo MP. Expression Levels of Insulin Receptor Substrate-1 Modulate the Osteoblastic Differentiation of Mesenchymal Stem Cells and Osteosarcoma Cells. Growth Factors (2014 ) 32(1):41–52

    Not in our library10.3109/08977194.2013.870168

  161. 161.

    Zhao Z Wu MS Zou C Tang Q Lu J Liu D. Downregulation of MCT1 Inhibits Tumor Growth, Metastasis and Enhances Chemotherapeutic Efficacy in Osteosarcoma Through Regulation of the NF-kappaB Pathway. Cancer Lett (2014 ) 342(1):150–8

    Not in our library10.1016/j.canlet.2013.08.042

  162. 162.

    Levings PP McGarry SV Currie TP Nickerson DM McClellan S Ghivizzani SC. Expression of an Exogenous Human Oct-4 Promoter Identifies Tumor-Initiating Cells in Osteosarcoma. Cancer Res (2009 ) 69(14):5648–55

    Not in our library10.1158/0008-5472.can-08-3580

  163. 163.

    Wang Z Cao CJ Huang LL Ke ZF Luo CJ Lin ZW. EFEMP1 Promotes the Migration and Invasion of Osteosarcoma via MMP-2 With Induction by AEG-1 via NF-kappaB Signaling Pathway. Oncotarget (2015 ) 6(16):14191–208

    Not in our library10.18632/oncotarget.3691

  164. 164.
    Fascin-1 enhances experimental osteosarcoma tumor formation and metastasis and is related to poor patient outcome · 2019
    Not checked
  165. 165.

    Zandueta C Ormazabal C Perurena N Martinez-Canarias S Zalacain M Julian MS. Matrix-Gla Protein Promotes Osteosarcoma Lung Metastasis and Associates With Poor Prognosis. J Pathol (2016 ) 239(4):438–49

    Not in our library10.1002/path.4740

  166. 166.

    Long F Cai X Luo W Chen L Li K. Role of Aldolase A in Osteosarcoma Progression and Metastasis: In Vitro and In Vivo Evidence. Oncol Rep (2014 ) 32(5):2031–7

    Not in our library10.3892/or.2014.3473

  167. 167.

    Xu L Xia C Sheng F Sun Q Xiong J Wang S. CEP55 Promotes the Proliferation and Invasion of Tumour Cells via the AKT Signalling Pathway in Osteosarcoma. Carcinogenesis (2018 ) 39(4):623–31

    Not in our library10.1093/carcin/bgy017

  168. 168.

    Ma C Zhang Z Cui Y Yuan H Wang F. Silencing FAT10 Inhibits Metastasis of Osteosarcoma. Int J Oncol (2016 ) 49(2):666–74

    Not in our library10.3892/ijo.2016.3549

  169. 169.

    Ren L Mendoza A Zhu J Briggs JW Halsey C Hong ES. Characterization of the Metastatic Phenotype of a Panel of Established Osteosarcoma Cells. Oncotarget (2015 ) 6(30):29469–81

    Not in our library10.18632/oncotarget.5177

  170. 170.

    Niinaka Y Harada K Fujimuro M Oda M Haga A Hosoki M. Silencing of Autocrine Motility Factor Induces Mesenchymal-to-Epithelial Transition and Suppression of Osteosarcoma Pulmonary Metastasis. Cancer Res (2010 ) 70(22):9483–93

    Not in our library10.1158/0008-5472.can-09-3880

  171. 171.

    Yu W Zhang Z Min D Yang Q Du X Tang L. Mediator of RNA Polymerase II Transcription Subunit 19 Promotes Osteosarcoma Growth and Metastasis and Associates With Prognosis. Eur J Cancer (2014 ) 50(6):1125–36

    Not in our library10.1016/j.ejca.2014.01.030

  172. 172.

    Zhang Y Cheng H Li W Wu H Yang Y. Highly-Expressed P2X7 Receptor Promotes Growth and Metastasis of Human HOS/MNNG Osteosarcoma Cells via PI3K/Akt/GSK3beta/beta-Catenin and mTOR/HIF1alpha/VEGF Signaling. Int J Cancer (2019 ) 145(4):1068–82

    Not in our library10.1002/ijc.32207

  173. 173.

    Hou CH Yang RS Tsao YT. Connective Tissue Growth Factor Stimulates Osteosarcoma Cell Migration and Induces Osteosarcoma Metastasis by Upregulating VCAM-1 Expression. Biochem Pharmacol (2018 ) 155:71–81

    Not in our library10.1016/j.bcp.2018.06.015

  174. 174.

    Zhao SJ Jiang YQ Xu NW Li Q Zhang Q Wang SY. SPARCL1 Suppresses Osteosarcoma Metastasis and Recruits Macrophages by Activation of Canonical WNT/beta-Catenin Signaling Through Stabilization of the WNT-Receptor Complex. Oncogene (2018 ) 37(8):1049–61

    Not in our library10.1038/onc.2017.403

  175. 175.

    McManus M Kleinerman E Yang Y Livingston JA Mortus J Rivera R. Hes4: A Potential Prognostic Biomarker for Newly Diagnosed Patients With High-Grade Osteosarcoma. Pediatr Blood Cancer (2017 ) 64(5):10

    Not in our library10.1002/pbc.26318

  176. 176.

    Dai H Lv YF Yan GN Meng G Zhang X Guo QN. RanBP9/TSSC3 Complex Cooperates to Suppress Anoikis Resistance and Metastasis via Inhibiting Src-Mediated Akt Signaling in Osteosarcoma. Cell Death Dis (2016 ) 7(12):e2572

    Not in our library10.1038/cddis.2016.436

  177. 177.

    Zhang P Yang Y Zweidler-McKay PA Hughes DP. Critical Role of Notch Signaling in Osteosarcoma Invasion and Metastasis. Clin Cancer Res (2008 ) 14(10):2962–9

    Not in our library10.1158/1078-0432.ccr-07-1992

  178. 178.

    Brun J Dieudonne FX Marty C Muller J Schule R Patino-Garcia A. FHL2 Silencing Reduces Wnt Signaling and Osteosarcoma Tumorigenesis In Vitro and In Vivo. PloS One (2013 ) 8(1):e55034

    Not in our library10.1371/journal.pone.0055034

  179. 179.

    Hughes DP. How the NOTCH Pathway Contributes to the Ability of Osteosarcoma Cells to Metastasize. Cancer Treat Res (2009 ) 152:479–96

    Not in our library10.1007/978-1-4419-0284-9_28

  180. 180.

    Cheng Q Yin G. Cullin-1 Regulates MG63 Cell Proliferation and Metastasis and Is a Novel Prognostic Marker of Osteosarcoma. Int J Biol Markers (2017 ) 32(2):e202–9

    Not in our library10.5301/jbm.5000247

  181. 181.

    Zhang Y Zvi YS Batko B Zaphiros N O'Donnell EF Wang J. Down-Regulation of Skp2 Expression Inhibits Invasion and Lung Metastasis in Osteosarcoma. Sci Rep (2018 ) 8(1):14294

    Not in our library10.1038/s41598-018-32428-9

  182. 182.

    Morrow JJ Mendoza A Koyen A Lizardo MM Ren L Waybright TJ. mTOR Inhibition Mitigates Enhanced mRNA Translation Associated With the Metastatic Phenotype of Osteosarcoma Cells In Vivo. Clin Cancer Res (2016 ) 22(24):6129–41

    Not in our library10.1158/1078-0432.ccr-16-0326

  183. 183.

    Zhang N Xie T Xian M Wang YJ Li HY Ying MD. SIRT1 Promotes Metastasis of Human Osteosarcoma Cells. Oncotarget (2016 ) 7(48):79654–69

    Not in our library10.18632/oncotarget.12916

  184. 184.
    Novel oncogene COPS3 interacts with Beclin1 and Raf-1 to regulate metastasis of osteosarcoma through autophagy · 2018
    Not checked
  185. 185.

    Lv YF Dai H Yan GN Meng G Zhang X Guo QN. Downregulation of Tumor Suppressing STF cDNA 3 Promotes Epithelial-Mesenchymal Transition and Tumor Metastasis of Osteosarcoma by the Wnt/GSK-3beta/Beta-Catenin/Snail Signaling Pathway. Cancer Lett (2016 ) 373(2):164–73

    Not in our library10.1016/j.canlet.2016.01.046

  186. 186.

    Techavichit P Gao Y Kurenbekova L Shuck R Donehower LA Yustein JT. Secreted Frizzled-Related Protein 2 (Sfrp2) Promotes Osteosarcoma Invasion and Metastatic Potential. BMC Cancer (2016 ) 16(1):869

    Not in our library10.1186/s12885-016-2909-6

  187. 187.

    Zhao GS Gao ZR Zhang Q Tang XF Lv YF Zhang ZS. TSSC3 Promotes Autophagy via Inactivating the Src-Mediated PI3K/Akt/mTOR Pathway to Suppress Tumorigenesis and Metastasis in Osteosarcoma, and Predicts a Favorable Prognosis. J Exp Clin Cancer Res (2018 ) 37(1):188

    Not in our library10.1186/s13046-018-0856-6

  188. 188.

    Ma J Gao W Gao J. sCLU as Prognostic Biomarker and Therapeutic Target in Osteosarcoma. Bioengineered (2019 ) 10(1):229–39

    Not in our library10.1080/21655979.2019.1621136

  189. 189.

