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The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited

Kevin Dzobo, Dimakatso A. Senthebane, Collet Dandara

Cancers · 2023 · Review · CC BY

doi:10.20944/preprints202211.0170.v1

Abstract

Simple Summary. Tumors are not masses of cancer cells alone but made up of cancer cells, other cells including fibroblasts, macrophages, endothelial cells, as well as secreted factors, blood vessels and the extracellular matrix (ECM). This comprehensive review presents new findings on the role of each component of the tumor cell surroundings and the effect on the success of cancer drugs. We show in this paper that the tumor cell’s surroundings are not simply ‘bystanders’ but are actively involved in tumor growth and can cause resistance to treatment. Initially, cells and ECM around tumor cells do not promote their growth but over time, tumor cells ‘convert’ their surroundings to promote their growth. An increase in tumor size means tumor cells must overcome a lack of oxygen and nutrients, be able to remove waste and form secondary tumors. A better knowledge of tumor cells and their surrounding means better drugs for tumor cells and their surroundings.

Abstract. Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, and highlight various ways through which tumor cells reprogram normal cells into phenotypes that are pro-tumorigenic, including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to the transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells, including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic, but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to the formation of new vascular networks in order to actively promote and sustain tumor growth via the supply of oxygen and nutrients, whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to the targeting of tumor cells. The reprogramming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centered therapies under investigation.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 27, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Methodology

1We retrieved relevant published manuscripts via an electronic search on Embase, Scopus, PubMed and Web of Science using keywords including tumor microenvironment; stromal cells; immune cells; extracellular matrix (ECM); cancer hallmarks; hypoxia; chemotherapy; multi-drug resistance and targeted therapy. This search yielded a rich source of data on the role of tumor microenvironment in tumorigenesis and therapy resistance (Figure 1). We removed duplicate articles and only full articles were included in compiling this review.

2. The Tumor Microenvironment in Brief

2It is universally accepted that cancer has major hallmarks including the presence of genomic instability and mutations, unrestricted growth, the evasion of growth suppressors, resisting cell death, enhanced inflammation, enhanced metabolism, and the ability to promote angiogenesis, invasion, and metastasis. It is also scientifically accepted that tumors are more than just tumor cells and include recruited stromal cells and the non-cellular component, the ECM (Figure 2). Stromal cells and the ECM are active participants during tumorigenesis, starting as anti-tumorigenic during the initial stages to being pro-tumorigenic over time and contributing to the attainment of specific cancer hallmarks. Thus, the study and understanding of cancer and tumorigenesis now extends beyond tumor cells to include the stromal cells and the ECM, which make up the tumor microenvironment (TME). Stromal cells include normal fibroblasts, cancer associated fibroblasts (CAFs), cancer associated macrophages (CAMs), mesenchymal stem cells (MSCs), inflammatory cells and endothelial cells. Beside the contribution of the TME during tumorigenesis and metastasis, the TME and common features including hypoxia also play a critical role in therapy resistance. Cell-cell and cell-ECM interactions involve a myriad of biomolecular factors, such as growth factors, cytokines, enzymes, and chemokines. In addition, exosomes and apoptotic bodies are shown to play roles in promoting tumorigenesis and drug resistance. This review provides a comprehensive description of how the TME, characterized by hypoxia, contribute to tumorigenesis and therapy resistance, and presents ways to reprogram cells and factors to increase therapy efficacy.

3.1. Cancer Associated Fibroblasts

3Reports have shown that resident and recruited fibroblasts are part of the TME, where they contribute during tumorigenesis and in drug resistance. Initially, fibroblasts are anti-tumorigenic as they are involved in the synthesis of the ECM, which surrounds and isolates tumor cells from normal tissue during the early stages of tumorigenesis. Over time, a subpopulation of activated fibroblasts, referred to as cancer associated fibroblasts, obtain a myofibroblastic phenotype characterized by the increased synthesis of ECM and the release of pro-tumorigenic factors (Figure 3). Similar to myofibroblasts linked to fibrosis, the CAFs are perpetually activated and promote tumorigenesis via the release of factors, the activation of pro-tumorigenic signaling, angiogenesis, microRNA, and cytokines. At each stage of tumorigenesis, CAFs continue to produce and interact with various TME components including the ECM, cytokines, and growth factors.

4Together with several other stromal cells including CAMs and MSCs, CAFs release factors such as TGF-β and cytokines involved in ECM remodeling, the promotion of tumor cell proliferation, the suppression of immune response, the recruitment of MSCs as well as the induction of angiogenesis. For example, TGF-β, from both tumor cells and CAFs, has been shown to promote tumor cell proliferation and to induce EMT transition. TGF-β overexpression is correlated with poor prognosis in prostate cancer, colorectal cancer, and hepatocellular carcinoma. In addition to the expression of TGF-β, CAFs also express vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF), and this allow their involvement in tumor metastasis. CAF-derived interleukin-6 (IL-6) activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) (JAK-STAT) signaling pathway leads to increased TGF-β signaling, promoting tumor growth and metastasis. In addition, increased CAFs within the TME and synthesized CXC chemokines correlated with low patient survival in various cancers including colorectal cancer and esophageal cancer. Several investigations also show that CAF-derived matrix metalloproteases (MMPs) participate in tumor cell migration and invasion through the creation of ‘matrix highways’ after ECM molecules degradation. Using a cell-derived ECM, Senthebane and colleagues demonstrated that fibroblast-derived MMPs contribute towards cancer cell migratory and invasive behavior.

5Mounting reports indicate that CAFs originate from different cells and therefore display complex heterogeneity (Figure 4). Tissue-resident fibroblasts contribute to most CAFs within the TME in addition to other stromal cells such as stellate cells, bone marrow derived- and tissue adult derived-MSCs, pericytes and endothelial cells (Figure 3). In the case of an injury, the activation of tissue-resident fibroblasts and stellate cells in the liver, for example, reversibly transform these cells into a myofibroblast phenotype characterized by the elevated expression of α-SMA. Many studies have shown the involvement of growth factors including fibroblast growth factor 2 and TGF-β signaling in the transformation of stromal cells into myofibroblastic cells or CAFs. These myofibroblastic cells are the activated fibroblasts responsible for enhanced ECM synthesis in liver cancers. Several studies have also shown that fibrocytes are present in blood. Barth and colleagues demonstrated the presence and the role of CD34+ fibrocytes in invasive ductal carcinoma. Besides breast cancer, the same authors also demonstrated a role for fibrocytes in pancreatic and cervical cancer. Overall, the increased levels of CAFs within the TME is associated with tumor relapse and poor prognosis in various cancers.

6Another potential origin of CAFs is epithelial cells. Epithelial cells near cancer cells can undergo epithelial-to-mesenchymal transition (EMT) and end up as CAFs. Epithelial cancers may display elevated levels of CAFs that drive tumorigenesis. Epithelial cells lose the normal cell-cell adhesive abilities and gain migratory abilities. Endothelial cells can undergo endothelial-to-mesenchymal transition (EMT), transforming these cells into CAFs. CAFs originating from epithelial and endothelial cells produce CAF markers such as S100A4. Both adipocytes and pericytes can undergo trans-differentiation into CAFs. It is important to note that while CAFs are pro-tumorigenic, studies also indicate that CAFs can act in an anti-tumorigenic manner. Only recently, is a clear and well-defined picture of CAFs and their role in tumorigenesis emerging.

7CAFs heterogeneity means numerous subgroups exist with contrasting phenotypes and functions within the TME. Reports also show that CAFs heterogeneity is linked to stage of tumor development. ECM remodeling and stromal cell transformations during different stages of tumorigenesis can lead to CAFs being genetically unstable. Thus, CAFs co-evolve with tumor cells during tumorigenesis. The initial anti-tumor activity of stromal cells becomes ‘tumor-promoting’ activity over time. Various signaling cascades modulate CAFs activation and activity and these include the lysophosphatidic acid and TGF-β family ligands which influence serum response factor (SRF) and SMAD transcription factors activities, respectively, to promote the expression of the activated fibroblast marker α-SMA. A co-culture of cancer cells and fibroblasts demonstrate the promotion of CAF activation in breast cancer via the Notch signaling. Furthermore, inflammatory modulators including interleukin-1β (IL-1β) can induce NF-KB activation in CAFs. CAF markers include FAP, PDGFRα/β, tenascin C, vimentin, desmin, CD90 and podoplanin (PDPN) (Table 1). CAFs heterogeneity means that there is no universal marker and early studies utilized α-SMA and FAP-alpha. A combination of these markers is the ideal means to identify CAFs. Other markers include α-SMA, vimentin and CD10. The expression of α-SMA is not exclusive to CAFs as other cells such as smooth muscle cells and pericytes express the same marker. CAFs found in several cancers, such as breast and pancreatic cancers, express high levels of α-SMA and vimentin.

8Targeting CAFs, with their significant heterogeneity, involves reversal of the transformation from normal fibroblasts into CAFs. Reports indicate that the use of microRNA can achieve such de-activation or reprogramming of CAFs into normal fibroblasts. De-differentiation of CAFs into quiescent cells is another strategy under consideration.

3.2. Cancer Associated Endothelial Cells

9New blood vessel formation during tumorigenesis is initiated by endothelial cells and these cells constitute the innermost layer of blood vessels. The usually thin vascular endothelium separates blood from tissues in addition to delivering important nutrients, ions, and water. The vascular endothelium is also important in carrying away all toxic metabolic waste products. Immune cells are also carried to tumors via the blood stream. Whilst diffusion is responsible for oxygen supply and carbon dioxide removal during the initial stages of tumorigenesis, increase in the size of tumor will require increased supply of oxygen as well as removal of metabolic waste. As the tumor increase in size, a hypoxic core is formed, activating the tumor to form new blood vessels to supply much-needed nutrients and oxygen. Vascular networks are formed as a result of the action of various transcription factors induced by hypoxia. The transcription factors induced by hypoxia act on endothelial cells which release growth factors, such as epidermal growth factor (EGF), and PDGF to form new blood vessels. Old blood vessels can also sprout and form new branching vessels. Beside growth factors, endothelial cells also release proteins required for the formation of basement membranes. Due to the unregulated release of cytokines and growth factors, blood vessel formation is not proper within a tumor. This results in ‘makeshift’ blood vessels that are leaky. Being responsible for new blood vessel formation makes endothelial cells important for cancer cell migration and metastasis. As the blood vessels within tumors are leaky, cancer cells can easily invade new tissues and intravasate into blood vessels to be transported to new sites. Endothelial cells can also undergo ‘endothelial to mesenchymal transition’ to become cancer associated fibroblasts as they are very plastic. Various growth factors, including TGF-β, are known to be involved in this transition. Cancer associated endothelial cells promotes tumorigenesis by being immunosuppressive, growth factor synthesis and the enhanced migratory behavior of tumor cells. Cancer associated endothelial cells also aid immunosuppressing myeloid cells’ infiltration into tumors. Reports show that cancer associated endothelial cells can modulate anti-tumor immunity via the disruption of cytotoxic T cell infiltration, whilst at the same time allowing immunosuppressive cells to move into the tumor. Cancer associated-endothelial cells also demonstrate enhanced angiogenic ability leading to increased drug resistance versus normal endothelial cells.

3.3. Cancer-Associated Macrophages

10In the human body, macrophages, mostly originating from circulating monocytes, participate in various processes from clearing infections and wound healing, as well as the repair of tissues. As part of the innate immune system macrophages respond to the presence of pathogens by presenting antigens and carrying out phagocytosis. M1 macrophages are the predominant type of macrophages during the initial stages of tumorigenesis, as they participate in phagocytosis of pathogens and antigen presentation. A tumor is sometimes referred to as a ‘wound’ that does not heal. Thus, within the tumor microenvironment, the M2 macrophages are present and actively participate in suppressing the immune system and wound healing. Deep inside the tumor, la ack of oxygen and various cytokines are known to promote the M2 type of macrophages. The infiltration of tumors with macrophages occur throughout the process of tumorigenesis and macrophages can account up to a third of the mass of the tumor at some stages. Reports indicate that an elevated levels of macrophages within tumors are associated with low survival rates in various cancers. This is attributed to macrophages’ promotion of angiogenesis via release of various cytokines and thus enhance formation of new blood vessels. Recent data also show that CAMs play key roles in chemoresistance to drugs such as paclitaxel and 5-fluorouracil. Furthermore, CAMs have been shown to promote CSCs tumorigenic capacity as well as their therapeutic resistance via increased enzyme synthesis (cytidine deaminase) involved in drug metabolism.