    Jin PY Lu HJ Tang Y Fan SH Zhang ZF Wang Y. The Effect of DNA-PKcs Gene Silencing on Proliferation, Migration, Invasion and Apoptosis, and In Vivo Tumorigenicity of Human Osteosarcoma MG-63 Cells. BioMed Pharmacother (2017 ) 96:1324–34

    Not in our library10.1016/j.biopha.2017.11.079

  190. 190.

    Hou CH Lin FL Tong KB Hou SM Liu JF. Transforming Growth Factor Alpha Promotes Osteosarcoma Metastasis by ICAM-1 and PI3K/Akt Signaling Pathway. Biochem Pharmacol (2014 ) 89(4):453–63

    Not in our library10.1016/j.bcp.2014.03.010

  191. 191.

    Tieken C Verboom MC Ruf W Gelderblom H Bovee JV Reitsma PH. Tissue Factor Associates With Survival and Regulates Tumour Progression in Osteosarcoma. Thromb Haemost (2016 ) 115(5):1025–33

    Not in our library10.1160/th15-07-0541

  192. 192.

    Chang H Dong T Ma X Zhang T Chen Z Yang Z. Spondin 1 Promotes Metastatic Progression Through Fak and Src Dependent Pathway in Human Osteosarcoma. Biochem Biophys Res Commun (2015 ) 464(1):45–50

    Not in our library10.1016/j.bbrc.2015.05.092

  193. 193.

    Yu L Liu S Guo W Zhang B Liang Y Feng Q. Upregulation of Mad2 Facilitates In Vivo and In Vitro Osteosarcoma Progression. Oncol Rep (2012 ) 28(6):2170–6

    Not in our library10.3892/or.2012.2032

  194. 194.

    El-Naggar AM Veinotte CJ Cheng H Grunewald TG Negri GL Somasekharan SP. Translational Activation of HIF1alpha by YB-1 Promotes Sarcoma Metastasis. Cancer Cell (2015 ) 27(5):682–97

    Not in our library10.1016/j.ccell.2015.04.003

  195. 195.

    Rubin EM Guo Y Tu K Xie J Zi X Hoang BH. Wnt Inhibitory Factor 1 Decreases Tumorigenesis and Metastasis in Osteosarcoma. Mol Cancer Ther (2010 ) 9(3):731–41

    Not in our library10.1158/1535-7163.mct-09-0147

  196. 196.

    Hu X Liu Y Qin C Pan Z Luo J Yu A. Up-Regulated Isocitrate Dehydrogenase 1 Suppresses Proliferation, Migration and Invasion in Osteosarcoma: In Vitro and In Vivo. Cancer Lett (2014 ) 346(1):114–21

    Not in our library10.1016/j.canlet.2013.12.020

  197. 197.

    Cantiani L Manara MC Zucchini C De Sanctis P Zuntini M Valvassori L. Caveolin-1 Reduces Osteosarcoma Metastases by Inhibiting C-Src Activity and Met Signaling. Cancer Res (2007 ) 67(16):7675–85

    Not in our library10.1158/0008-5472.can-06-4697

  198. 198.

    Severe N Dieudonne FX Marty C Modrowski D Patino-Garcia A Lecanda F. Targeting the E3 Ubiquitin Casitas B-Lineage Lymphoma Decreases Osteosarcoma Cell Growth and Survival and Reduces Tumorigenesis. J Bone Miner Res (2012 ) 27(10):2108–17

    Not in our library10.1002/jbmr.1667

  199. 199.

    Zhang W Zhao JM Lin J Hu CZ Zhang WB Yang WL. Adaptive Fibrogenic Reprogramming of Osteosarcoma Stem Cells Promotes Metastatic Growth. Cell Rep (2018 ) 24(5):1266–1277 e5

    Not in our library10.1016/j.celrep.2018.06.103

  200. 200.

    Koshkina NV Khanna C Mendoza A Guan H DeLauter L Kleinerman ES. Fas-Negative Osteosarcoma Tumor Cells Are Selected During Metastasis to the Lungs: The Role of the Fas Pathway in the Metastatic Process of Osteosarcoma. Mol Cancer Res (2007 ) 5(10):991–9

    Not in our library10.1158/1541-7786.mcr-07-0007

  201. 201.

    Gordon N Kleinerman ES. The Role of Fas/FasL in the Metastatic Potential of Osteosarcoma and Targeting This Pathway for the Treatment of Osteosarcoma Lung Metastases. Cancer Treat Res (2009 ) 152:497–508

    Not in our library10.1007/978-1-4419-0284-9_29

  202. 202.

    Huang G Nishimoto K Yang Y Kleinerman ES. Participation of the Fas/FasL Signaling Pathway and the Lung Microenvironment in the Development of Osteosarcoma Lung Metastases. Adv Exp Med Biol (2014 ) 804:203–17

    Not in our library10.1007/978-3-319-04843-7_11

  203. 203.

    Gordon N Koshkina NV Jia SF Khanna C Mendoza A Worth LL. Corruption of the Fas Pathway Delays the Pulmonary Clearance of Murine Osteosarcoma Cells, Enhances Their Metastatic Potential, and Reduces the Effect of Aerosol Gemcitabine. Clin Cancer Res (2007 ) 13(15 Pt 1):4503–10

    Not in our library10.1158/1078-0432.ccr-07-0313

  204. 204.

    Koshkina N Yang Y Kleinerman ES. The Fas/FasL Signaling Pathway: Its Role in the Metastatic Process and as a Target for Treating Osteosarcoma Lung Metastases. Adv Exp Med Biol (2020 ) 1258:177–87

    Not in our library10.1007/978-3-030-43085-6_12

  205. 205.

    Rodriguez CO Jr. Crabbs TA Wilson DW Cannan VA Skorupski KA Gordon N. Aerosol Gemcitabine: Preclinical Safety and In Vivo Antitumor Activity in Osteosarcoma-Bearing Dogs. J Aerosol Med Pulm Drug Deliv (2010 ) 23(4):197–206

    Not in our library10.1089/jamp.2009.0773

  206. 206.

    Ruivo CF Adem B Silva M Melo SA. The Biology of Cancer Exosomes: Insights and New Perspectives. Cancer Res (2017 ) 77(23):6480–8

    Not in our library10.1158/0008-5472.can-17-0994

  207. 207.

    Bao Q Gong L Wang J Wen J Shen Y Zhang W. Extracellular Vesicle RNA Sequencing Reveals Dramatic Transcriptomic Alterations Between Metastatic and Primary Osteosarcoma in a Liquid Biopsy Approach. Ann Surg Oncol (2018 ) 25(9):2642–51

    Not in our library10.1245/s10434-018-6642-z

  208. 208.

    Jerez S Araya H Thaler R Charlesworth MC Lopez-Solis R Kalergis AM. Proteomic Analysis of Exosomes and Exosome-Free Conditioned Media From Human Osteosarcoma Cell Lines Reveals Secretion of Proteins Related to Tumor Progression. J Cell Biochem (2017 ) 118(2):351–60

    Not in our library10.1002/jcb.25642

  209. 209.

    Kok VC Yu CC. Cancer-Derived Exosomes: Their Role in Cancer Biology and Biomarker Development. Int J Nanomed (2020 ) 15:8019–36

    Not in our library10.2147/ijn.s272378

  210. 210.

    Zhao W Qin P Zhang D Cui X Gao J Yu Z. Long non-Coding RNA PVT1 Encapsulated in Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Promotes Osteosarcoma Growth and Metastasis by Stabilizing ERG and Sponging miR-183-5p. Aging (Albany NY) (2019 ) 11(21):9581–96

    Not in our library10.18632/aging.102406

  211. 211.

    Wang Y Chu Y Li K Zhang G Guo Z Wu X. Exosomes Secreted by Adipose-Derived Mesenchymal Stem Cells Foster Metastasis and Osteosarcoma Proliferation by Increasing COLGALT2 Expression. Front Cell Dev Biol (2020 ) 8:353

    Not in our library10.3389/fcell.2020.00353

  212. 212.

    Liu W Long Q Zhang W Zeng D Hu B Liu S. miRNA-221-3p Derived From M2-Polarized Tumor-Associated Macrophage Exosomes Aggravates the Growth and Metastasis of Osteosarcoma Through SOCS3/JAK2/STAT3 Axis. Aging (Albany NY) (2021 ) 13(15):19760–75

    Not in our library10.18632/aging.203388

  213. 213.

    Zhang H Yu Y Wang J Han Y Ren T Huang Y. Macrophages-Derived Exosomal lncRNA LIFR-AS1 Promotes Osteosarcoma Cell Progression via miR-29a/NFIA Axis. Cancer Cell Int (2021 ) 21(1):192

    Not in our library10.1186/s12935-021-01893-0

  214. 214.

    Balkwill F. Cancer and the Chemokine Network. Nat Rev Cancer (2004 ) 4(7):540–50

    Not in our library10.1038/nrc1388

  215. 215.

    Li B Wang Z Wu H Xue M Lin P Wang S. Epigenetic Regulation of CXCL12 Plays a Critical Role in Mediating Tumor Progression and the Immune Response In Osteosarcoma. Cancer Res (2018 ) 78(14):3938–53

    Not in our library10.1158/0008-5472.can-17-3801

  216. 216.

    Benslimane-Ahmim Z Pereira J Lokajczyk A Dizier B Galy-Fauroux I Fischer AM. Osteoprotegerin Regulates Cancer Cell Migration Through SDF-1/CXCR4 Axis and Promotes Tumour Development by Increasing Neovascularization. Cancer Lett (2017 ) 395:11–9

    Not in our library10.1016/j.canlet.2017.02.032

  217. 217.