3.4. Cancer-Associated Neutrophils

11When an infection occurs, circulating leukocytes, and specifically neutrophils, provide the first line of defense against pathogens. Within the tumor microenvironment, neutrophils can have both pro- and anti-tumorigenic properties. During the initial stages of tumorigenesis, recruited neutrophils release various cytokines including IL6 thereby inducing inflammation. This causes tumor cells to undergo apoptosis. Neutrophils also release reactive oxygen species that induce apoptosis in tumor cells. In later stages of tumorigenesis, neutrophils release various growth factors such as VEGF involved in angiogenesis, and therefore promotes tumorigenesis through new blood vessel formation. Neutrophils are also involved in ECM remodeling via the production of matrix metalloproteases (MMPs). MMPs are also actively involved in promoting tumor cell invasion and eventual metastasis via the degradation of ECM molecules. Cancer-associated neutrophils have been shown to contribute towards the attainment of acquired cancer drug resistance via their ability to suppress the immune system, enhancement of angiogenesis, as well as enhancing tumor cell proliferation. Cancer associated neutrophils also activate various signaling cascades that prevent the proper functioning of many cancer drugs such as immune checkpoint blockers and common cytotoxic drugs. In combination with standard therapies, drugs targeting cancer associated neutrophils can sensitizes tumor cells to drugs and prevent drug resistance and relapse.

3.5. T Cells

12Various populations of T cells have been identified within the tumor microenvironment at various stages of tumor development. Specific T cell populations have specific receptors used in antigen identification. For example, cytotoxic T cells with specific receptors identify abnormal antigens expressed on tumor cells and their attachment to tumor cells leads to the destruction of the cells. Cytotoxic T cells also play a key role in preventing formation of new blood vessels via the release of the pleiotropic cytokine interferon-gamma. Thus, cytotoxic T cells demonstrate anti-tumorigenic behavior within the tumor microenvironment. Another population of T cells found within the tumor microenvironment are the CD4+ T cells. CD4+ T cells are mainly involved in immune responses within the tumor microenvironment and over time differentiate into several cells. For example, CD4+ T cells can become T-helper 1 cells, which participate in inflammation induction and their presence within various tumors is linked to increased patient survival. Another T cell type found within tumors is the regulatory T cells. Regulatory T cells participate in suppressing inflammation and anti-tumor immune responses. Regulatory T cells releases interleukin-2, which controls the function of natural killer cells. Furthermore, regulatory T cells secrete various growth factors and cytokines and advertently supports tumorigenesis.

3.6. B Cells

13B cells are responsible for antibody production in the body as well as secretion of various cytokines. B cells are mostly localized at the periphery of tumors and within lymph nodes near the tumor site. Thus, few B cells are found within tumors. The main function of B cells during tumorigenesis is their close relationship with T cells, allowing T cells to act against tumor cells. B cells act as antigen presenting cells to T cells. B cells are also involved in secretion of anti-tumorigenic cytokines such as IFN-γ. However, several studies also show that B cells are pro-tumorigenic in some tumors. It has been shown that regulatory B cells produce various cytokines including IL-10 and TGF-β that promote immune suppression via their effects on macrophages and T cells.

3.7. Natural Killer Cells

14Natural killer cells are able to destroy cells infected with viruses in blood. Two functional sub-categories of natural killer cells have been identified: those that directly kill tumor cells; whilst another sub-category produces inflammatory cytokines. Inflammation will lead to the accumulation of various immune cells involved in tumor cell killing. By seeking and destroying tumor cells within the bloodstream, natural killer cells are important in preventing metastasis and formation of secondary tumors. Both natural killer cells and innate natural killer cells use both adhesion and cytokine receptors to identify their cellular targets and in so doing can spare normal healthy cells. Within tumors, natural killer cells are less efficient at killing tumor cells. Reports indicate that both natural killer cells and innate natural killer cells are able to detect ‘stress’ or biological changes in host tissues and the cells can activate innate and adaptive immune cells within the TME. Reports indicate that natural killer cells may express multi-drug resistance-like activity, and this can be inhibited through the use of drugs such as verapamil or solutol HS-15.

3.8. Dendritic Cells

15The function of dendritic cells is mostly to recognize and capture antigens as well as present them to T cells. Dendritic cells are mostly found within lymph nodes where they participate in T cell response to specific pathogen infection. Depending on the prevailing environment within tumors, dendritic cells can be both anti- and pro-tumorigenic. The over-production of pro-tumorigenic growth factors and cytokines can lead to dendritic cells tolerating the presence of tumor cells and act to prevent an immune reaction. Tumors have been shown to exploit dendritic cells. For example, reports show that local dendritic cells may be conditioned by tumor cells to form suppressive T cells, leading drug resistance.

3.9. Stellate Cells

16Found in the liver and the pancreas, stellate cells originated from mesenchymal tissue and are mostly involved in promoting tumorigenesis via differentiation into myofibroblasts. Injury to the liver and pancreas induce stellate cell differentiation into myofibroblasts, after which they synthesize enormous quantities of ECM molecules and growth factors including VEGF. The development of a tumor, akin to ‘wound healing’ induce stellate cells differentiation into myofibroblasts. One major function of stellate cells is the accumulation of vitamin A in lipids droplets. The lipid droplets are then utilized during ECM synthesis and production of MMPs. Tumor cell-derived TGF-β is known to be involved in the activation of hepatic stellate cells into myofibroblast in liver cancer. Both liver cancer and pancreatic cancer tend to be associated with fibrosis. Quiescent pancreatic stellate cells are involved in remodeling of the ECM via MMPs synthesis and ECM protein synthesis. Once activated, pancreatic stellate cells secrete various biomolecules leading to their increased migratory behavior and proliferation. Various reports demonstrated the involvement of stellate cells in tumorigenesis. For example, a classic study by Hessmann and colleagues showed that pancreatic stellate cells traps drugs such as gemcitabine and this reduces the efficacy of the drug during treatment.

3.10. Adipocytes

17Two cell types, adipocytes, and white adipose tissue, constitute the adipose tissue. Energy storage as well as maintenance of energy balance in the body is the function of adipocytes or fat cells. Given the high energy required by tumor cells during tumor initiation and progression, it is not surprising therefore that adipocytes play a key role in this process. Adipocytes have been shown to secrete various biomolecules from growth factors, enzymes to cytokines. The secretion of enzymes including MMPs leads to ECM remodeling, allowing tumor cells to migrate and metastasize. Obesity is considered a high-risk factor in many cancers with close to half cancer patients being obese for example in breast and ovarian cancers. Reports show that white adipose tissue is linked to an increased risk of cancers and the formation of secondary tumors in lungs, for example. Organs with a high number of adipocytes include the breast and these cells have been shown to be pro-tumorigenic. As tumor cells require a lot of energy, adipocytes can be induced to undergo lipolysis, which converts lipids into fatty acids that can be used by tumor cells during tumorigenesis. Furthermore, adipocytes secrete various hormones including leptin that promotes tumor cell proliferation and migration as well as the recruitment of immune cells to the TME. Adipose-derived adult stem cells, which can differentiate into different cell lineages, also come from adipose tissue. These stem cells have the ability to enhance inflammation within the TME and thus are pro-tumorigenic. It is possible that adipose-derived stem cells can differentiate into cancer-associated stromal cells such as CAFs.

3.11. Mesenchymal Stem Cells

18Important for the maintenance of healthy tissue and the repair of tissue in the case of injury, mesenchymal stem cells, or mesenchymal stromal cells, are able to differentiate into cell types such as osteoblasts, and chondrocytes. This differentiation ability is the reason why MSCs recruited to tumors can transform into various tumor associated cells. Reports indicate that beside resident fibroblasts differentiation into CAFs, recruited MSCs can also be transformed into CAFs. Whilst resident fibroblasts may initially have an anti-tumorigenic phenotype, it is reported that over time all fibroblasts are pro-tumorigenic. During the initial stages of tumorigenesis, fibroblasts synthesize large quantities of ECM proteins, in what appear to be an attempt at isolating the tumor from the rest of the tissue. An increase in ECM synthesis also causes the stiffening of tissue. An increase in tissue stiffness has been associated with tumorigenesis. In later stages of tumorigenesis, MSCs demonstrate immunoregulatory effects by contributing to the dampening of the anti-tumor immunity. Importantly, the differentiation of MSCs into CAFs has long-lasting effect with regard to the promotion of tumorigenesis as CAFs will continue to synthesize and release various factors needed by tumor cells. Our earlier study clearly demonstrated the involvement of MSCs in CAFs differentiation and the release of TGF-β, for example.

3.12. Pericytes

19Pericytes have multiple roles within the tumor microenvironment including covering endothelial cells along the surface of the endothelium, in the remodeling of the basement membrane during tumorigenesis and the formation of new blood vessels. Pericytes have also been involved in immunoregulatory process through the activation of immune cells such as lymphocytes, and in phagocytosis. Although clinical trials targeting pericytes involvement in angiogenesis has been carried out, results so far are not promising. Some reports even show that targeting pericytes leads to more tumor cells metastasizing. For example, targeting pericytes in animal models of breast cancer resulted in aggressive pulmonary tumor process. It has been postulated that pericytes may display heterogeneity and there is need to target the correct pericyte subpopulation with a specific phenotype to stop tumorigenesis. Reports indicate that pericytes can cause resistance to vemurafenib and sorafenib in thyroid cancer and the mechanism involved occur via the TGF-β signaling. Other reports show that pericytes participate in tumorigenesis via the promotion of angiogenesis.

4. The Extracellular Matrix

20One key component of the TME is the ECM. Forming the structural part of the TME, the ECM is located under the epithelial layer surrounding the connective tissue cells. CAFs are the main source of ECM components. It is made up of many macromolecules including vitronectin, collagens, proteoglycans, and glycoproteins (e.g., fibronectin, laminin) (Figure 5). Its composition is always changing depending on the stage of tumorigenesis, and this is facilitated by enzymes such as cathepsins, lysyl oxidase (LOX), MMPs, and their inhibitors. In solid tumors, the ECM can constitute about half of the tumor mass (desmoplastic tumors) and has been linked to poor patient survival.

21The elasticity and rigidity of the ECM promote tumorigenesis via integrin signaling. Changes in ECM composition and elasticity influence many aspects of tumorigenesis varying from cancer cell growth, survival and therapy resistance. Collagen, the most abundant ECM molecule in tumors, provides structural support to tumor cells and regulating other processes such as tumor cell adhesion, supporting chemotaxis and migration. Enhanced levels of type I collagen also increase ECM stiffness and promote tumorigenesis in the process. Enzyme-linked changes in ECM composition and levels facilitate tumor cell migration via the creation of ‘pores’ allowing tumor cells to invade surrounding tissues and travel to distant tissues and organs. Increased collagen production and the resulting stiffness influence integrin signaling and tumor cell survival.

22Importantly, the ECM presents a physical hindrance to drug distribution within tumors. In most cases, this physical hindrance as well as the sequestration of drugs through direct binding to ECM molecules contributes to the development of drug resistance in many solid tumors. Furthermore, various reports show that the ECM is key to tumor vascularization. New blood vessel formation is important to tumorigenesis. As production of ECM molecules such as collagen increases, the resulting increased ECM density causes a decrease in vascularization. A stiff ECM compresses blood vessels, limiting the flow of drugs and oxygen within the TME. The lack of enough oxygen within tumors influence vascularization via the activation of HIF-1α. HIF-1α promotes chemoresistance via activation of MDR1 expression in hypoxic colon cancer, for example. Lastly, the ECM can sequester various growth factors and cytokines that can promote tumorigenesis such as TGF-β, VEGF and PDGF.

5. Vascular Networks

23Tumor cells require supplies of oxygen and nutrients to maintain their uncontrolled growth. This is achieved through the vascular networks that allows gaseous exchange and the removal of toxic waste from the tumor (Figure 6). A major hallmark of cancer is the process of angiogenesis. The tumor microenvironment becomes hypoxic as the tumor continue to grow as the vasculature cannot supply oxygen to all cells within the TME. New blood vessels formed from pre-existing ones are ‘leaky’ and convoluted. Similar to the growth of tumor cells, which is uncontrolled, blood vessel formation continues unabated with no proper control, resulting in a complex structure. Leaky vessels also help tumor cells to migrate to other tissues and organs to form secondary tumors, as well as contribute to the ineffective distribution of drugs within the TME. Lymphatic vessels also provide a ‘throughfare’ through which tumor cells can migrate to other sites. Indeed, lymph nodes have been shown to be the common sites through which tumor cells migrate to other tissue and organs. In many cancers, lymph node metastases are linked to poor prognosis. Once in the lymph nodes, cancer cells can easily migrate to other organs and tissues and in many cases lymph nodes metastases must be treated together with solid tumors for successful therapy.

6. Hypoxia within the TME

24A hallmark of the unregulated proliferation of tumor cells is the unavailability of oxygen or hypoxia and nutrients in some parts of a growing solid tumor. Synthesis of new blood vessels via angiogenesis does not occur fast enough to provide oxygen to rapidly growing tumor cells. The result is tumors with some regions having less than 2% oxygen levels, thus are hypoxic. Importantly, angiogenesis within a growing tumor leads to dysregulated vasculature and oxygenated blood is not supplied to all regions. Tumor cells within hypoxic regions obtain a different phenotype to those in regions properly supplied with oxygenated blood, are more aggressive and become resistant to commonly used drugs. Indeed, oxygen gradients within solid tumors is a common feature. Tumor cells within hypoxic regions also express elevated levels of hypoxia-inducible factor alpha (HIF-1α), with three isoforms having been found in mammals. HIFs play central roles in tumorigenesis in which they influence hypoxia-induced gene expression and metabolism. For example, HIF-1 is especially important in tumor cell response to therapy. HIF-1α also enhances the activities of transcriptional factors including Twist and Snail, leading to increased endothelial-to-mesenchymal transition (EMT). By modulating collagen synthesis and collagen fiber alignment as well as integrin-ECM interactions within the TME, HIF-1α also aid tumor cell migration and metastasis. In addition, due to a lack of oxygen, tumor cells within hypoxic regions of TME divide slowly, thus can circumvent common drugs targeting rapidly dividing tumor cells.

25As a tumor grows, de novo angiogenesis leads to the formation of leaky blood vessels leading to an increase in interstitial fluid pressure. Furthermore, leaky blood vessels aid tumor cell metastasis as tumor cells can easily escape the blood vessels with discontinuous endothelium. Various reports documented that cells within hypoxic TME region also promote immunosuppression. For example, cancer-associated macrophages of the M2 type have been found in hypoxic regions. The immunosuppressive properties of CAMs are well documented. HIF-1α can modulate the behavior of myeloid-derived suppressor cells within the hypoxic regions of TME. Hypoxia also cause the TME to be acidic and under these conditions T cells are not able to perform their cytotoxic functions. Further data show that hypoxia can induce the over-expression of various proteins involved in drug efflux. Reports show that the blocking of HIF-1α expression can reverse drug resistance in cancers. Drug resistance can also emanate from tumor cells altering their metabolism and avoiding apoptosis. Hypoxia can also induce autophagy, which can lead to multi-drug resistance. Overall, hypoxia within the TME can be used as an independent prognostic factor in cancers and predicts poor outcomes. Thus, novel strategies must target tumor hypoxia together with various components of the TME.

7. Exosomes and Exosomal miRNAs in Tumor Microenvironment

26Ranging in size from 30 to 200 nm, exosomes play key roles in cellular communication between tumor cells and stromal cells and are secreted into the extracellular space by cells regularly. The contents of exosomes depend on their origin, with stromal cell-derived exosomes containing various growth factors, cytokines and other signaling molecules that can impact tumor cell behavior as well as cell-cell interactions. In most cases, the contents of exosomes promote tumorigenesis via impacting processes such as angiogenesis, migration, and metastasis. Reports indicate that tumor cells under conditions of low oxygen and nutrients produce increased levels of exosomes and leads to alterations of stromal cells into pro-tumorigenic cells including CAFs and CAMs. Tumor cell-derived exosomes also have the ability to prepare some tissue-specific cells for colonization by tumor cells.

27Importantly, exosomes are key to transporting microRNAs. Stromal cells can alter microRNAs (miRNAs) expression in both tumor cells and stromal cells. The alteration of miRNA expression can be induced by tumor and stromal cell interactions through the release of auto- and paracrine factors. For example, microRNA-122 from breast cancer cells has been shown to reprogram normal cell metabolism by reducing the uptake of glucose by lung cells, in preparation for lung colonization. This will make sure there are enough nutrients for metastatic breast tumor cells upon lung colonization. Delineating miRNAs functions within the TME can lead to new therapeutic targets identification. Exosomes are useful as diagnostic biomarkers as well as therapeutic targets. Exosomes are stable within the circulatory system and their contents can be used for diagnosis purposes and can predict tumor metastasis accurately. Given their many functions during tumorigenesis, reports indicate that the abrogation of exosome production can inhibit tumorigenesis. The suppression of tumor-derived exosomes uptake through the use of heparin resulted in decreased metastatic ability of oral squamous cell carcinoma.

28In terms of cancer treatment, exosomes can be used to deliver drugs as they are non-toxic and biodegradable. Ligands specific for certain tumors can be expressed on the surface of the exosomes so as to direct them to specific tumor cells. Such tumor cell-specific exosomes can then deliver therapeutic siRNA or drugs, for example, to kill cancer cells.

8. Advances in Therapeutic Targeting of TME

29Great improvements have been brought to cancer treatment through combinations of various drugs and immunotherapy in the past few years. Chemotherapy, used mostly as the first line of cancer treatment, target rapidly growing cancer cells, and tends to be broad in its focus. Whilst cancer is initially caused by changes in genes, its progression is associated with major biological and metabolic changes that over time negatively affect bodily functions. By specifically targeting sub-populations of cancer cells within the TME including CSCs, improvements have been made in cancer treatment. In addition, the introduction of immunotherapy and specifically immune checkpoint blockade such as PD1 that targets several immune cells within the TME brought remarkable success in cancer treatment. Immune checkpoint inhibitors are antibodies or drugs that block proteins called checkpoints from immune system cells including T cells as well as some cancer cells. Programmed death ligand 1(PDL-1) on cancer cells and the programmed death 1 (PD-1) on normal healthy cells are important in the maintenance of immune responses. When cancer cell PDL-1 interacts with PD-1 on normal cells, this prevents the immune reaction of the normal cells to the presence of tumor cell. Checkpoint inhibitors prevent the interaction between PDL-1 and PD-1 and thus allow normal cells to activate the immune reaction to the presence of cancer cells. Currently, checkpoint inhibitors have been clinically proven for various cancers including renal cell carcinoma, colon cancer and lung cancer, among others. The major advantages of checkpoint inhibitors include low toxicity and being able to reduce tumor mass efficiently. Normally, these checkpoints prevent the immune responses from being too strong and this impact T cells’ ability to kill cancer cells. Importantly, the identification of biomarkers can lead to the grouping of patients that can benefit from specific drugs and therapies.

30New therapies also include the prevention of new blood vessel formation. Tumorigenesis is a process that depends on the constant supply of oxygen and nutrients to growing tumor cells. Furthermore, metabolic waste must be removed, without which the microenvironment becomes toxic even for tumor cells. Thus, the prevention of angiogenesis through the use of anti-angiogenic drugs including those neutralizing growth factors such as VEGF, decoy receptors for growth factors is an appealing strategy under intense investigation. Small molecule inhibitors of several factors released within the TME including AMD3465 can prevent stromal cell-derived factors from being pro-tumorigenic. Antagonists of integrins can prevent cell-cell and cell-ECM interactions within the TME, increasing cancer cell response to drugs in the process. ECM proteins play key roles in cancer cell migration, invasion and survival and thus blocking ECM protein interactions with their major surface receptor, integrins, can influence drug efficacy and tumor progression. For example, the combination of celengitide, an integrin antagonist, and temozolomide, resulted in improved antitumor activity against malignant melanoma. The inactivation of HIF-1α has been shown to enhance the effect of carboplatin on tumor cell proliferation and thus can be used as a hypoxia-centered therapy. Tumor acidification has been identified to be a major characteristic of tumor progression as well as a regulator of tumor response to drugs. The acidification of the TME by hypoxia also reduces some drug effectiveness as this depends on the surrounding pH. The pH of the TME also regulates cellular metabolic rates and can influence tumor cell metastatic abilities. An adjustment of TME pH can therefore be used to enhance or decrease the efficacy of drugs. Drugs that can be activated in the hypoxic regions of tumors have been suggested. These hypoxic pro-drugs can be activated into cytotoxic drugs by enzymes found within the hypoxic regions of tumors. For example, TH-302 is a hypoxic pro-drug utilized together with gemcitabine in the treatment of pancreatic cancer, which is highly hypoxic with oxygen levels averaging around 0.7%. Various signaling cascades important in hypoxia including the unfolded protein response are appealing targets to treat solid tumors characterized by hypoxia. Other strategies to avoid hypoxia-induced changes to drug effectiveness make use of nanoparticles to deliver drugs directly to tumor cells. Other strategies to inhibit hypoxia-mediated HIF response if to use small-interfering RNA. Detailed reviews on TME-centered therapies has already been published elsewhere.

31As expected, therapy resistance is a major problem when these strategies are used. Combination therapy involving the use of two or more anti-tumor strategies results in better responses. More research is needed, including evaluating the efficiency of these strategies before these strategies are commonplace in clinics.

9. Conclusions

32The treatment of cancer, ranging from the use of surgery, chemotherapy, radiotherapy, and recently introduced immunotherapy, have all had limited success when used alone. In most cases, combination therapy is the best strategy to use for successful treatment. However, therapy resistance develops as tumor cells are heterogenous and plastic in nature, and tumor cells can convert a non-supporting ‘anti-tumorigenic’ environment into a ‘pro-tumorigenic’ environment. The contribution of the tumor microenvironment to tumorigenesis, metastasis, and the development of therapy resistance, is of note. Thus, it is important to delineate the role played by various TME components in tumorigenesis, metastasis, and therapy development. This review discusses the identification of predictive, prognostic biomarkers via the analysis of TME components and how this reveals the complexity of tumor biology, as well as lead to the development of targeted therapies for specific cancers and patients. Importantly, the recruitment of non-tumorigenic cells and non-cellular components by tumor cells for their benefit, allows tumorigenesis to proceed without hindrances. Stromal cells and immune cells are reprogrammed by tumor cells to release various factors that favor tumor cell growth and survival. The hypoxic microenvironment has been noted to play key roles in tumorigenesis and drug resistance. Understanding the processes involved in regulating hypoxia can lead to new therapeutic targets. In this regard, exosomes have been identified as useful as diagnostic and therapeutic tools by revealing tumor-derived secretome and can deliver drugs to tumor cells, respectively. Currently, combination therapy targeting various components of the TME can lead to the best results during treatment.