    Liao YX Fu ZZ Zhou CH Shan LC Wang ZY Yin F. AMD3100 Reduces CXCR4-Mediated Survival and Metastasis of Osteosarcoma by Inhibiting JNK and Akt, But Not P38 or Erk1/2, Pathways in In Vitro and Mouse Experiments. Oncol Rep (2015 ) 34(1):33–42

    Not in our library10.3892/or.2015.3992

  218. 218.

    Georges S Chesneau J Hervouet S Taurelle J Gouin F Redini F. A Disintegrin And Metalloproteinase 12 Produced by Tumour Cells Accelerates Osteosarcoma Tumour Progression and Associated Osteolysis. Eur J Cancer (2013 ) 49(9):2253–63

    Not in our library10.1016/j.ejca.2013.02.020

  219. 219.

    Ory B Baud'huin M Verrecchia F Royer BB Quillard T Amiaud J. Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts With Zoledronic Acid to Delay Osteosarcoma Progression. Clin Cancer Res (2016 ) 22(10):2520–33

    Not in our library10.1158/1078-0432.ccr-15-1925

  220. 220.

    Akiyama T Dass CR Choong PF. Novel Therapeutic Strategy for Osteosarcoma Targeting Osteoclast Differentiation, Bone-Resorbing Activity, and Apoptosis Pathway. Mol Cancer Ther (2008 ) 7(11):3461–9

    Not in our library10.1158/1535-7163.mct-08-0530

  221. 221.

    Costa-Rodrigues J Fernandes A Fernandes MH. Reciprocal Osteoblastic and Osteoclastic Modulation in Co-Cultured MG63 Osteosarcoma Cells and Human Osteoclast Precursors. J Cell Biochem (2011 ) 112(12):3704–13

    Not in our library10.1002/jcb.23295

  222. 222.

    Saharinen P Eklund L Pulkki K Bono P Alitalo K. VEGF and Angiopoietin Signaling in Tumor Angiogenesis and Metastasis. Trends Mol Med (2011 ) 17(7):347–62

    Not in our library10.1016/j.molmed.2011.01.015

  223. 223.

    Zetter BR. Angiogenesis and Tumor Metastasis. Annu Rev Med (1998 ) 49:407–24

    Not in our library10.1146/annurev.med.49.1.407

  224. 224.

    Wang X Hu Z Wang Z Cui Y Cui X. Angiopoietin-Like Protein 2 is an Important Facilitator of Tumor Proliferation, Metastasis, Angiogenesis and Glycolysis in Osteosarcoma. Am J Transl Res (2019 ) 11(10):6341–55.

    Not in our library

  225. 225.

    Wang G Sun M Jiang Y Zhang T Sun W Wang H. Anlotinib, a Novel Small Molecular Tyrosine Kinase Inhibitor, Suppresses Growth and Metastasis via Dual Blockade of VEGFR2 and MET in Osteosarcoma. Int J Cancer (2019 ) 145(4):979–93

    Not in our library10.1002/ijc.32180

  226. 226.

    Broadhead ML Choong PF Dass CR. Efficacy of Continuously Administered PEDF-Derived Synthetic Peptides Against Osteosarcoma Growth and Metastasis. J BioMed Biotechnol (2012 ) 2012:230298

    Not in our library10.1155/2012/230298

  227. 227.

    Xie L Ji T Guo W. Anti-Angiogenesis Target Therapy for Advanced Osteosarcoma (Review). Oncol Rep (2017 ) 38(2):625–36

    Not in our library10.3892/or.2017.5735

  228. 228.

    Liu Y Huang N Liao S Rothzerg E Yao F Li Y. Current Research Progress in Targeted Anti-Angiogenesis Therapy for Osteosarcoma. Cell Prolif (2021 ) 54(9):e13102

    Not in our library10.1111/cpr.13102

  229. 229.

    Lehuede C Dupuy F Rabinovitch R Jones RG Siegel PM. Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis. Cancer Res (2016 ) 76(18):5201–8

    Not in our library10.1158/0008-5472.can-16-0266

  230. 230.

    Giang AH Raymond T Brookes P de Mesy Bentley K Schwarz E O'Keefe R. Mitochondrial Dysfunction and Permeability Transition in Osteosarcoma Cells Showing the Warburg Effect. J Biol Chem (2013 ) 288(46):33303–11

    Not in our library10.1074/jbc.m113.507129

  231. 231.

    Liberti MV Locasale JW. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem Sci (2016 ) 41(3):211–8

    Not in our library10.1016/j.tibs.2015.12.001

  232. 232.

    Hua Y Qiu Y Zhao A Wang X Chen T Zhang Z. Dynamic Metabolic Transformation in Tumor Invasion and Metastasis in Mice With LM-8 Osteosarcoma Cell Transplantation. J Proteome Res (2011 ) 10(8):3513–21

    Not in our library10.1021/pr200147g

  233. 233.

    Roy J Dibaeinia P Fan TM Sinha S Das A. Global Analysis of Osteosarcoma Lipidomes Reveal Altered Lipid Profiles in Metastatic Versus Nonmetastatic Cells. J Lipid Res (2019 ) 60(2):375–87

    Not in our library10.1194/jlr.m088559

  234. 234.

    Kort WJ Hulsmann WC Stehman TE. Modulation of Metastatic Ability by Inhibition of Cholesterol Synthesis. Clin Exp Metastasis (1989 ) 7(5):517–23

    Not in our library10.1007/bf01753812

  235. 235.
    Emerging roles of lipid metabolism in cancer metastasis · 2017
    No notice
  236. 236.

    Ren L Hong ES Mendoza A Issaq S Tran Hoang C Lizardo M. Metabolomics Uncovers a Link Between Inositol Metabolism and Osteosarcoma Metastasis. Oncotarget (2017 ) 8(24):38541–53

    Not in our library10.18632/oncotarget.15872

  237. 237.

    Zhao H Wu Y Chen Y Liu H. Clinical Significance of Hypoxia-Inducible Factor 1 and VEGF-A in Osteosarcoma. Int J Clin Oncol (2015 ) 20(6):1233–43

    Not in our library10.1007/s10147-015-0848-x

  238. 238.

    Guan G Zhang Y Lu Y Liu L Shi D Wen Y. The HIF-1alpha/CXCR4 Pathway Supports Hypoxia-Induced Metastasis of Human Osteosarcoma Cells. Cancer Lett (2015 ) 357(1):254–64

    Not in our library10.1016/j.canlet.2014.11.034

  239. 239.

    Kunz M Moeller S Koczan D Lorenz P Wenger RH Glocker MO. Mechanisms of Hypoxic Gene Regulation of Angiogenesis Factor Cyr61 in Melanoma Cells. J Biol Chem (2003 ) 278(46):45651–60

    Not in our library10.1074/jbc.m301373200

  240. 240.

    Liapis V Labrinidis A Zinonos I Hay S Ponomarev V Panagopoulos V. Hypoxia-Activated Pro-Drug TH-302 Exhibits Potent Tumor Suppressive Activity and Cooperates With Chemotherapy Against Osteosarcoma. Cancer Lett (2015 ) 357(1):160–9

    Not in our library10.1016/j.canlet.2014.11.020

  241. 241.

    Abu-Remaileh M Aqeilan RI. Tumor Suppressor WWOX Regulates Glucose Metabolism via HIF1alpha Modulation. Cell Death Differ (2014 ) 21(11):1805–14

    Not in our library10.1038/cdd.2014.95

  242. 242.

    Gaudio E Palamarchuk A Palumbo T Trapasso F Pekarsky Y Croce CM. Physical Association With WWOX Suppresses C-Jun Transcriptional Activity. Cancer Res (2006 ) 66(24):11585–9

    Not in our library10.1158/0008-5472.can-06-3376

  243. 243.

    Del Mare S Aqeilan RI. Tumor Suppressor WWOX Inhibits Osteosarcoma Metastasis by Modulating RUNX2 Function. Sci Rep 5:12959

    Not in our library10.1038/srep12959

  244. 244.

    Ozanne BW Spence HJ McGarry LC Hennigan RF. Transcription Factors Control Invasion: AP-1 the First Among Equals. Oncogene (2007 ) 26(1):1–10

    Not in our library10.1038/sj.onc.1209759

  245. 245.

    Leaner VD Chick JF Donninger H Linniola I Mendoza A Khanna C. Inhibition of AP-1 Transcriptional Activity Blocks the Migration, Invasion, and Experimental Metastasis of Murine Osteosarcoma. Am J Pathol (2009 ) 174(1):265–75

    Not in our library10.2353/ajpath.2009.071006

  246. 246.

    Kunita A Kashima TG Ohazama A Grigoriadis AE Fukayama M. Podoplanin Is Regulated by AP-1 and Promotes Platelet Aggregation and Cell Migration in Osteosarcoma. Am J Pathol (2011 ) 179(2):1041–9

    Not in our library10.1016/j.ajpath.2011.04.027

  247. 247.

    Weekes D Kashima TG Zandueta C Perurena N Thomas DP Sunters A. Regulation of Osteosarcoma Cell Lung Metastasis by the C-Fos/AP-1 Target FGFR1. Oncogene (2016 ) 35(22):2852–61

    Not in our library10.1038/onc.2015.344

  248. 248.

    Chano T Avnet S Kusuzaki K Bonuccelli G Sonveaux P Rotili D. Tumour-Specific Metabolic Adaptation to Acidosis is Coupled to Epigenetic Stability in Osteosarcoma Cells. Am J Cancer Res (2016 ) 6(4):859–75.

    Not in our library

  249. 249.

    Avnet S Di Pompo G Chano T Errani C Ibrahim-Hashim A Gillies RJ. Cancer-Associated Mesenchymal Stroma Fosters the Stemness of Osteosarcoma Cells in Response to Intratumoral Acidosis via NF-kappaB Activation. Int J Cancer (2017 ) 140(6):1331–45

    Not in our library10.1002/ijc.30540

  250. 250.

    Avnet S Chano T Massa A Bonuccelli G Lemma S Falzetti L. Acid Microenvironment Promotes Cell Survival of Human Bone Sarcoma Through the Activation of cIAP Proteins and NF-kappaB Pathway. Am J Cancer Res (2019 ) 9(6):1127–44.

    Not in our library

  251. 251.

    Orrenius S Gogvadze V Zhivotovsky B. Mitochondrial Oxidative Stress: Implications for Cell Death. Annu Rev Pharmacol Toxicol (2007 ) 47:143–83

    Not in our library10.1146/annurev.pharmtox.47.120505.105122

  252. 252.

    Ott M Gogvadze V Orrenius S Zhivotovsky B. Mitochondria, Oxidative Stress and Cell Death. Apoptosis (2007 ) 12(5):913–22

    Not in our library10.1007/s10495-007-0756-2

  253. 253.

    Qiu H Orr FW Jensen D Wang HH McIntosh AR Hasinoff BB. Arrest of B16 Melanoma Cells in the Mouse Pulmonary Microcirculation Induces Endothelial Nitric Oxide Synthase-Dependent Nitric Oxide Release That Is Cytotoxic to the Tumor Cells. Am J Pathol (2003 ) 162(2):403–12

    Not in our library10.1016/s0002-9440(10)63835-7

  254. 254.

    Poderoso JJ Helfenberger K Poderoso C. The Effect of Nitric Oxide on Mitochondrial Respiration. Nitric Oxide (2019 ) 88:61–72

    Not in our library10.1016/j.niox.2019.04.005

  255. 255.

    Ridnour LA Thomas DD Mancardi D Espey MG Miranda KM Paolocci N. The Chemistry of Nitrosative Stress Induced by Nitric Oxide and Reactive Nitrogen Oxide Species. Putting Perspective on Stressful Biological Situations. Biol Chem (2004 ) 385(1):1–10

    Not in our library10.1515/bc.2004.001

  256. 256.

    Winterbourn CC. Revisiting the Reactions of Superoxide With Glutathione and Other Thiols. Arch Biochem Biophys (2016 ) 595:68–71

    Not in our library10.1016/j.abb.2015.11.028

  257. 257.

    Buddingh EP Kuijjer ML Duim RA Burger H Agelopoulos K Myklebost O. Tumor-Infiltrating Macrophages are Associated With Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment With Macrophage Activating Agents. Clin Cancer Res (2011 ) 17(8):2110–9

    Not in our library10.1158/1078-0432.ccr-10-2047

  258. 258.
    Dysregulation of macrophage polarization is associated with the metastatic process in osteosarcoma · 2016
    No notice
  259. 259.

    Han Q Shi H Liu F. CD163(+) M2-Type Tumor-Associated Macrophage Support the Suppression of Tumor-Infiltrating T Cells in Osteosarcoma. Int Immunopharmacol (2016 ) 34:101–6

    Not in our library10.1016/j.intimp.2016.01.023

  260. 260.

    Hingorani P Maas ML Gustafson MP Dickman P Adams RH Watanabe M. Increased CTLA-4(+) T Cells and an Increased Ratio of Monocytes With Loss of Class II (CD14(+) HLA-DR(lo/neg)) Found in Aggressive Pediatric Sarcoma Patients. J Immunother Cancer 3:35

    Not in our library10.1186/s40425-015-0082-0

  261. 261.

    Gomez-Brouchet A Illac C Gilhodes J Bouvier C Aubert S Guinebretiere JM. CD163-Positive Tumor-Associated Macrophages and CD8-Positive Cytotoxic Lymphocytes are Powerful Diagnostic Markers for the Therapeutic Stratification of Osteosarcoma Patients: An Immunohistochemical Analysis of the Biopsies Fromthe French OS2006 Phase 3 Trial. Oncoimmunology (2017 ) 6(9):e1331193

    Not in our library10.1080/2162402x.2017.1331193

  262. 262.

    Pahl JH Kwappenberg KM Varypataki EM Santos SJ Kuijjer ML Mohamed S. Macrophages Inhibit Human Osteosarcoma Cell Growth After Activation With the Bacterial Cell Wall Derivative Liposomal Muramyl Tripeptide in Combination With Interferon-Gamma. J Exp Clin Cancer Res (2014 ) 33:27

    Not in our library10.1186/1756-9966-33-27

  263. 263.

    Shao XJ Xiang SF Chen YQ Zhang N Cao J Zhu H. Inhibition of M2-Like Macrophages by All-Trans Retinoic Acid Prevents Cancer Initiation and Stemness in Osteosarcoma Cells. Acta Pharmacol Sin (2019 ) 40(10):1343–50

    Not in our library10.1038/s41401-019-0262-4

  264. 264.

    Zhou Q Xian M Xiang S Xiang D Shao X Wang J. All-Trans Retinoic Acid Prevents Osteosarcoma Metastasis by Inhibiting M2 Polarization of Tumor-Associated Macrophages. Cancer Immunol Res (2017 ) 5(7):547–59

    Not in our library10.1158/2326-6066.cir-16-0259

  265. 265.
    Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma · 2016
    No notice
  266. 266.

    Fritzsching B Fellenberg J Moskovszky L Sapi Z Krenacs T Machado I. CD8(+)/FOXP3(+)-Ratio in Osteosarcoma Microenvironment Separates Survivors From Non-Survivors: A Multicenter Validated Retrospective Study. Oncoimmunology (2015 ) 4(3):e990800

    Not in our library10.4161/2162402x.2014.990800

  267. 267.

    Sundara YT Kostine M Cleven AH Bovee JV Schilham MW Cleton-Jansen AM. Increased PD-L1 and T-Cell Infiltration in the Presence of HLA Class I Expression in Metastatic High-Grade Osteosarcoma: A Rationale for T-Cell-Based Immunotherapy. Cancer Immunol Immunother (2017 ) 66(1):119–28

    Not in our library10.1007/s00262-016-1925-3

  268. 268.

    Chen C Xie L Ren T Huang Y Xu J Guo W. Immunotherapy for Osteosarcoma: Fundamental Mechanism, Rationale, and Recent Breakthroughs. Cancer Lett (2021 ) 500:1–10

    Not in our library10.1016/j.canlet.2020.12.024

  269. 269.

    Yang JX Rastetter RH Wilhelm D. Non-Coding RNAs: An Introduction. Adv Exp Med Biol (2016 ) 886:13–32

    Not in our library10.1007/978-94-017-7417-8_2

  270. 270.

    Gao Y Luo LH Li S Yang C. miR-17 Inhibitor Suppressed Osteosarcoma Tumor Growth and Metastasis via Increasing PTEN Expression. Biochem Biophys Res Commun (2014 ) 444(2):230–4

    Not in our library10.1016/j.bbrc.2014.01.061

  271. 271.

    Ding J Sha L Shen P Huang M Cai Q Li J. MicroRNA-18a Inhibits Cell Growth and Induces Apoptosis in Osteosarcoma by Targeting MED27. Int J Oncol (2018 ) 53(1):329–38

    Not in our library10.3892/ijo.2018.4374

  272. 272.

    Sun Z Liu Q Hong H Zhang H Zhang T. miR-19 Promotes Osteosarcoma Progression by Targeting SOCS6. Biochem Biophys Res Commun (2018 ) 495(1):1363–9

    Not in our library10.1016/j.bbrc.2017.10.002

  273. 273.
    miR-22 inhibits tumor growth and metastasis by targeting ATP citrate lyase: evidence in osteosarcoma, prostate cancer, cervical cancer and lung cancer · 2016
    No notice
  274. 274.

    He Y Meng C Shao Z Wang H Yang S. MiR-23a Functions as a Tumor Suppressor in Osteosarcoma. Cell Physiol Biochem (2014 ) 34(5):1485–96

    Not in our library10.1159/000366353

  275. 275.
    MicroRNA-25 suppresses proliferation, migration, and invasion of osteosarcoma by targeting SOX4 · 2017
    Not checked
  276. 276.

    Lu J Song G Tang Q Yin J Zou C Zhao Z. MiR-26a Inhibits Stem Cell-Like Phenotype and Tumor Growth of Osteosarcoma by Targeting Jagged1. Oncogene (2017 ) 36(2):231–41

    Not in our library10.1038/onc.2016.194

  277. 277.

    Zhang R Yan S Wang J Deng F Guo Y Li Y. MiR-30a Regulates the Proliferation, Migration, and Invasion of Human Osteosarcoma by Targeting Runx2. Tumour Biol (2016 ) 37(3):3479–88

    Not in our library10.1007/s13277-015-4086-7

  278. 278.

    Tao J Cong H Wang H Zhang D Liu C Chu H. MiR-30a-5p Inhibits Osteosarcoma Cell Proliferation and Migration by Targeting FOXD1. Biochem Biophys Res Commun (2018 ) 503(2):1092–7

    Not in our library10.1016/j.bbrc.2018.06.121

  279. 279.