References 306

1.
Hanahan D., Weinberg R.A. Hallmarks of cancer: The next generation. Cell. 2011;144:646-674.
Not in our library10.1016/j.cell.2011.02.013
2.
Fouad Y.A., Aanei C. Revisiting the hallmarks of cancer. Am. J. Cancer Res. 2017;7:1016.
Not in our library
3.
Dzobo K. Taking a Full Snapshot of Cancer Biology: Deciphering the Tumor Microenvironment for Effective Cancer Therapy in the Oncology Clinic. Omics. 2020;24:175-179.
Not in our library10.1089/omi.2020.0019
4.
Erin N., Grahovac J., Brozovic A., Efferth T. Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance. Drug Resist. Updates. 2020;53:100715.
Not in our library10.1016/j.drup.2020.100715
5.
Senthebane D.A., Jonker T., Rowe A., Thomford N.E., Munro D., Dandara C., Wonkam A., Govender D., Calder B., Soares N.C., et al. The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices. Int. J. Mol. Sci. 2018;19:2861.
Not in our library10.3390/ijms19102861
6.
The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer · 2017
No notice
7.
Tumor Microenvironment · 2019
No notice
8.
Hinshaw D.C., Shevde L.A. The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Res. 2019;79:4557-4566.
Not in our library10.1158/0008-5472.can-18-3962
9.
Hui L., Chen Y. Tumor microenvironment: Sanctuary of the devil. Cancer Lett. 2015;368:7-13.
Not in our library10.1016/j.canlet.2015.07.039
10.
Tumor Microenvironment as A “Game Changer” in Cancer Radiotherapy · 2019
No notice
11.
Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment · 2016
No notice
12.
Soysal S.D., Tzankov A., Muenst S.E. Role of the Tumor Microenvironment in Breast Cancer. Pathobiology. 2015;82:142-152.
Not in our library10.1159/000430499
13.
Vitale I., Manic G., Coussens L.M., Kroemer G., Galluzzi L. Macrophages and Metabolism in the Tumor Microenvironment. Cell Metab. 2019;30:36-50.
Not in our library10.1016/j.cmet.2019.06.001
14.
Wu T., Dai Y. Tumor microenvironment and therapeutic response. Cancer Lett. 2017;387:61-68.
Not in our library10.1016/j.canlet.2016.01.043
15.
Dzobo K. Integrins Within the Tumor Microenvironment: Biological Functions, Importance for Molecular Targeting, and Cancer Therapeutics Innovation. Omics. 2021;25:417-430.
Not in our library10.1089/omi.2021.0069
16.
Dzobo K., Dandara C. Broadening Drug Design and Targets to Tumor Microenvironment? Cancer-Associated Fibroblast Marker Expression in Cancers and Relevance for Survival Outcomes. Omics A J. Integr. Biol. 2020;24:340-351.
Not in our library10.1089/omi.2020.0042
17.
Dzobo K., Dandara C. Architecture of Cancer-Associated Fibroblasts in Tumor Microenvironment: Mapping Their Origins, Heterogeneity, and Role in Cancer Therapy Resistance. Omics. 2020;24:314-339.
Not in our library10.1089/omi.2020.0023
18.
Dzobo K., Senthebane D.A., Ganz C., Thomford N.E., Wonkam A., Dandara C. Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review. Cells. 2020;9:1896.
Not in our library10.3390/cells9081896
19.
Tumor-associated stromal cells as key contributors to the tumor microenvironment · 2016
No notice
20.
Denton A.E., Roberts E.W., Fearon D.T. Stromal Cells in the Tumor Microenvironment. Adv. Exp. Med. Biol. 2018;1060:99-114.
Not in our library10.1007/978-3-319-78127-3_6
21.
Zhao L., Liu W., Xiao J., Cao B. The role of exosomes and “exosomal shuttle microRNA” in tumorigenesis and drug resistance. Cancer Lett. 2015;356:339-346.
Not in our library10.1016/j.canlet.2014.10.027
22.
Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4 · 2017
No notice
23.
Cancer-Associated Fibroblasts as Another Polarized Cell Type of the Tumor Microenvironment · 2014
No notice
24.
Orimo A., Gupta P.B., Sgroi D.C., Arenzana-Seisdedos F., Delaunay T., Naeem R., Carey V.J., Richardson A.L., Weinberg R.A. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121:335-348.
Not in our library10.1016/j.cell.2005.02.034
25.
Olumi A.F., Grossfeld G.D., Hayward S.W., Carroll P.R., Tlsty T.D., Cunha G.R. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999;59:5002-5011.
Not in our library10.1186/bcr138
26.
Busch S., Acar A., Magnusson Y., Gregersson P., Rydén L., Landberg G. TGF-beta receptor type-2 expression in cancer-associated fibroblasts regulates breast cancer cell growth and survival and is a prognostic marker in pre-menopausal breast cancer. Oncogene. 2015;34:27-38.
Not in our library10.1038/onc.2013.527
27.
Tanaka K., Miyata H., Sugimura K., Fukuda S., Kanemura T., Yamashita K., Miyazaki Y., Takahashi T., Kurokawa Y., Yamasaki M., et al. miR-27 is associated with chemoresistance in esophageal cancer through transformation of normal fibroblasts to cancer-associated fibroblasts. Carcinogenesis. 2015;36:894-903.
Not in our library10.1093/carcin/bgv067
28.
Min A., Zhu C., Peng S., Shuai C., Sun L., Han Y., Qian Y., Gao S., Su T. Downregulation of Microrna-148a in Cancer-Associated Fibroblasts from Oral Cancer Promotes Cancer Cell Migration and Invasion by Targeting Wnt10b. J. Biochem. Mol. Toxicol. 2016;30:186-191.
Not in our library10.1002/jbt.21777
29.
Wiseman B.S., Werb Z. Stromal effects on mammary gland development and breast cancer. Science. 2002;296:1046-1049.
Not in our library10.1126/science.1067431
30.
Xue X., Lu Z., Tang D., Yao J., An Y., Wu J., Li Q., Gao W., Xu Z., Qian Z., et al. Galectin-1 secreted by activated stellate cells in pancreatic ductal adenocarcinoma stroma promotes proliferation and invasion of pancreatic cancer cells: An in vitro study on the microenvironment of pancreatic ductal adenocarcinoma. Pancreas. 2011;40:832-839.
Not in our library10.1097/mpa.0b013e318217945e
31.
Sun D.-Y., Wu J.-Q., He Z.-H., He M.-F., Sun H.-B. Cancer-associated fibroblast regulate proliferation and migration of prostate cancer cells through TGF-β signaling pathway. Life Sci. 2019;235:116791.
Not in our library10.1016/j.lfs.2019.116791
32.
Maluccio M., Sharma V., Lagman M., Vyas S., Yang H., Li B., Suthanthiran M. Tacrolimus enhances transforming growth factor-β1 expression and promotes tumor progression. Transplantation. 2003;76:597-602.
Not in our library10.1097/01.tp.0000081399.75231.3b
33.
Moses H., Barcellos-Hoff M.H. TGF-β biology in mammary development and breast cancer. Cold Spring Harb. Perspect. Biol. 2011;3:a003277.
Not in our library10.1101/cshperspect.a003277
34.
Cancer-associated fibroblasts enhance metastatic potential of lung cancer cells through IL-6/STAT3 signaling pathway · 2017
No notice
35.
Yu Y., Xiao C., Tan L., Wang Q., Li X., Feng Y. Cancer-associated fibroblasts induce epithelial–mesenchymal transition of breast cancer cells through paracrine TGF-β signalling. Br. J. Cancer. 2014;110:724-732.
Not in our library10.1038/bjc.2013.768
36.
TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis · 2019
No notice
37.
Tgf-β1 expression as a biomarker of poor prognosis in prostate cancer · 2011
Not checked
38.
Robson H., Anderson E., James R.D., Schofield P.F. Transforming growth factor β 1 expression in human colorectal tumours: An independent prognostic marker in a subgroup of poor prognosis patients. Br. J. Cancer. 1996;74:753-758.
Not in our library10.1038/bjc.1996.432
39.
Huang C.Y., Wang H., Liao W., Han F., Li Y.Q., Chen S.W., Lao X.M. Transforming growth factor β is a poor prognostic factor and inhibits the favorable prognostic value of CD8+ CTL in human hepatocellular carcinoma. J. Immunother. 2017;40:175-186.
Not in our library10.1097/cji.0000000000000166
40.
Desmouliere A., Guyot C., Gabbiani G. The stroma reaction myofibroblast: A key player in the control of tumor cell behavior. Int. J. Dev. Biol. 2004;48:509-517.
Not in our library10.1387/ijdb.041802ad
41.
Huang J., Li Z., Ding Z., Luo Q., Lu S. Different roles of myofibroblasts in the tumorigenesis of nonsmall cell lung cancer. Tumor Biol. 2016;37:15525-15534.
Not in our library10.1007/s13277-015-3862-8
42.
Shi J., Feng J., Xie J., Mei Z., Shi T., Wang S., Du Y., Yang G., Wu Y., Cheng X., et al. Targeted blockade of TGF-β and IL-6/JAK2/STAT3 pathways inhibits lung cancer growth promoted by bone marrow-derived myofibroblasts. Sci. Rep. 2017;7:8660.
Not in our library10.1038/s41598-017-09020-8
43.
Yamamoto T., Matsuda T., Muraguchi A., Miyazono K., Kawabata M. Cross-talk between IL-6 and TGF-β signaling in hepatoma cells. FEBS Lett. 2001;492:247-253.
Not in our library10.1016/s0014-5793(01)02258-x
44.
O’Reilly S., Ciechomska M., Cant R., van Laar J.M. Interleukin-6 (IL-6) Trans Signaling Drives a STAT3-dependent Pathway That Leads to Hyperactive Transforming Growth Factor-β (TGF-β) Signaling Promoting SMAD3 Activation and Fibrosis via Gremlin Protein. J. Biol. Chem. 2014;289:9952-9960.
Not in our library10.1074/jbc.m113.545822
45.
Verbeke H., Struyf S., Laureys G., Van Damme J. The expression and role of CXC chemokines in colorectal cancer. Cytokine Growth Factor Rev. 2011;22:345-358.
Not in our library10.1016/j.cytogfr.2011.09.002
46.
Yang F., Zhang S., Meng Q., Zhou F., Pan B., Liu F., Yu Y. CXCR1 correlates to poor outcomes of EGFR-TKI against advanced non-small cell lung cancer by activating chemokine and JAK/STAT pathway. Pulm. Pharmacol. Ther. 2021;67:102001.
Not in our library10.1016/j.pupt.2021.102001
47.
Goto M., Liu M. Chemokines and their receptors as biomarkers in esophageal cancer. Esophagus. 2020;17:113-121.
Not in our library10.1007/s10388-019-00706-8
48.
Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers · 2020
No notice
49.
Cui N., Hu M., Khalil R.A. Biochemical and Biological Attributes of Matrix Metalloproteinases. Prog. Mol. Biol. Transl. Sci. 2017;147:1-73.
Not in our library10.1016/bs.pmbts.2017.02.005
50.
Matrix Metalloproteinase-9 (MMP-9) as a Cancer Biomarker and MMP-9 Biosensors: Recent Advances · 2018
No notice
51.
Karamanou K., Franchi M., Vynios D., Brézillon S. Epithelial-to-mesenchymal transition and invadopodia markers in breast cancer: Lumican a key regulator. Semin. Cancer Biol. 2020;62:125-133.
Not in our library10.1016/j.semcancer.2019.08.003
52.
Najafi M., Farhood B., Mortezaee K. Extracellular matrix (ECM) stiffness and degradation as cancer drivers. J. Cell. Biochem. 2019;120:2782-2790.
Not in our library10.1002/jcb.27681
53.
Role of Matrix Metalloproteinases in Photoaging and Photocarcinogenesis · 2016
No notice
54.
Yin C., Evason K.J., Asahina K., Stainier D.Y. Hepatic stellate cells in liver development, regeneration, and cancer. J. Clin. Investig. 2013;123:1902-1910.
Not in our library10.1172/jci66369
55.
Gomperts B.N., Strieter R.M. Fibrocytes in lung disease. J. Leukoc. Biol. 2007;82:449-456.
Not in our library10.1189/jlb.0906587
56.
Barth P.J., Ebrahimsade S., Ramaswamy A., Moll R. CD34+ fibrocytes in invasive ductal carcinoma, ductal carcinoma in situ, and benign breast lesions. Virchows Arch. 2002;440:298-303.