    Zhao Y Tu MJ Yu YF Wang WP Chen QX Qiu JX. Combination Therapy With Bioengineered miR-34a Prodrug and Doxorubicin Synergistically Suppresses Osteosarcoma Growth. Biochem Pharmacol (2015 ) 98(4):602–13

    Not in our library10.1016/j.bcp.2015.10.015

  280. 280.

    Liu Q Song Y Duan X Chang Y Guo J. MiR-92a Inhibits the Progress of Osteosarcoma Cells and Increases the Cisplatin Sensitivity by Targeting Notch1. BioMed Res Int (2018 ) 2018:9870693

    Not in our library10.1155/2018/9870693

  281. 281.

    Yu B Jiang K Zhang J. MicroRNA-124 Suppresses Growth and Aggressiveness of Osteosarcoma and Inhibits TGF-Beta-Mediated AKT/GSK-3beta/SNAIL-1 Signaling. Mol Med Rep (2018 ) 17(5):6736–44

    Not in our library10.3892/mmr.2018.8637

  282. 282.

    Liu LH Li H Li JP Zhong H Zhang HC Chen J. miR-125b Suppresses the Proliferation and Migration of Osteosarcoma Cells Through Down-Regulation of STAT3. Biochem Biophys Res Commun (2011 ) 416(1-2):31–8

    Not in our library10.1016/j.bbrc.2011.10.117

  283. 283.

    Bao Y Peng L Ma J Liu K Li W. Decreased miR-134 Expression and its Tumor-Suppressive Function in Human Osteosarcoma. Genet Mol Res (2015 ) 14(4):16771–81

    Not in our library10.4238/2015.december.14.4

  284. 284.

    Li ZM Zhang HY Wang YX Wang WB. MicroRNA-137 Is Downregulated in Human Osteosarcoma and Regulates Cell Proliferation and Migration Through Targeting FXYD6. J Drug Target (2016 ) 24(2):102–10

    Not in our library10.3109/1061186x.2015.1057149

  285. 285.

    Shi YK Guo YH. MiR-139-5p Suppresses Osteosarcoma Cell Growth and Invasion Through Regulating DNMT1. Biochem Biophys Res Commun (2018 ) 503(2):459–66

    Not in our library10.1016/j.bbrc.2018.04.124

  286. 286.

    Gu R Sun YF Wu MF Liu JB Jiang JL Wang SH. Biological Roles of microRNA-140 in Tumor Growth, Migration, and Metastasis of Osteosarcoma In Vivo and In Vitro. Tumour Biol (2016 ) 37(1):353–60

    Not in our library10.1007/s13277-015-3801-8

  287. 287.

    Xiao Q Huang L Zhang Z Chen X Luo J Zhang Z. Overexpression of miR-140 Inhibits Proliferation of Osteosarcoma Cells via Suppression of Histone Deacetylase 4. Oncol Res (2017 ) 25(2):267–75

    Not in our library10.3727/096504016x14732510786564

  288. 288.

    Wang W Zhou X Wei M. MicroRNA-144 Suppresses Osteosarcoma Growth and Metastasis by Targeting ROCK1 and ROCK2. Oncotarget (2015 ) 6(12):10297–308

    Not in our library10.18632/oncotarget.3305

  289. 289.

    Li Y Liu J Liu ZZ Wei WB. MicroRNA-145 Inhibits Tumour Growth and Metastasis in Osteosarcoma by Targeting Cyclin-Dependent Kinase, CDK6. Eur Rev Med Pharmacol Sci (2016 ) 20(24):5117–25.

    Not in our library

  290. 290.

    Yang H Peng Z Da Z Li X Cheng Y Tan B. MicroRNA-148a Acts as a Tumor Suppressor in Osteosarcoma via Targeting Rho-Associated Coiled-Coil Kinase. Oncol Res (2017 ) 25(8):1231–43

    Not in our library10.3727/096504017x14850134190255

  291. 291.

    Zhou H Zhang M Yuan H Zheng W Meng C Zhao D. MicroRNA-154 Functions as a Tumor Suppressor in Osteosarcoma by Targeting Wnt5a. Oncol Rep (2016 ) 35(3):1851–8

    Not in our library10.3892/or.2015.4495

  292. 292.

    Jiang C Fang X Zhang H Wang X Li M Jiang W. Triptolide Inhibits the Growth of Osteosarcoma by Regulating microRNA-181a via Targeting PTEN Gene In Vivo and Vitro. Tumour Biol (2017 ) 39(4):1010428317697556

    Not in our library10.1177/1010428317697556

  293. 293.

    Zhang Z Zhang W Mao J Xu Z Fan M. miR-186-5p Functions as a Tumor Suppressor in Human Osteosarcoma by Targeting Foxk1. Cell Physiol Biochem (2019 ) 52(3):553–64

    Not in our library10.33594/000000039

  294. 294.

    Pan L Meng L Liang F Cao L. Mir188 Suppresses Tumor Progression by Targeting SOX4 in Pediatric Osteosarcoma. Mol Med Rep (2018 ) 18(1):441–6

    Not in our library10.3892/mmr.2018.8997

  295. 295.

    Pu Y Zhao F Cai W Meng X Li Y Cai S. MiR-193a-3p and miR-193a-5p Suppress the Metastasis of Human Osteosarcoma Cells by Down-Regulating Rab27B and SRR, Respectively. Clin Exp Metastasis (2016 ) 33(4):359–72

    Not in our library10.1007/s10585-016-9783-0

  296. 296.

    Li M Shen Y Wang Q Zhou X. MiR-204-5p Promotes Apoptosis and Inhibits Migration of Osteosarcoma via Targeting EBF2. Biochimie (2019 ) 158:224–32

    Not in our library10.1016/j.biochi.2018.12.003

  297. 297.

    Jiang Z Jiang C Yu C Fang J. MicroRNA-208b Inhibits Human Osteosarcoma Progression by Targeting ROR2. Tumour Biol (2017 ) 39(6):1010428317705751

    Not in our library10.1177/1010428317705751

  298. 298.

    Liu C Tang X. Downregulation of microRNA-210 Inhibits Osteosarcoma Growth In Vitro and In Vivo. Mol Med Rep (2015 ) 12(3):3674–80

    Not in our library10.3892/mmr.2015.3880

  299. 299.

    Luo XJ Tang DG Gao TL Zhang YL Wang M Quan ZX. MicroRNA-212 Inhibits Osteosarcoma Cells Proliferation and Invasion by Down-Regulation of Sox4. Cell Physiol Biochem (2014 ) 34(6):2180–8

    Not in our library10.1159/000369661

  300. 300.

    Xu Z Wang T. miR-214 Promotes the Proliferation and Invasion of Osteosarcoma Cells Through Direct Suppression of LZTS1. Biochem Biophys Res Commun (2014 ) 449(2):190–5

    Not in our library10.1016/j.bbrc.2014.04.140

  301. 301.

    Sun B Yang M Li M Wang F. The microRNA-217 Functions as a Tumor Suppressor and is Frequently Downregulated in Human Osteosarcoma. BioMed Pharmacother (2015 ) 71:58–63

    Not in our library10.1016/j.biopha.2015.02.014

  302. 302.

    Jiang W Liu J Xu T Yu X. MiR-329 Suppresses Osteosarcoma Development by Downregulating Rab10. FEBS Lett (2016 ) 590(17):2973–81

    Not in our library10.1002/1873-3468.12337

  303. 303.

    He F Fang L Yin Q. miR-363 Acts as a Tumor Suppressor in Osteosarcoma Cells by Inhibiting PDZD2. Oncol Rep (2019 ) 41(5):2729–38

    Not in our library10.3892/or.2019.7078

  304. 304.

    Xu SY Xu PF Gao TT. MiR-372-3p Inhibits the Growth and Metastasis of Osteosarcoma Cells by Targeting FXYD6. Eur Rev Med Pharmacol Sci (2018 ) 22(1):62–9

    Not in our library10.26355/eurrev_201801_14101

  305. 305.

    Li Z Shen J Chan MT Wu WK. MicroRNA-379 Suppresses Osteosarcoma Progression by Targeting PDK1. J Cell Mol Med (2017 ) 21(2):315–23

    Not in our library10.1111/jcmm.12966

  306. 306.

    Zhao D Jia P Wang W Zhang G. VEGF-Mediated Suppression of Cell Proliferation and Invasion by miR-410 in Osteosarcoma. Mol Cell Biochem 400(1-2):87–95

    Not in our library10.1007/s11010-014-2265-2

  307. 307.

    Yang G Zhang C Wang N Chen J. miR-425-5p Decreases LncRNA MALAT1 and TUG1 Expressions and Suppresses Tumorigenesis in Osteosarcoma via Wnt/beta-Catenin Signaling Pathway. Int J Biochem Cell Biol (2019 ) 111:42–51

    Not in our library10.1016/j.biocel.2019.04.004

  308. 308.

    Yuan J Lang J Liu C Zhou K Chen L Liu Y. The Expression and Function of miRNA-451 in Osteosarcoma. Med Oncol (2015 ) 32(1):324

    Not in our library10.1007/s12032-014-0324-x

  309. 309.

    Yuan W Wang D Liu Y Tian D Wang Y Zhang R. Mir494 Inhibits Cell Proliferation and Metastasis via Targeting of CDK6 in Osteosarcoma. Mol Med Rep (2017 ) 16(6):8627–34

    Not in our library10.3892/mmr.2017.7709

  310. 310.

    Qi NN Tian S Li X Wang FL Liu B. Up-Regulation of microRNA-496 Suppresses Proliferation, Invasion, Migration and In Vivo Tumorigenicity of Human Osteosarcoma Cells by Targeting Eif4e. Biochimie (2019 ) 163:1–11

    Not in our library10.1016/j.biochi.2019.04.017

  311. 311.

    Pang PC Shi XY Huang WL Sun K. miR-497 as a Potential Serum Biomarker for the Diagnosis and Prognosis of Osteosarcoma. Eur Rev Med Pharmacol Sci (2016 ) 20(18):3765–9.

    Not in our library

  312. 312.

    Cai W Xu Y Yin J Zuo W Su Z. Mir5905p Suppresses Osteosarcoma Cell Proliferation and Invasion via Targeting KLF5. Mol Med Rep (2018 ) 18(2):2328–34

    Not in our library10.3892/mmr.2018.9173

  313. 313.

    Liu K Sun X Zhang Y Liu L Yuan Q. MiR-598: A Tumor Suppressor With Biomarker Significance in Osteosarcoma. Life Sci (2017 ) 188:141–8

    Not in our library10.1016/j.lfs.2017.09.003

  314. 314.

    Ma C Zhan C Yuan H Cui Y Zhang Z. MicroRNA-603 Functions as an Oncogene by Suppressing BRCC2 Protein Translation in Osteosarcoma. Oncol Rep (2016 ) 35(6):3257–64

    Not in our library10.3892/or.2016.4718

  315. 315.

    Wang H Xing D Ren D Feng W Chen Y Zhao Z. MicroRNA643 Regulates the Expression of ZEB1 and Inhibits Tumorigenesis in Osteosarcoma. Mol Med Rep (2017 ) 16(4):5157–64

    Not in our library10.3892/mmr.2017.7273

  316. 316.

    Zhang L Wang Y Zhang L Xia X Chao Y He R. ZBTB7A, a miR-663a Target Gene, Protects Osteosarcoma From Endoplasmic Reticulum Stress-Induced Apoptosis by Suppressing LncRNA GAS5 Expression. Cancer Lett (2019 ) 448:105–16

    Not in our library10.1016/j.canlet.2019.01.046

  317. 317.

    Liu Y Wang Y Yang H Zhao L Song R Tan H. MicroRNA873 Targets HOXA9 to Inhibit the Aggressive Phenotype of Osteosarcoma by Deactivating the Wnt/betacatenin Pathway. Int J Oncol (2019 ) 54(5):1809–20

    Not in our library10.3892/ijo.2019.4735

  318. 318.

    Ghosh T Varshney A Kumar P Kaur M Kumar V Shekhar R. MicroRNA-874-Mediated Inhibition of the Major G1/S Phase Cyclin, CCNE1, is Lost in Osteosarcomas. J Biol Chem (2017 ) 292(52):21264–81

    Not in our library10.1074/jbc.m117.808287

  319. 319.

    Zhong L Zheng C Fang H Xu M Chen B Li C. MicroRNA-1270 is Associated With Poor Prognosis and its Inhibition Yielded Anticancer Mechanisms in Human Osteosarcoma. IUBMB Life (2018 ) 70(7):625–32

    Not in our library10.1002/iub.1753

  320. 320.

    Yuan H Gao Y. MicroRNA-1908 is Upregulated in Human Osteosarcoma and Regulates Cell Proliferation and Migration by Repressing PTEN Expression. Oncol Rep (2015 ) 34(5):2706–14

    Not in our library10.3892/or.2015.4242

  321. 321.
    LncRNA AFAP1-AS1 promotes tumorigenesis and epithelial-mesenchymal transition of osteosarcoma through RhoC/ROCK1/p38MAPK/Twist1 signaling pathway · 2019
    Not checked
  322. 322.

    Li R Liu S Li Y Tang Q Xie Y Zhai R. Long Noncoding RNA AFAP1AS1 Enhances Cell Proliferation and Invasion in Osteosarcoma Through Regulating Mir46955p/TCF4betacatenin Signaling. Mol Med Rep (2018 ) 18(2):1616–22

    Not in our library10.3892/mmr.2018.9131

  323. 323.

    Lu L Dai Z Luo Q Lv G. The Long Noncoding RNA Cancer Susceptibility Candidate 2 Inhibits Tumor Progression in Osteosarcoma. Mol Med Rep (2018 ) 17(1):1947–53

    Not in our library10.3892/mmr.2017.8080

  324. 324.

    Zhao W Zhang D Qin P Zhang J Cui X Gao J. Long non-Coding RNA EPIC1 Inhibits Viability and Invasion of Osteosarcoma Cells by Promoting MEF2D Ubiquitylation. Int J Biol Macromol (2019 ) 128:566–73

    Not in our library10.1016/j.ijbiomac.2019.01.156

  325. 325.

    Kun-Peng Z Chun-Lin Z Xiao-Long M. Antisense lncRNA FOXF1-AS1 Promotes Migration and Invasion of Osteosarcoma Cells Through the FOXF1/MMP-2/-9 Pathway. Int J Biol Sci (2017 ) 13(9):1180–91

    Not in our library10.7150/ijbs.21722

  326. 326.

    Sun J Wang X Fu C Wang X Zou J Hua H. Long Noncoding RNA FGFR3-AS1 Promotes Osteosarcoma Growth Through Regulating its Natural Antisense Transcript FGFR3. Mol Biol Rep (2016 ) 43(5):427–36

    Not in our library10.1007/s11033-016-3975-1

  327. 327.

    Ren Z Hu Y Li G Kang Y Liu Y Zhao H. HIF-1alpha Induced Long Noncoding RNA FOXD2-AS1 Promotes the Osteosarcoma Through Repressing P21. BioMed Pharmacother (2019 ) 117:109104

    Not in our library10.1016/j.biopha.2019.109104

  328. 328.

    Ye K Wang S Zhang H Han H Ma B Nan W. Long Noncoding RNA GAS5 Suppresses Cell Growth and Epithelial-Mesenchymal Transition in Osteosarcoma by Regulating the miR-221/ARHI Pathway. J Cell Biochem (2017 ) 118(12):4772–81

    Not in our library10.1002/jcb.26145

  329. 329.

    Qu Y Zheng S Kang M Dong R Zhou H Zhao D. Knockdown of Long non-Coding RNA HOXD-AS1 Inhibits the Progression of Osteosarcoma. BioMed Pharmacother (2018 ) 98:899–906

    Not in our library10.1016/j.biopha.2018.01.024

  330. 330.

    Wang B Su Y Yang Q Lv D Zhang W Tang K. Overexpression of Long Non-Coding RNA HOTAIR Promotes Tumor Growth and Metastasis in Human Osteosarcoma. Mol Cells (2015 ) 38(5):432–40

    Not in our library10.14348/molcells.2015.2327

  331. 331.

    Gu Z Hou Z Zheng L Wang X Wu L Zhang C. Long Noncoding RNA LINC00858 Promotes Osteosarcoma Through Regulating miR-139-CDK14 Axis. Biochem Biophys Res Commun (2018 ) 503(2):1134–40

    Not in our library10.1016/j.bbrc.2018.06.131

  332. 332.

    Zhang B Yu L Han N Hu Z Wang S Ding L. LINC01116 Targets miR-520a-3p and Affects IL6R to Promote the Proliferation and Migration of Osteosarcoma Cells Through the Jak-Stat Signaling Pathway. BioMed Pharmacother (2018 ) 107:270–82

    Not in our library10.1016/j.biopha.2018.07.119

  333. 333.

    Han Z Shi L. Long non-Coding RNA LUCAT1 Modulates Methotrexate Resistance in Osteosarcoma via miR-200c/ABCB1 Axis. Biochem Biophys Res Commun (2018 ) 495(1):947–53

    Not in our library10.1016/j.bbrc.2017.11.121

  334. 334.

    Chen Y Huang W Sun W Zheng B Wang C Luo Z. LncRNA MALAT1 Promotes Cancer Metastasis in Osteosarcoma via Activation of the PI3K-Akt Signaling Pathway. Cell Physiol Biochem (2018 ) 51(3):1313–26

    Not in our library10.1159/000495550

  335. 335.

    Dong Y Liang G Yuan B Yang C Gao R Zhou X. MALAT1 Promotes the Proliferation and Metastasis of Osteosarcoma Cells by Activating the PI3K/Akt Pathway. Tumour Biol (2015 ) 36(3):1477–86

    Not in our library10.1007/s13277-014-2631-4

  336. 336.

    Duan G Zhang C Xu C Xu C Zhang L Zhang Y. Knockdown of MALAT1 Inhibits Osteosarcoma Progression via Regulating the Mir34a/Cyclin D1 Axis. Int J Oncol (2019 ) 54(1):17–28

    Not in our library10.3892/ijo.2018.4600

  337. 337.

    Li J Wu QM Wang XQ Zhang CQ. Long Noncoding RNA Mir210hg Sponges miR-503 to Facilitate Osteosarcoma Cell Invasion and Metastasis. DNA Cell Biol (2017 ) 36(12):1117–25

    Not in our library10.1089/dna.2017.3888

  338. 338.