Not in our library10.1007/s004280100530
57.
Barth P.J., Ebrahimsade S., Hellinger A., Moll R., Ramaswamy A. CD34+ fibrocytes in neoplastic and inflammatory pancreatic lesions. Virchows Arch. 2002;440:128-133.
Not in our library10.1007/s00428-001-0551-3
58.
Iwano M., Plieth D., Danoff T.M., Xue C., Okada H., Neilson E.G. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Investig. 2002;110:341-350.
Not in our library10.1172/jci0215518
59.
Orimo A., Weinberg R.A. Stromal fibroblasts in cancer: A novel tumor-promoting cell type. Cell Cycle. 2006;5:1597-1601.
Not in our library10.4161/cc.5.15.3112
60.
Zeisberg E.M., Potenta S., Xie L., Zeisberg M., Kalluri R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 2007;67:10123-10128.
Not in our library10.1158/0008-5472.can-07-3127
61.
Jotzu C., Alt E., Welte G., Li J., Hennessy B.T., Devarajan E., Krishnappa S., Pinilla S., Droll L., Song Y.-H. Adipose tissue derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor derived factors. Cell. Oncol. 2011;34:55-67.
Not in our library10.1007/s13402-011-0012-1
62.
Gorchs L., Ahmed S., Mayer C., Knauf A., Fernández Moro C., Svensson M., Heuchel R., Rangelova E., Bergman P., Kaipe H. The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity. Sci. Rep. 2020;10:1-15.
Not in our library10.1038/s41598-020-74368-3
63.
Öhlund D., Elyada E., Tuveson D. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 2014;211:1503-1523.
Not in our library10.1084/jem.20140692
64.
Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer · 2017
No notice
65.
Huelsken J., Hanahan D. A subset of cancer-associated fibroblasts determines therapy resistance. Cell. 2018;172:643-644.
Not in our library10.1016/j.cell.2018.01.028
66.
Campbell I., Qiu W., Haviv I. Genetic changes in tumour microenvironments. J. Pathol. 2011;223:450-458.
Not in our library10.1002/path.2842
67.
Lim K.P., Cirillo N., Hassona Y., Wei W., Thurlow J.K., Cheong S.C., Pitiyage G., Parkinson E.K., Prime S.S. Fibroblast gene expression profile reflects the stage of tumour progression in oral squamous cell carcinoma. J. Pathol. 2011;223:459-469.
Not in our library10.1002/path.2841
68.
A framework for advancing our understanding of cancer-associated fibroblasts · 2020
No notice
69.
Strell C., Paulsson J., Jin S.B., Tobin N.P., Mezheyeuski A., Roswall P., Mutgan C., Mitsios N., Johansson H., Wickberg S.M., et al. Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ. J. Natl. Cancer Inst. 2019;111:983-995.
Not in our library10.1093/jnci/djy234
70.
Erez N., Truitt M., Olson P., Arron S.T., Hanahan D. Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-kappaB-Dependent Manner. Cancer Cell. 2010;17:135-147.
Not in our library10.1016/j.ccr.2009.12.041
71.
Kalluri R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer. 2016;16:582.
Not in our library10.1038/nrc.2016.73
72.
Ayala G., Tuxhorn J.A., Wheeler T.M., Frolov A., Scardino P.T., Ohori M., Wheeler M., Spitler J., Rowley D.R. Reactive stroma as a predictor of biochemical-free recurrence in prostate cancer. Clin. Cancer Res. 2003;9:4792-4801.
Not in our library
73.
Muchlińska A., Nagel A., Popęda M., Szade J., Niemira M., Zieliński J., Skokowski J., Bednarz-Knoll N., Żaczek A.J. Alpha-smooth muscle actin-positive cancer-associated fibroblasts secreting osteopontin promote growth of luminal breast cancer. Cell. Mol. Biol. Lett. 2022;27:1-14.
Not in our library10.1186/s11658-022-00351-7
74.
Sha M., Jeong S., Qiu B.j., Tong Y., Xia L., Xu N., Zhang J.j., Xia Q. Isolation of cancer-associated fibroblasts and its promotion to the progression of intrahepatic cholangiocarcinoma. Cancer Med. 2018;7:4665-4677.
Not in our library10.1002/cam4.1704
75.
Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages · 2016
No notice
76.
Ni W.-D., Yang Z.-T., Cui C.-A., Cui Y., Fang L.-Y., Xuan Y.-H. Tenascin-C is a potential cancer-associated fibroblasts marker and predicts poor prognosis in prostate cancer. Biochem. Biophys. Res. Commun. 2017;486:607-612.
Not in our library10.1016/j.bbrc.2017.03.021
77.
Yang Z., Ni W., Cui C., Fang L., Xuan Y. Tenascin C is a prognostic determinant and potential cancer-associated fibroblasts marker for breast ductal carcinoma. Exp. Mol. Pathol. 2017;102:262-267.
Not in our library10.1016/j.yexmp.2017.02.012
78.
Nishishita R., Morohashi S., Seino H., Wu Y., Yoshizawa T., Haga T., Saito K., Hakamada K., Fukuda S., Kijima H. Expression of cancer-associated fibroblast markers in advanced colorectal cancer. Oncol. Lett. 2018;15:6195-6202.
Not in our library10.3892/ol.2018.8097
79.
Ortiz-Otero N., Clinch A.B., Hope J., Wang W., Reinhart-King C.A., King M.R. Cancer associated fibroblasts confer shear resistance to circulating tumor cells during prostate cancer metastatic progression. Oncotarget. 2020;11:1037.
Not in our library10.18632/oncotarget.27510
80.
Su S., Chen J., Yao H., Liu J., Yu S., Lao L., Wang M., Luo M., Xing Y., Chen F., et al. CD10(+)GPR77(+) Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness. Cell. 2018;172:841-856.e16.
Not in our library10.1016/j.cell.2018.01.009
81.
Zhao X., He Y., Gao J., Fan L., Li Z., Yang G., Chen H. Caveolin-1 expression level in cancer associated fibroblasts predicts outcome in gastric cancer. PLoS ONE. 2013;8:e59102.
Not in our library10.1371/journal.pone.0059102
82.
Simpkins S.A., Hanby A.M., Holliday D.L., Speirs V. Clinical and functional significance of loss of caveolin-1 expression in breast cancer-associated fibroblasts. J. Pathol. 2012;227:490-498.
Not in our library10.1002/path.4034
83.
Musumeci M., Coppola V., Addario A., Patrizii M., Maugeri-Saccà M., Memeo L., Colarossi C., Francescangeli F., Biffoni M., Collura D., et al. Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer. Oncogene. 2011;30:4231-4242.
Not in our library10.1038/onc.2011.140
84.
Bronisz A., Godlewski J., Wallace J.A., Merchant A.S., Nowicki M.O., Mathsyaraja H., Srinivasan R., Trimboli A.J., Martin C.K., Li F., et al. Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nat. Cell Biol. 2011;14:159-167.
Not in our library10.1038/ncb2396
85.
Aprelikova O., Palla J., Hibler B., Yu X., Greer Y.E., Yi M., Stephens R., Maxwell G.L., Jazaeri A., Risinger J.I., et al. Silencing of miR-148a in cancer-associated fibroblasts results in WNT10B-mediated stimulation of tumor cell motility. Oncogene. 2013;32:3246-3253.
Not in our library10.1038/onc.2012.351
86.
Role of Exosomes in Crosstalk Between Cancer-Associated Fibroblasts and Cancer Cells · 2019
No notice
87.
Davies G., Cunnick G.H., Mansel R.E., Mason M.D., Jiang W.G. Levels of expression of endothelial markers specific to tumour-associated endothelial cells and their correlation with prognosis in patients with breast cancer. Clin. Exp. Metastasis. 2004;21:31-37.
Not in our library10.1023/b:clin.0000017168.83616.d0
88.
De Sanctis F., Ugel S., Facciponte J., Facciabene A. The dark side of tumor-associated endothelial cells. Proceedings of the Seminars in Immunology. 2018;35-47.
Not in our library10.1016/j.smim.2018.02.002
89.
Ronca R., Van Ginderachter J.A., Turtoi A. Paracrine interactions of cancer-associated fibroblasts, macrophages and endothelial cells: Tumor allies and foes. Curr. Opin. Oncol. 2018;30:45-53.
Not in our library10.1097/cco.0000000000000420
90.
Rankin E.á., Giaccia A. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 2008;15:678-685.
Not in our library10.1038/cdd.2008.21
91.
Jensen R.L. Hypoxia in the tumorigenesis of gliomas and as a potential target for therapeutic measures. Neurosurg. Focus. 2006;20:E24.
Not in our library10.3171/foc.2006.20.4.16
92.
Ye J., Koumenis C. ATF4, an ER stress and hypoxia-inducible transcription factor and its potential role in hypoxia tolerance and tumorigenesis. Curr. Mol. Med. 2009;9:411-416.
Not in our library10.2174/156652409788167096
93.
Jensen R.L. Brain tumor hypoxia: Tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target. J. Neuro-Oncol. 2009;92:317-335.
Not in our library10.1007/s11060-009-9827-2
94.
Bergers G., Benjamin L.E. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer. 2003;3:401-410.
Not in our library10.1038/nrc1093
95.
Yehya A.H.S., Asif M., Petersen S.H., Subramaniam A.V., Kono K., Majid A.M.S.A., Oon C.E. Angiogenesis: Managing the culprits behind tumorigenesis and metastasis. Medicina. 2018;54:8.
Not in our library10.3390/medicina54010008
96.
Kovacic J.C., Mercader N., Torres M., Boehm M., Fuster V. Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: From cardiovascular development to disease. Circulation. 2012;125:1795-1808.
Not in our library10.1161/circulationaha.111.040352
97.
The role of endothelial-to-mesenchymal transition in cancer progression · 2008
No notice
98.
Wesseling M., Sakkers T., De Jager S., Pasterkamp G., Goumans M. The morphological and molecular mechanisms of epithelial/endothelial-to-mesenchymal transition and its involvement in atherosclerosis. Vasc. Pharmacol. 2018;106:1-8.
Not in our library10.1016/j.vph.2018.02.006
99.
Motz G.T., Coukos G. The parallel lives of angiogenesis and immunosuppression: Cancer and other tales. Nat. Rev. Immunol. 2011;11:702-711.
Not in our library10.1038/nri3064
100.
Frumento G., Piazza T., Di Carlo E., Ferrini S. Targeting tumor-related immunosuppression for cancer immunotherapy. Endocr. Metab. Immune Disord.-Drug Targets Former. Curr. Drug Targets-Immune Endocr. Metab. Disord. 2006;6:223-237.
Not in our library10.2174/187153006778250019
101.
Virrey J.J., Guan S., Li W., Schönthal A.H., Chen T.C., Hofman F.M. Increased survivin expression confers chemoresistance to tumor-associated endothelial cells. Am. J. Pathol. 2008;173:575-585.
Not in our library10.2353/ajpath.2008.071079
102.
Xiong Y.-Q., Sun H.-C., Zhang W., Zhu X.-D., Zhuang P.-Y., Zhang J.-B., Wang L., Wu W.-z., Qin L.-X., Tang Z.-Y. Human Hepatocellular Carcinoma Tumor–derived Endothelial Cells Manifest Increased Angiogenesis Capability and Drug Resistance Compared with Normal Endothelial CellsTEC Cells Increase Drug Resistance. Clin. Cancer Res. 2009;15:4838-4846.
Not in our library10.1158/1078-0432.ccr-08-2780
103.
Matsuda K., Ohga N., Hida Y., Muraki C., Tsuchiya K., Kurosu T., Akino T., Shih S.-C., Totsuka Y., Klagsbrun M. Isolated tumor endothelial cells maintain specific character during long-term culture. Biochem. Biophys. Res. Commun. 2010;394:947-954.
Not in our library10.1016/j.bbrc.2010.03.089
104.
Galdiero M.R., Bonavita E., Barajon I., Garlanda C., Mantovani A., Jaillon S. Tumor associated macrophages and neutrophils in cancer. Immunobiology. 2013;218:1402-1410.