    Hu Y Yang Q Wang L Wang S Sun F Xu D. Knockdown of the Oncogene lncRNA NEAT1 Restores the Availability of miR-34c and Improves the Sensitivity to Cisplatin in Osteosarcoma. Biosci Rep (2018 ) 38(3):BSR20180375

    Not in our library10.1042/bsr20180375

  339. 339.

    Ye H Lin J Yao X Li Y Lin X Lu H. Overexpression of Long Non-Coding RNA NNT-AS1 Correlates With Tumor Progression and Poor Prognosis in Osteosarcoma. Cell Physiol Biochem (2018 ) 45(5):1904–14

    Not in our library10.1159/000487966

  340. 340.

    Zhu KP Ma XL Zhang CL. LncRNA ODRUL Contributes to Osteosarcoma Progression Through the miR-3182/MMP2 Axis. Mol Ther (2017 ) 25(10):2383–93

    Not in our library10.1016/j.ymthe.2017.06.027

  341. 341.

    Wang J Cao L Wu J Wang Q. Long non-Coding RNA SNHG1 Regulates NOB1 Expression by Sponging miR-326 and Promotes Tumorigenesis in Osteosarcoma. Int J Oncol (2018 ) 52(1):77–88

    Not in our library10.3892/ijo.2017.4187

  342. 342.

    Jiang Z Jiang C Fang J. Up-Regulated lnc-SNHG1 Contributes to Osteosarcoma Progression Through Sequestration of miR-577 and Activation of WNT2B/Wnt/beta-Catenin Pathway. Biochem Biophys Res Commun (2018 ) 495(1):238–45

    Not in our library10.1016/j.bbrc.2017.11.012

  343. 343.

    Deng Y Zhao F Zhang Z Sun F Wang M. Long Noncoding RNA SNHG7 Promotes the Tumor Growth and Epithelial-To-Mesenchymal Transition via Regulation of miR-34a Signals in Osteosarcoma. Cancer Biother Radiopharm (2018 ) 33(9):365–72

    Not in our library10.1089/cbr.2018.2503

  344. 344.

    Yang G Song R Wang L Wu X. Knockdown of Long non-Coding RNA TP73-AS1 Inhibits Osteosarcoma Cell Proliferation and Invasion Through Sponging miR-142. BioMed Pharmacother (2018 ) 103:1238–45

    Not in our library10.1016/j.biopha.2018.04.146

  345. 345.

    Wang H Yu Y Fan S Luo L. Knockdown of Long Noncoding RNA TUG1 Inhibits the Proliferation and Cellular Invasion of Osteosarcoma Cells by Sponging miR-153. Oncol Res (2018 ) 26(5):665–73

    Not in our library10.3727/096504017x14908298412505

  346. 346.

    Yang C Wu K Wang S Wei G. Long non-Coding RNA XIST Promotes Osteosarcoma Progression by Targeting YAP via miR-195-5p. J Cell Biochem (2018 ) 119(7):5646–56

    Not in our library10.1002/jcb.26743

  347. 347.

    Zhang R Xia T. Long non-Coding RNA XIST Regulates PDCD4 Expression by Interacting With miR-21-5p and Inhibits Osteosarcoma Cell Growth and Metastasis. Int J Oncol (2017 ) 51(5):1460–70

    Not in our library10.3892/ijo.2017.4127

  348. 348.
    CircFAT1 sponges miR-375 to promote the expression of Yes-associated protein 1 in osteosarcoma cells · 2018
    No notice
  349. 349.

    Bartel DP. MicroRNAs: Genomics, Biogenesis, Mechanism, and Function. Cell (2004 ) 116(2):281–97

    Not in our library10.1016/s0092-8674(04)00045-5

  350. 350.

    Pasquinelli AE Hunter S Bracht J. MicroRNAs: A Developing Story. Curr Opin Genet Dev (2005 ) 15(2):200–5

    Not in our library10.1016/j.gde.2005.01.002

  351. 351.

    Kim VN Nam JW. Genomics of microRNA. Trends Genet (2006 ) 22(3):165–73

    Not in our library10.1016/j.tig.2006.01.003

  352. 352.

    Mao JH Zhou RP Peng AF Liu ZL Huang SH Long XH. microRNA-195 Suppresses Osteosarcoma Cell Invasion and Migration In Vitro by Targeting FASN. Oncol Lett (2012 ) 4(5):1125–9

    Not in our library10.3892/ol.2012.863

  353. 353.

    Cai H Zhao H Tang J Wu H. Serum miR-195 is a Diagnostic and Prognostic Marker for Osteosarcoma. J Surg Res (2015 ) 194(2):505–10

    Not in our library10.1016/j.jss.2014.11.025

  354. 354.

    Lian F Cui Y Zhou C Gao K Wu L. Identification of a Plasma four-microRNA Panel as Potential Noninvasive Biomarker for Osteosarcoma. PloS One (2015 ) 10(3):e0121499

    Not in our library10.1371/journal.pone.0121499

  355. 355.

    Salah Z Arafeh R Maximov V Galasso M Khawaled S Abou-Sharieha S. miR-27a and miR-27a* Contribute to Metastatic Properties of Osteosarcoma Cells. Oncotarget (2015 ) 6(7):4920–35

    Not in our library10.18632/oncotarget.3025

  356. 356.

    Jones KB Salah Z Del Mare S Galasso M Gaudio E Nuovo GJ. miRNA Signatures Associate With Pathogenesis and Progression of Osteosarcoma. Cancer Res (2012 ) 72(7):1865–77

    Not in our library10.1158/0008-5472.can-11-2663

  357. 357.

    Pan W Wang H Jianwei R Ye Z. MicroRNA-27a Promotes Proliferation, Migration and Invasion by Targeting MAP2K4 in Human Osteosarcoma Cells. Cell Physiol Biochem (2014 ) 33(2):402–12

    Not in our library10.1159/000356679

  358. 358.

    Dai N Zhong ZY Cun YP Qing Y Chen C Jiang P. Alteration of the microRNA Expression Profile in Human Osteosarcoma Cells Transfected With APE1 siRNA. Neoplasma (2013 ) 60(4):384–94

    Not in our library10.4149/neo_2013_050

  359. 359.

    Zhang Y Hu H Song L Cai L Wei R Jin W. Epirubicin-Mediated Expression of miR-302b is Involved in Osteosarcoma Apoptosis and Cell Cycle Regulation. Toxicol Lett (2013 ) 222(1):1–9

    Not in our library10.1016/j.toxlet.2013.06.242

  360. 360.

    Li Y Zhang J Zhang L Si M Yin H Li J. Diallyl Trisulfide Inhibits Proliferation, Invasion and Angiogenesis of Osteosarcoma Cells by Switching on Suppressor microRNAs and Inactivating of Notch-1 Signaling. Carcinogenesis (2013 ) 34(7):1601–10

    Not in our library10.1093/carcin/bgt065

  361. 361.

    Chen Y Zhu X Zhang X Liu B Huang L. Nanoparticles Modified With Tumor-Targeting scFv Deliver siRNA and miRNA for Cancer Therapy. Mol Ther (2010 ) 18(9):1650–6

    Not in our library10.1038/mt.2010.136

  362. 362.

    Varshney J Subramanian S. MicroRNAs as Potential Target in Human Bone and Soft Tissue Sarcoma Therapeutics. Front Mol Biosci (2015 ) 2:31

    Not in our library10.3389/fmolb.2015.00031

  363. 363.

    Qi P Du X. The Long non-Coding RNAs, a New Cancer Diagnostic and Therapeutic Gold Mine. Mod Pathol (2013 ) 26(2):155–65

    Not in our library10.1038/modpathol.2012.160

  364. 364.
    Long noncoding RNAs in the progression, metastasis, and prognosis of osteosarcoma · 2016
    No notice
  365. 365.

    Ji P Diederichs S Wang W Boing S Metzger R Schneider PM. MALAT-1, a Novel Noncoding RNA, and Thymosin Beta4 Predict Metastasis and Survival in Early-Stage non-Small Cell Lung Cancer. Oncogene (2003 ) 22(39):8031–41

    Not in our library10.1038/sj.onc.1206928

  366. 366.

    Gao KT Lian D. Long non-Coding RNA MALAT1 is an Independent Prognostic Factor of Osteosarcoma. Eur Rev Med Pharmacol Sci (2016 ) 20(17):3561–5.

    Not in our library

  367. 367.

    Zhu L Liu J Ma S Zhang S. Long Noncoding RNA MALAT-1 Can Predict Metastasis and a Poor Prognosis: A Meta-Analysis. Pathol Oncol Res (2015 ) 21(4):1259–64

    Not in our library10.1007/s12253-015-9960-5

  368. 368.

    Liu M Yang P Mao G Deng J Peng G Ning X. Long non-Coding RNA MALAT1 as a Valuable Biomarker for Prognosis in Osteosarcoma: A Systematic Review and Meta-Analysis. Int J Surg (2019 ) 72:206–13

    Not in our library10.1016/j.ijsu.2019.11.004

  369. 369.

    Huo Y Li Q Wang X Jiao X Zheng J Li Z. MALAT1 Predicts Poor Survival in Osteosarcoma Patients and Promotes Cell Metastasis Through Associating With EZH2. Oncotarget (2017 ) 8(29):46993–7006

    Not in our library10.18632/oncotarget.16551

  370. 370.