Not in our library10.1016/j.imbio.2013.06.003
105.
Solinas G., Germano G., Mantovani A., Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J. Leukoc. Biol. 2009;86:1065-1073.
Not in our library10.1189/jlb.0609385
106.
Chen J.J., Lin Y.-C., Yao P.-L., Yuan A., Chen H.-Y., Shun C.-T., Tsai M.-F., Chen C.-H., Yang P.-C. Tumor-associated macrophages: The double-edged sword in cancer progression. J. Clin. Oncol. 2005;23:953-964.
Not in our library10.1200/jco.2005.12.172
107.
Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice · 2020
No notice
108.
Hu W., Li X., Zhang C., Yang Y., Jiang J., Wu C. Tumor-associated macrophages in cancers. Clin. Transl. Oncol. 2016;18:251-258.
Not in our library10.1007/s12094-015-1373-0
109.
Almatroodi S.A., McDonald C.F., Darby I.A., Pouniotis D.S. Characterization of M1/M2 tumour-associated macrophages (TAMs) and Th1/Th2 cytokine profiles in patients with NSCLC. Cancer Microenviron. 2016;9:1-11.
Not in our library10.1007/s12307-015-0174-x
110.
Identification and manipulation of tumor associated macrophages in human cancers · 2011
No notice
111.
Paulus P., Stanley E.R., Schäfer R., Abraham D., Aharinejad S. Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts. Cancer Res. 2006;66:4349-4356.
Not in our library10.1158/0008-5472.can-05-3523
112.
DeNardo D.G., Brennan D.J., Rexhepaj E., Ruffell B., Shiao S.L., Madden S.F., Gallagher W.M., Wadhwani N., Keil S.D., Junaid S.A. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011;1:54-67.
Not in our library10.1158/2159-8274.cd-10-0028
113.
Dijkgraaf E.M., Heusinkveld M., Tummers B., Vogelpoel L.T., Goedemans R., Jha V., Nortier J.W., Welters M.J., Kroep J.R., van der Burg S.H. Chemotherapy Alters Monocyte Differentiation to Favor Generation of Cancer-Supporting M2 Macrophages in the Tumor MicroenvironmentEffect of Chemotherapy on Tumor Microenvironment. Cancer Res. 2013;73:2480-2492.
Not in our library10.1158/0008-5472.can-12-3542
114.
Mantovani A., Allavena P. The interaction of anticancer therapies with tumor-associated macrophages. J. Exp. Med. 2015;212:435-445.
Not in our library10.1084/jem.20150295
115.
Jinushi M., Komohara Y. Tumor-associated macrophages as an emerging target against tumors: Creating a new path from bench to bedside. Biochim. Biophys. Acta (BBA)-Rev. Cancer. 2015;1855:123-130.
Not in our library10.1016/j.bbcan.2015.01.002
116.
Weizman N., Krelin Y., Shabtay-Orbach A., Amit M., Binenbaum Y., Wong R., Gil Z. Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene. 2014;33:3812-3819.
Not in our library10.1038/onc.2013.357
117.
Shaul M.E., Fridlender Z.G. Tumour-associated neutrophils in patients with cancer. Nat. Rev. Clin. Oncol. 2019;16:601-620.
Not in our library10.1038/s41571-019-0222-4
118.
Coffelt S.B., Wellenstein M.D., de Visser K.E. Neutrophils in cancer: Neutral no more. Nat. Rev. Cancer. 2016;16:431-446.
Not in our library10.1038/nrc.2016.52
119.
Tumor-Associated Neutrophils in Cancer: Going Pro · 2019
No notice
120.
Gregory A.D., McGarry Houghton A. Tumor-associated neutrophils: New targets for cancer therapy. Cancer Res. 2011;71:2411-2416.
Not in our library10.1158/0008-5472.can-10-2583
121.
Tumor Associated Neutrophils. Their Role in Tumorigenesis, Metastasis, Prognosis and Therapy · 2019
No notice
122.
Tolle F., Umansky V., Utikal J., Kreis S., Bréchard S. Neutrophils in Tumorigenesis: Missing Targets for Successful Next Generation Cancer Therapies? Int. J. Mol. Sci. 2021;22:6744.
Not in our library10.3390/ijms22136744
123.
Houghton A.M. The paradox of tumor-associated neutrophils: Fueling tumor growth with cytotoxic substances. Cell Cycle. 2010;9:1732-1737.
Not in our library10.4161/cc.9.9.11297
124.
Jabłońska-Trypuć A., Matejczyk M., Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J. Enzym. Inhib. Med. Chem. 2016;31:177-183.
Not in our library10.3109/14756366.2016.1161620
125.
Bui T.M., Yalom L.K., Sumagin R. Tumor-associated neutrophils: Orchestrating cancer pathobiology and therapeutic resistance. Expert Opin. Ther. Targets. 2021;25:573-583.
Not in our library10.1080/14728222.2021.1954162
126.
Maimela N.R., Liu S., Zhang Y. Fates of CD8+ T cells in tumor microenvironment. Comput. Struct. Biotechnol. J. 2019;17:1-13.
Not in our library10.1016/j.csbj.2018.11.004
127.
Vlachonikola E., Stamatopoulos K., Chatzidimitriou A. T cells in chronic lymphocytic leukemia: A two-edged sword. Front. Immunol. 2021;11:612244.
Not in our library10.3389/fimmu.2020.612244
128.
Andersen M.H., Schrama D., thor Straten P., Becker J.C. Cytotoxic T cells. J. Investig. Dermatol. 2006;126:32-41.
Not in our library10.1038/sj.jid.5700001
129.
Finlay D., Cantrell D.A. Metabolism, migration and memory in cytotoxic T cells. Nat. Rev. Immunol. 2011;11:109-117.
Not in our library10.1038/nri2888
130.
Lindau D., Gielen P., Kroesen M., Wesseling P., Adema G.J. The immunosuppressive tumour network: Myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology. 2013;138:105-115.
Not in our library10.1111/imm.12036
131.
Navasardyan I., Bonavida B. Regulation of T Cells in Cancer by Nitric Oxide. Cells. 2021;10:2655.
Not in our library10.3390/cells10102655
132.
Clinical Relevance of CD4 Cytotoxic T Cells in High-Risk Neuroblastoma · 2021
Not checked
133.
Immune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment · 2020
No notice
134.
Dees S., Ganesan R., Singh S., Grewal I.S. Regulatory T cell targeting in cancer: Emerging strategies in immunotherapy. Eur. J. Immunol. 2021;51:280-291.
Not in our library10.1002/eji.202048992
135.
Elkord E., Sasidharan Nair V. T-Regulatory Cells in Health and Disease. J. Immunol. Res. 2018;2018:5025238.
Not in our library10.1155/2018/5025238
136.
Sasidharan Nair V., Saleh R., Toor S.M., Cyprian F.S., Elkord E. Metabolic reprogramming of T regulatory cells in the hypoxic tumor microenvironment. Cancer Immunol. Immunother. 2021;70:2103-2121.
Not in our library10.1007/s00262-020-02842-y
137.
Wang H., Zhang H., Wang Y., Brown Z.J., Xia Y., Huang Z., Shen C., Hu Z., Beane J., Ansa-Addo E.A., et al. Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis. J. Hepatol. 2021;75:1271-1283.
Not in our library10.1016/j.jhep.2021.07.032
138.
Kordasti S.Y., Ingram W., Hayden J., Darling D., Barber L., Afzali B., Lombardi G., Wlodarski M.W., Maciejewski J.P., Farzaneh F., et al. CD4+CD25high Foxp3+ regulatory T cells in myelodysplastic syndrome (MDS). Blood. 2007;110:847-850.
Not in our library10.1182/blood-2007-01-067546
139.
Lim K.P., Chun N.A., Ismail S.M., Abraham M.T., Yusoff M.N., Zain R.B., Ngeow W.C., Ponniah S., Cheong S.C. CD4+CD25hiCD127low regulatory T cells are increased in oral squamous cell carcinoma patients. PLoS ONE. 2014;9:e103975.
Not in our library10.1371/journal.pone.0103975
140.
Mitchell D.A., Cui X., Schmittling R.J., Sanchez-Perez L., Snyder D.J., Congdon K.L., Archer G.E., Desjardins A., Friedman A.H., Friedman H.S., et al. Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans. Blood. 2011;118:3003-3012.
Not in our library10.1182/blood-2011-02-334565
141.
Chen V.E., Greenberger B.A., Taylor J.M., Edelman M.J., Lu B. The Underappreciated Role of the Humoral Immune System and B Cells in Tumorigenesis and Cancer Therapeutics: A Review. Int. J. Radiat. Oncol. Biol. Phys. 2020;108:38-45.
Not in our library10.1016/j.ijrobp.2020.03.022
142.
Corsiero E., Delvecchio F.R., Bombardieri M., Pitzalis C. B cells in the formation of tertiary lymphoid organs in autoimmunity, transplantation and tumorigenesis. Curr. Opin. Immunol. 2019;57:46-52.
Not in our library10.1016/j.coi.2019.01.004
143.
Mintz M.A., Cyster J.G. T follicular helper cells in germinal center B cell selection and lymphomagenesis. Immunol. Rev. 2020;296:48-61.
Not in our library10.1111/imr.12860
144.
Roghanian A., Fraser C., Kleyman M., Chen J. B Cells Promote Pancreatic Tumorigenesis. Cancer Discov. 2016;6:230-232.
Not in our library10.1158/2159-8290.cd-16-0100
145.
Bruno T.C., Ebner P.J., Moore B.L., Squalls O.G., Waugh K.A., Eruslanov E.B., Singhal S., Mitchell J.D., Franklin W.A., Merrick D.T., et al. Antigen-Presenting Intratumoral B Cells Affect CD4(+) TIL Phenotypes in Non-Small Cell Lung Cancer Patients. Cancer Immunol. Res. 2017;5:898-907.
Not in our library10.1158/2326-6066.cir-17-0075
146.
Chen X., Jensen P.E. The role of B lymphocytes as antigen-presenting cells. Arch. Immunol. Ther. Exp. 2008;56:77-83.
Not in our library10.1007/s00005-008-0014-5
147.
Ghosh D., Jiang W., Mukhopadhyay D., Mellins E.D. New insights into B cells as antigen presenting cells. Curr. Opin. Immunol. 2021;70:129-137.
Not in our library10.1016/j.coi.2021.06.003
148.
Role of B cells as antigen presenting cells · 2022
No notice
149.
Edechi C.A., Ikeogu N., Uzonna J.E., Myal Y. Regulation of Immunity in Breast Cancer. Cancers. 2019;11:1080.
Not in our library10.3390/cancers11081080
150.
Gupta S.L., Khan N., Basu S., Soni V. B-Cell-Based Immunotherapy: A Promising New Alternative. Vaccines. 2022;10:879.
Not in our library10.3390/vaccines10060879
151.
Kuroda H., Jamiyan T., Yamaguchi R., Kakumoto A., Abe A., Harada O., Masunaga A. Tumor microenvironment in triple-negative breast cancer: The correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes. Clin. Transl. Oncol. 2021;23:2513-2525.
Not in our library10.1007/s12094-021-02652-3
152.
Immunosuppressive Mechanisms of Regulatory B Cells · 2021
No notice
153.
Rosser E.C., Mauri C. Regulatory B cells: Origin, phenotype, and function. Immunity. 2015;42:607-612.
Not in our library10.1016/j.immuni.2015.04.005
154.
Wang L., Fu Y., Chu Y. Regulatory B Cells. Adv. Exp. Med. Biol. 2020;1254:87-103.
Not in our library10.1007/978-981-15-3532-1_8
155.
Barry K.C., Hsu J., Broz M.L., Cueto F.J., Binnewies M., Combes A.J., Nelson A.E., Loo K., Kumar R., Rosenblum M.D., et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat. Med. 2018;24:1178-1191.
Not in our library10.1038/s41591-018-0085-8
156.
NK Cell Metabolism and Tumor Microenvironment · 2019
No notice
157.
Chan I.S., Knútsdóttir H., Ramakrishnan G., Padmanaban V., Warrier M., Ramirez J.C., Dunworth M., Zhang H., Jaffee E.M., Bader J.S., et al. Cancer cells educate natural killer cells to a metastasis-promoting cell state. J. Cell Biol. 2020;219:e202001134.
Not in our library10.1083/jcb.202001134
158.
Guillerey C., Huntington N.D., Smyth M.J. Targeting natural killer cells in cancer immunotherapy. Nat. Immunol. 2016;17:1025-1036.
Not in our library10.1038/ni.3518
159.
López-Soto A., Gonzalez S., Smyth M.J., Galluzzi L. Control of Metastasis by NK Cells. Cancer Cell. 2017;32:135-154.
Not in our library10.1016/j.ccell.2017.06.009
160.
Vivier E., Ugolini S., Blaise D., Chabannon C., Brossay L. Targeting natural killer cells and natural killer T cells in cancer. Nat. Rev. Immunol. 2012;12:239-252.
Not in our library10.1038/nri3174
161.
Vivier E., Tomasello E., Baratin M., Walzer T., Ugolini S. Functions of natural killer cells. Nat. Immunol. 2008;9:503-510.
Not in our library10.1038/ni1582
162.
Marcus A., Gowen B.G., Thompson T.W., Iannello A., Ardolino M., Deng W., Wang L., Shifrin N., Raulet D.H. Recognition of tumors by the innate immune system and natural killer cells. Adv. Immunol. 2014;122:91-128.
Not in our library10.1016/b978-0-12-800267-4.00003-1
163.
Birbrair A., Zhang T., Wang Z.-M., Messi M.L., Olson J.D., Mintz A., Delbono O. Type-2 pericytes participate in normal and tumoral angiogenesis. Am. J. Physiol.-Cell Physiol. 2014;307:C25-C38.
Not in our library10.1152/ajpcell.00084.2014
164.
Iannello A., Thompson T.W., Ardolino M., Marcus A., Raulet D.H. Immunosurveillance and immunotherapy of tumors by innate immune cells. Curr. Opin. Immunol. 2016;38:52-58.
Not in our library10.1016/j.coi.2015.11.001
165.
Chong A.S.-F., Markham P.N., Gebel H.M., Bines S.D., Coon J.S. Diverse multidrug-resistance-modification agents inhibit cytolytic activity of natural killer cells. Cancer Immunol. Immunother. 1993;36:133-139.
Not in our library10.1007/bf01754414
166.
Savas B., Cole S., Akoglu T., Pross H. P-glycoprotein-mediated multidrug resistance and cytotoxic effector cells. Nat Immun. 1992;11:177-192.
Not in our library
167.
Takahashi M., Misawa Y., Watanabe N., Kawanishi T., Tanaka H., Shigenobu K., Kobayashi Y. Role of P-glycoprotein in human natural killer-like cell line-mediated cytotoxicity. Exp. Cell Res. 1999;253:396-402.
Not in our library10.1006/excr.1999.4696
168.
Gajewski T.F., Schreiber H., Fu Y.X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 2013;14:1014-1022.
Not in our library10.1038/ni.2703
169.
Gardner A., Ruffell B. Dendritic Cells and Cancer Immunity. Trends Immunol. 2016;37:855-865.
Not in our library10.1016/j.it.2016.09.006
170.
Lee Y.S., Radford K.J. The role of dendritic cells in cancer. Int. Rev. Cell Mol. Biol. 2019;348:123-178.
Not in our library10.1016/bs.ircmb.2019.07.006
171.
Volovitz I., Melzer S., Amar S., Bocsi J., Bloch M., Efroni S., Ram Z., Tárnok A. Dendritic Cells in the Context of Human Tumors: Biology and Experimental Tools. Int. Rev. Immunol. 2016;35:116-135.
Not in our library10.3109/08830185.2015.1096935
172.
Zhou B., Lawrence T., Liang Y. The Role of Plasmacytoid Dendritic Cells in Cancers. Front. Immunol. 2021;12:749190.
Not in our library10.3389/fimmu.2021.749190
173.
Aspord C., Pedroza-Gonzalez A., Gallegos M., Tindle S., Burton E.C., Su D., Marches F., Banchereau J., Palucka A.K. Breast cancer instructs dendritic cells to prime interleukin 13–secreting CD4+ T cells that facilitate tumor development. J. Exp. Med. 2007;204:1037-1047.
Not in our library10.1084/jem.20061120
174.
Vicari A.P., Caux C., Trinchieri G. Tumour escape from immune surveillance through dendritic cell inactivation. Proceedings of the Seminars in Cancer Biology. 2002;33-42.
Not in our library10.1006/scbi.2001.0400
175.
Hepatic Stellate Cells and Hepatocarcinogenesis · 2020
No notice
176.
The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives · 2021
Not checked
177.
Zhao S., Mi Y., Zheng B., Wei P., Gu Y., Zhang Z., Xu Y., Cai S., Li X., Li D. Highly-metastatic colorectal cancer cell released miR-181a-5p-rich extracellular vesicles promote liver metastasis by activating hepatic stellate cells and remodelling the tumour microenvironment. J. Extracell. Vesicles. 2022;11:e12186.
Not in our library10.1002/jev2.12186
178.
The Role of Fibrosis and Liver-Associated Fibroblasts in the Pathogenesis of Hepatocellular Carcinoma · 2019
No notice
179.
Elechalawar C.K., Hossen M.N., Shankarappa P., Peer C.J., Figg W.D., Robertson J.D., Bhattacharya R., Mukherjee P. Targeting Pancreatic Cancer Cells and Stellate Cells Using Designer Nanotherapeutics In Vitro. Int. J. Nanomed. 2020;15:991-1003.
Not in our library10.2147/ijn.s234112
180.
Tan H.X., Gong W.Z., Zhou K., Xiao Z.G., Hou F.T., Huang T., Zhang L., Dong H.Y., Zhang W.L., Liu Y., et al. CXCR4/TGF-β1 mediated hepatic stellate cells differentiation into carcinoma-associated fibroblasts and promoted liver metastasis of colon cancer. Cancer Biol. Ther. 2020;21:258-268.
Not in our library10.1080/15384047.2019.1685157
181.
Lua I., Li Y., Zagory J.A., Wang K.S., French S.W., Sévigny J., Asahina K. Characterization of hepatic stellate cells, portal fibroblasts, and mesothelial cells in normal and fibrotic livers. J. Hepatol. 2016;64:1137-1146.
Not in our library10.1016/j.jhep.2016.01.010
182.
Senoo H., Mezaki Y., Fujiwara M. The stellate cell system (vitamin A-storing cell system). Anat. Sci. Int. 2017;92:387-455.
Not in our library10.1007/s12565-017-0395-9
183.
Senoo H., Yoshikawa K., Morii M., Miura M., Imai K., Mezaki Y. Hepatic stellate cell (vitamin A-storing cell) and its relative--past, present and future. Cell Biol. Int. 2010;34:1247-1272.
Not in our library10.1042/cbi20100321
184.
Ferdek P.E., Jakubowska M.A. Biology of pancreatic stellate cells—More than just pancreatic cancer. Pflügers Arch.-Eur. J. Physiol. 2017;469:1039-1050.
Not in our library10.1007/s00424-017-1968-0
185.
Microfluidic co-culture of pancreatic tumor spheroids with stellate cells as a novel 3D model for investigation of stroma-mediated cell motility and drug resistance · 2018
No notice
186.
Dalin S., Sullivan M.R., Lau A.N., Grauman-Boss B., Mueller H.S., Kreidl E., Fenoglio S., Luengo A., Lees J.A., Vander Heiden M.G. Deoxycytidine Release from Pancreatic Stellate Cells Promotes Gemcitabine ResistanceDeoxycytidine from Stellate Cells Confers Drug Resistance. Cancer Res. 2019;79:5723-5733.
Not in our library10.1158/0008-5472.can-19-0960
187.
Habisch H., Zhou S., Siech M., Bachem M.G. Interaction of stellate cells with pancreatic carcinoma cells. Cancers. 2010;2:1661-1682.
Not in our library10.3390/cancers2031661
188.
Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer · 2017
No notice
189.
Nieman K.M., Romero I.L., Van Houten B., Lengyel E. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim. Biophys. Acta (BBA)-Mol. Cell Biol. Lipids. 2013;1831:1533-1541.
Not in our library10.1016/j.bbalip.2013.02.010
190.
Hefetz-Sela S., Scherer P.E. Adipocytes: Impact on tumor growth and potential sites for therapeutic intervention. Pharmacol. Ther. 2013;138:197-210.
Not in our library10.1016/j.pharmthera.2013.01.008
191.
Gao Y., Chen X., He Q., Gimple R.C., Liao Y., Wang L., Wu R., Xie Q., Rich J.N., Shen K. Adipocytes promote breast tumorigenesis through TAZ-dependent secretion of Resistin. Proc. Natl. Acad. Sci. USA. 2020;117:33295-33304.
Not in our library10.1073/pnas.2005950117
192.
Obesity as a Major Risk Factor for Cancer · 2013
No notice
193.
Ntikoudi E., Kiagia M., Boura P., Syrigos K. Hormones of adipose tissue and their biologic role in lung cancer. Cancer Treat. Rev. 2014;40:22-30.
Not in our library10.1016/j.ctrv.2013.06.005
194.
Wang Y.-Y., Lehuédé C., Laurent V., Dirat B., Dauvillier S., Bochet L., Le Gonidec S., Escourrou G., Valet P., Muller C. Adipose tissue and breast epithelial cells: A dangerous dynamic duo in breast cancer. Cancer Lett. 2012;324:142-151.
Not in our library10.1016/j.canlet.2012.05.019
195.
Camarda R., Williams J., Malkov S., Zimmerman L.J., Manning S., Aran D., Beardsley A., Van de Mark D., Chen Y., Berdan C.A. Tumor cell-adipocyte gap junctions activate lipolysis and are essential for breast tumorigenesis. bioRxiv. 2018;277939.
Not in our library10.1101/277939
196.
Strong A.L., Strong T.A., Rhodes L.V., Semon J.A., Zhang X., Shi Z., Zhang S., Gimble J.M., Burow M.E., Bunnell B.A. Obesity associated alterations in the biology of adipose stem cells mediate enhanced tumorigenesis by estrogen dependent pathways. Breast Cancer Res. 2013;15:1-15.
Not in our library10.1186/bcr3569
197.
El Atat O., Antonios D., Hilal G., Hokayem N., Abou-Ghoch J., Hashim H., Serhal R., Hebbo C., Moussa M., Alaaeddine N. An evaluation of the stemness, paracrine, and tumorigenic characteristics of highly expanded, minimally passaged adipose-derived stem cells. PLoS ONE. 2016;11:e0162332.
Not in our library10.1371/journal.pone.0162332
198.
MacIsaac Z.M., Shang H., Agrawal H., Yang N., Parker A., Katz A.J. Long-term in-vivo tumorigenic assessment of human culture-expanded adipose stromal/stem cells. Exp. Cell Res. 2012;318:416-423.
Not in our library10.1016/j.yexcr.2011.12.002
199.
Dzobo K. Recent trends in multipotent human mesenchymal stem/stromal cells: Learning from history and advancing clinical applications. OMICS A J. Integr. Biol. 2021;25:342-357.
Not in our library10.1089/omi.2021.0049
200.
Dzobo K., Turnley T., Wishart A., Rowe A., Kallmeyer K., Van Vollenstee F.A., Thomford N.E., Dandara C., Chopera D., Pepper M.S. Fibroblast-derived extracellular matrix induces chondrogenic differentiation in human adipose-derived mesenchymal stromal/stem cells in vitro. Int. J. Mol. Sci. 2016;17:1259.
Not in our library10.3390/ijms17081259
201.
Kass L., Erler J.T., Dembo M., Weaver V.M. Mammary epithelial cell: Influence of extracellular matrix composition and organization during development and tumorigenesis. Int. J. Biochem. Cell Biol. 2007;39:1987-1994.
Not in our library10.1016/j.biocel.2007.06.025
202.
Vieweg J., Su Z., Dahm P., Kusmartsev S. Reversal of tumor-mediated immunosuppression. Clin. Cancer Res. 2007;13:727s-732s.
Not in our library10.1158/1078-0432.ccr-06-1924
203.
Papait A., Stefani F.R., Cargnoni A., Magatti M., Parolini O., Silini A.R. The multifaceted roles of MSCs in the tumor microenvironment: Interactions with immune cells and exploitation for therapy. Front. Cell Dev. Biol. 2020;8:447.
Not in our library10.3389/fcell.2020.00447
204.
Baker S.G. The detached pericyte hypothesis: A novel explanation for many puzzling aspects of tumorigenesis. Org. J. Biol. Sci. 2018;2:25-42.
Not in our library
205.
Xian X., Håkansson J., Ståhlberg A., Lindblom P., Betsholtz C., Gerhardt H., Semb H. Pericytes limit tumor cell metastasis. J. Clin. Investig. 2006;116:642-651.
Not in our library10.1172/jci25705
206.
Greenberg J.I., Shields D.J., Barillas S.G., Acevedo L.M., Murphy E., Huang J., Scheppke L., Stockmann C., Johnson R.S., Angle N. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature. 2008;456:809-813.
Not in our library10.1038/nature07424
207.
Viski C., König C., Kijewska M., Mogler C., Isacke C.M., Augustin H.G. Endosialin-expressing pericytes promote metastatic dissemination. Cancer Res. 2016;76:5313-5325.
Not in our library10.1158/0008-5472.can-16-0932
208.