    Fang D Yang H Lin J Teng Y Jiang Y Chen J. 17beta-Estradiol Regulates Cell Proliferation, Colony Formation, Migration, Invasion and Promotes Apoptosis by Upregulating miR-9 and Thus Degrades MALAT-1 in Osteosarcoma Cell MG-63 in an Estrogen Receptor-Independent Manner. Biochem Biophys Res Commun (2015 ) 457(4):500–6

    Not in our library10.1016/j.bbrc.2014.12.114

  371. 371.

    Hu Q Li S Chen C Zhu M Chen Y Zhao Z. 17betaestradiol Treatment Drives Sp1 to Upregulate MALAT1 Expression and Epigenetically Affects Physiological Processes in U2OS Cells. Mol Med Rep (2017 ) 15(3):1335–42

    Not in our library10.3892/mmr.2017.6115

  372. 372.

    Deng R Zhang J Chen J. lncRNA SNHG1 Negatively Regulates Mirna1013p to Enhance the Expression of ROCK1 and Promote Cell Proliferation, Migration and Invasion in Osteosarcoma. Int J Mol Med (2019 ) 43(3):1157–66

    Not in our library10.3892/ijmm.2018.4039

  373. 373.

    Ruan W Wang P Feng S Xue Y Li Y. Long non-Coding RNA Small Nucleolar RNA Host Gene 12 (SNHG12) Promotes Cell Proliferation and Migration by Upregulating Angiomotin Gene Expression in Human Osteosarcoma Cells. Tumour Biol (2016 ) 37(3):4065–73

    Not in our library10.1007/s13277-015-4256-7

  374. 374.

    Zhou S Yu L Xiong M Dai G. LncRNA SNHG12 Promotes Tumorigenesis and Metastasis in Osteosarcoma by Upregulating Notch2 by Sponging miR-195-5p. Biochem Biophys Res Commun (2018 ) 495(2):1822–32

    Not in our library10.1016/j.bbrc.2017.12.047

  375. 375.

    Xu N Xu J Zuo Z Liu Y Yan F Han C. Downregulation of lncRNA SNHG12 Reversed IGF1R-Induced Osteosarcoma Metastasis and Proliferation by Targeting miR-195-5p. Gene (2020 ) 726:144145

    Not in our library10.1016/j.gene.2019.144145

  376. 376.
    Long noncoding RNA DANCR, working as a competitive endogenous RNA, promotes ROCK1-mediated proliferation and metastasis via decoying of miR-335-5p and miR-1972 in osteosarcoma · 2018
    No notice
  377. 377.

    Jiang N Wang X Xie X Liao Y Liu N Liu J. lncRNA DANCR Promotes Tumor Progression and Cancer Stemness Features in Osteosarcoma by Upregulating AXL via miR-33a-5p Inhibition. Cancer Lett (2017 ) 405:46–55

    Not in our library10.1016/j.canlet.2017.06.009

  378. 378.

    Jeck WR Sorrentino JA Wang K Slevin MK Burd CE Liu J. Circular RNAs are Abundant, Conserved, and Associated With ALU Repeats. RNA (2013 ) 19(2):141–57

    Not in our library10.1261/rna.035667.112

  379. 379.

    Ebbesen KK Kjems J Hansen TB. Circular RNAs: Identification, Biogenesis and Function. Biochim Biophys Acta (2016 ) 1859(1):163–8

    Not in our library10.1016/j.bbagrm.2015.07.007

  380. 380.

    Wang C Ren M Zhao X Wang A Wang J. Emerging Roles of Circular RNAs in Osteosarcoma. Med Sci Monit (2018 ) 24:7043–50

    Not in our library10.12659/msm.912092

  381. 381.

    Xiao-Long M Kun-Peng Z Chun-Lin Z. Circular RNA Circ_HIPK3 is Down-Regulated and Suppresses Cell Proliferation, Migration and Invasion in Osteosarcoma. J Cancer (2018 ) 9(10):1856–62

    Not in our library10.7150/jca.24619

  382. 382.
    Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs · 2016
    No notice
  383. 383.

    Li Y Zheng F Xiao X Xie F Tao D Huang C. CircHIPK3 Sponges miR-558 to Suppress Heparanase Expression in Bladder Cancer Cells. EMBO Rep (2017 ) 18(9):1646–59

    Not in our library10.15252/embr.201643581

  384. 384.
    circHIPK3 regulates cell proliferation and migration by sponging miR-124 and regulating AQP3 expression in hepatocellular carcinoma · 2018
    No notice
  385. 385.

    Kai D Yannian L Yitian C Dinghao G Xin Z Wu J. Circular RNA HIPK3 Promotes Gallbladder Cancer Cell Growth by Sponging microRNA-124. Biochem Biophys Res Commun (2018 ) 503(2):863–9

    Not in our library10.1016/j.bbrc.2018.06.088

  386. 386.
    CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7 · 2018
    Retracted
  387. 387.

    Wu Z Shi W Jiang C. Overexpressing Circular RNA Hsa_Circ_0002052 Impairs Osteosarcoma Progression via Inhibiting Wnt/beta-Catenin Pathway by Regulating miR-1205/APC2 Axis. Biochem Biophys Res Commun (2018 ) 502(4):465–71

    Not in our library10.1016/j.bbrc.2018.05.184

  388. 388.

    Ren C Liu J Zheng B Yan P Sun Y Yue B. The Circular RNA Circ-ITCH Acts as a Tumour Suppressor in Osteosarcoma via Regulating miR-22. Artif Cells Nanomed Biotechnol (2019 ) 47(1):3359–67

    Not in our library10.1080/21691401.2019.1649273

  389. 389.

    de Nigris F Mancini FP Schiano C Infante T Zullo A Minucci PB. Osteosarcoma Cells Induce Endothelial Cell Proliferation During Neo-Angiogenesis. J Cell Physiol (2013 ) 228(4):846–52

    Not in our library10.1002/jcp.24234

  390. 390.

    Yamanegi K Kawabe M Futani H Nishiura H Yamada N Kato-Kogoe N. Sodium Valproate, a Histone Deacetylase Inhibitor, Modulates the Vascular Endothelial Growth Inhibitor-Mediated Cell Death in Human Osteosarcoma and Vascular Endothelial Cells. Int J Oncol (2015 ) 46(5):1994–2002

    Not in our library10.3892/ijo.2015.2924

  391. 391.

    Vimalraj S Saravanan S Raghunandhakumar S Anuradha D. Melatonin Regulates Tumor Angiogenesis via miR-424-5p/VEGFA Signaling Pathway in Osteosarcoma. Life Sci (2020 ) 256:118011

    Not in our library10.1016/j.lfs.2020.118011

  392. 392.

    Bulut G Hong SH Chen K Beauchamp EM Rahim S Kosturko GW. Small Molecule Inhibitors of Ezrin Inhibit the Invasive Phenotype of Osteosarcoma Cells. Oncogene (2012 ) 31(3):269–81

    Not in our library10.1038/onc.2011.245

  393. 393.

    Sleeman J Steeg PS. Cancer Metastasis as a Therapeutic Target. Eur J Cancer (2010 ) 46(7):1177–80

    Not in our library10.1016/j.ejca.2010.02.039

  394. 394.

    Steeg PS. Perspective: The Right Trials. Nature (2012 ) 485(7400):S58–9

    Not in our library10.1038/485s58a

  395. 395.

    Liang C Li F Wang L Zhang ZK Wang C He B. Tumor Cell-Targeted Delivery of CRISPR/Cas9 by Aptamer-Functionalized Lipopolymer for Therapeutic Genome Editing of VEGFA in Osteosarcoma. Biomaterials (2017 ) 147:68–85

    Not in our library10.1016/j.biomaterials.2017.09.015

  396. 396.

    Chou AJ Gupta R Bell MD Riewe KO Meyers PA Gorlick R. Inhaled Lipid Cisplatin (ILC) in the Treatment of Patients With Relapsed/Progressive Osteosarcoma Metastatic to the Lung. Pediatr Blood Cancer (2013 ) 60(4):580–6

    Not in our library10.1002/pbc.24438

  397. 397.

    Dow S Elmslie R Kurzman I MacEwen G Pericle F Liggitt D. Phase I Study of Liposome-DNA Complexes Encoding the Interleukin-2 Gene in Dogs With Osteosarcoma Lung Metastases. Hum Gene Ther (2005 ) 16(8):937–46

    Not in our library10.1089/hum.2005.16.937

  398. 398.

    Bruland OS Hoifodt H Saeter G Smeland S Fodstad O. Hematogenous Micrometastases in Osteosarcoma Patients. Clin Cancer Res (2005 ) 11(13):4666–73

    Not in our library10.1158/1078-0432.ccr-05-0165

  399. 399.

    Bruland OS Hoifodt H Hall KS Smeland S Fodstad O. Bone Marrow Micrometastases Studied by an Immunomagnetic Isolation Procedure in Extremity Localized non-Metastatic Osteosarcoma Patients. Cancer Treat Res (2009 ) 152:509–15

    Not in our library10.1007/978-1-4419-0284-9_30

  400. 400.

    Guan G Lu Y Zhu X Liu L Chen J Ma Q. CXCR4-Targeted Near-Infrared Imaging Allows Detection of Orthotopic and Metastatic Human Osteosarcoma in a Mouse Model. Sci Rep (2015 ) 5:15244

    Not in our library10.1038/srep15244

  401. 401.

    Wang L Li P Xiao X Li J Li J Yang HH. Generating Lung-Metastatic Osteosarcoma Targeting Aptamers for In Vivo and Clinical Tissue Imaging. Talanta (2018 ) 188:66–73

    Not in our library10.1016/j.talanta.2018.05.011

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