Raza A., Franklin M.J., Dudek A.Z. Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am. J. Hematol. 2010;85:593-598.
Not in our library10.1002/ajh.21745
209.
Cooke V.G., LeBleu V.S., Keskin D., Khan Z., O’Connell J.T., Teng Y., Duncan M.B., Xie L., Maeda G., Vong S. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell. 2012;21:66-81.
Not in our library10.1016/j.ccr.2011.11.024
210.
Pieterse Z., Sinha D., Kaur P. Pericytes in metastasis. Adv. Exp. Med. Biol. 2019;1147:125-135.
Not in our library10.1007/978-3-030-16908-4_5
211.
Gerhardt H., Semb H. Pericytes: Gatekeepers in tumour cell metastasis? J. Mol. Med. 2008;86:135-144.
Not in our library10.1007/s00109-007-0258-2
212.
Prazeres P.H.D.M., Sena I.F.G., da Terra Borges I., de Azevedo P.O., Andreotti J.P., de Paiva A.E., de Almeida V.M., de Paula Guerra D.A., Dos Santos G.S.P., Mintz A. Pericytes are heterogeneous in their origin within the same tissue. Dev. Biol. 2017;427:6-11.
Not in our library10.1016/j.ydbio.2017.05.001
213.
Prete A., Lo A.S., Sadow P.M., Bhasin S.S., Antonello Z.A., Vodopivec D.M., Ullas S., Sims J.N., Clohessy J., Dvorak A.M. Pericytes Elicit Resistance to Vemurafenib and Sorafenib Therapy in Thyroid Carcinoma via the TSP-1/TGFβ1 AxisTSP-1, TGFβ1, and Drug Resistance in Thyroid Cancer. Clin. Cancer Res. 2018;24:6078-6097.
Not in our library10.1158/1078-0432.ccr-18-0693
214.
Nilendu P., Sarode S.C., Jahagirdar D., Tandon I., Patil S., Sarode G.S., Pal J.K., Sharma N.K. Mutual concessions and compromises between stromal cells and cancer cells: Driving tumor development and drug resistance. Cell. Oncol. 2018;41:353-367.
Not in our library10.1007/s13402-018-0388-2
215.
Huang M., Lin Y., Wang C., Deng L., Chen M., Assaraf Y.G., Chen Z.-S., Ye W., Zhang D. New insights into antiangiogenic therapy resistance in cancer: Mechanisms and therapeutic aspects. Drug Resist. Updates. 2022;64:100849.
Not in our library10.1016/j.drup.2022.100849
216.
Dzobo K., Leaner V.D., Parker M.I. Feedback regulation of the alpha2(1) collagen gene via the Mek-Erk signaling pathway. IUBMB Life. 2012;64:87-98.
Not in our library10.1002/iub.568
217.
Dzobo K., Leaner V.D., Parker M.I. Absence of feedback regulation in the synthesis of COL1A1. Life Sci. 2014;103:25-33.
Not in our library10.1016/j.lfs.2014.03.006
218.
Stupack D.G., Cheresh D.A. ECM remodeling regulates angiogenesis: Endothelial integrins look for new ligands. Sci. STKE. 2002;2002:pe7.
Not in our library10.1126/stke.2002.119.pe7
219.
Cox T.R., Erler J.T. Remodeling and homeostasis of the extracellular matrix: Implications for fibrotic diseases and cancer. Dis. Model. Mech. 2011;4:165-178.
Not in our library10.1242/dmm.004077
220.
Sirica A.E., Gores G.J. Desmoplastic stroma and cholangiocarcinoma: Clinical implications and therapeutic targeting. Hepatol. (Baltim. Md.). 2014;59:2397.
Not in our library10.1002/hep.26762
221.
Lu P., Weaver V.M., Werb Z. The extracellular matrix: A dynamic niche in cancer progression. J. Cell Biol. 2012;196:395-406.
Not in our library10.1083/jcb.201102147
222.
Page-McCaw A., Ewald A.J., Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat. Rev. Mol. Cell Biol. 2007;8:221-233.
Not in our library10.1038/nrm2125
223.
Holle A.W., Young J.L., Spatz J.P. In vitro cancer cell-ECM interactions inform in vivo cancer treatment. Adv. Drug Deliv. Rev. 2016;97:270-279.
Not in our library10.1016/j.addr.2015.10.007
224.
Morin P.J. Drug resistance and the microenvironment: Nature and nurture. Drug Resist. Updates Rev. Comment. Antimicrob. Anticancer Chemother. 2003;6:169-172.
Not in our library10.1016/s1368-7646(03)00059-1
225.
Campbell N.E., Kellenberger L., Greenaway J., Moorehead R.A., Linnerth-Petrik N.M., Petrik J. Extracellular Matrix Proteins and Tumor Angiogenesis. J. Oncol. 2010;2010:586905.
Not in our library10.1155/2010/586905
226.
Cox T.R. The matrix in cancer. Nat. Rev. Cancer. 2021;21:217-238.
Not in our library10.1038/s41568-020-00329-7
227.
Rohwer N., Cramer T. Hypoxia-mediated drug resistance: Novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist. Updates Rev. Comment. Antimicrob. Anticancer Chemother. 2011;14:191-201.
Not in our library10.1016/j.drup.2011.03.001
228.
Lv Y., Zhao S., Han J., Zheng L., Yang Z., Zhao L. Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer. OncoTargets Ther. 2015;8:1941-1948.
Not in our library10.2147/ott.s82835
229.
Wang M., Zhao J., Zhang L., Wei F., Lian Y., Wu Y., Gong Z., Zhang S., Zhou J., Cao K. Role of tumor microenvironment in tumorigenesis. J. Cancer. 2017;8:761.
Not in our library10.7150/jca.17648
230.
Franco P.I.R., Rodrigues A.P., de Menezes L.B., Miguel M.P. Tumor microenvironment components: Allies of cancer progression. Pathol.-Res. Pract. 2020;216:152729.
Not in our library10.1016/j.prp.2019.152729
231.
Targeting Tumor Microenvironment for Cancer Therapy · 2019
No notice
232.
Vaahtomeri K., Alitalo K. Lymphatic Vessels in Tumor Dissemination versus ImmunotherapyLymphatics in Metastasis vs. Immunotherapy. Cancer Res. 2020;80:3463-3465.
Not in our library10.1158/0008-5472.can-20-0156
233.
Nathanson S.D. Insights into the mechanisms of lymph node metastasis. Cancer. 2003;98:413-423.
Not in our library10.1002/cncr.11464
234.
Cady B. Lymph node metastases: Indicators, but not governors of survival. Arch. Surg. 1984;119:1067-1072.
Not in our library10.1001/archsurg.1984.01390210063014
235.
Som P.M. Detection of metastasis in cervical lymph nodes: CT and MR criteria and differential diagnosis. AJR Am. J. Roentgenol. 1992;158:961-969.
Not in our library10.2214/ajr.158.5.1566697
236.
Deng J.-Y., Liang H. Clinical significance of lymph node metastasis in gastric cancer. World J. Gastroenterol. WJG. 2014;20:3967.
Not in our library10.3748/wjg.v20.i14.3967
237.
Harris A.L. Hypoxia—A key regulatory factor in tumour growth. Nat. Rev. Cancer. 2002;2:38-47.
Not in our library10.1038/nrc704
238.
Brown J.M., Giaccia A.J. The unique physiology of solid tumors: Opportunities (and problems) for cancer therapy. Cancer Res. 1998;58:1408-1416.
Not in our library
239.
Role of hypoxia in cancer therapy by regulating the tumor microenvironment · 2019
No notice
240.
Finger E.C., Giaccia A.J. Hypoxia, inflammation, and the tumor microenvironment in metastatic disease. Cancer Metastasis Rev. 2010;29:285-293.
Not in our library10.1007/s10555-010-9224-5
241.
Denko N.C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer. 2008;8:705-713.
Not in our library10.1038/nrc2468
242.
Ke Q., Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol. Pharmacol. 2006;70:1469-1480.
Not in our library10.1124/mol.106.027029
243.
Ziello J.E., Jovin I.S., Huang Y. Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J. Biol. Med. 2007;80:51.
Not in our library
244.
Hung J.-J., Yang M.-H., Hsu H.-S., Hsu W.-H., Liu J., Wu K. Prognostic significance of hypoxia-inducible factor-1α, TWIST1 and Snail expression in resectable non-small cell lung cancer. Thorax. 2009;64:1082-1089.
Not in our library10.1136/thx.2009.115691
245.
Liu K., Sun B., Zhao X., Wang X., Li Y., Qiu Z., Liu T., Gu Q., Dong X., Zhang Y. Hypoxia promotes vasculogenic mimicry formation by the Twist1-Bmi1 connection in hepatocellular carcinoma. Int. J. Mol. Med. 2015;36:783-791.
Not in our library10.3892/ijmm.2015.2293
246.
Gilkes D.M., Bajpai S., Chaturvedi P., Wirtz D., Semenza G.L. Hypoxia-inducible factor 1 (HIF-1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts. J. Biol. Chem. 2013;288:10819-10829.
Not in our library10.1074/jbc.m112.442939
247.
Gilkes D.M., Semenza G.L., Wirtz D. Hypoxia and the extracellular matrix: Drivers of tumour metastasis. Nat. Rev. Cancer. 2014;14:430-439.
Not in our library10.1038/nrc3726
248.
Shieh A.C. Biomechanical forces shape the tumor microenvironment. Ann. Biomed. Eng. 2011;39:1379-1389.
Not in our library10.1007/s10439-011-0252-2
249.
Comito G., Giannoni E., Segura C., Barcellos-de-Souza P., Raspollini M., Baroni G., Lanciotti M., Serni S., Chiarugi P. Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene. 2014;33:2423-2431.
Not in our library10.1038/onc.2013.191
250.
Macrophages are recruited to hypoxic tumor areas and acquire a Pro-Angiogenic M2-Polarized phenotype via hypoxic cancer cell derived cytokines Oncostatin M and Eotaxin · 2014
No notice
251.
Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma · 2017
No notice
252.
Švastová E., Hulíková A., Rafajová M., Zat’ovičová M., Gibadulinová A., Casini A., Cecchi A., Scozzafava A., Supuran C.T., Pastorek J.r. Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett. 2004;577:439-445.
Not in our library10.1016/j.febslet.2004.10.043
253.
du Souich P., Fradette C. The effect and clinical consequences of hypoxia on cytochrome P450, membrane carrier proteins activity and expression. Expert Opin. Drug Metab. Toxicol. 2011;7:1083-1100.
Not in our library10.1517/17425255.2011.586630
254.
Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies · 2019
No notice
255.
Mazure N.M., Pouysségur J. Hypoxia-induced autophagy: Cell death or cell survival? Curr. Opin. Cell Biol. 2010;22:177-180.
Not in our library10.1016/j.ceb.2009.11.015
256.
Brouqui P., Amrane S., Million M., Cortaredona S., Parola P., Lagier J.-C., Raoult D. Asymptomatic hypoxia in COVID-19 is associated with poor outcome. Int. J. Infect. Dis. 2021;102:233-238.
Not in our library10.1016/j.ijid.2020.10.067
257.
Kashani K.B. Hypoxia in COVID-19: Sign of severity or cause for poor outcomes. Proceedings of the Mayo Clinic Proceedings. 2020;1094-1096.
Not in our library10.1016/j.mayocp.2020.04.021
258.
Pegtel D.M., Gould S.J. Exosomes. Annu. Rev. Biochem. 2019;88:487-514.
Not in our library10.1146/annurev-biochem-013118-111902
259.
Kalluri R. The biology and function of exosomes in cancer. J. Clin. Investig. 2016;126:1208-1215.
Not in our library10.1172/jci81135
260.
Milman N., Ginini L., Gil Z. Exosomes and their role in tumorigenesis and anticancer drug resistance. Drug Resist. Updates. 2019;45:1-12.
Not in our library10.1016/j.drup.2019.07.003
261.
Melo S.A., Sugimoto H., O’Connell J.T., Kato N., Villanueva A., Vidal A., Qiu L., Vitkin E., Perelman L.T., Melo C.A. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell. 2014;26:707-721.
Not in our library10.1016/j.ccell.2014.09.005
262.
Su L.-L., Chang X.-J., Zhou H.-D., Hou L.-B., Xue X.-Y. Exosomes in esophageal cancer: A review on tumorigenesis, diagnosis and therapeutic potential. World J. Clin. Cases. 2019;7:908.
Not in our library10.12998/wjcc.v7.i8.908
263.
Yu D.D., Wu Y., Shen H.Y., Lv M.M., Chen W.X., Zhang X.H., Zhong S.L., Tang J.H., Zhao J.H. Exosomes in development, metastasis and drug resistance of breast cancer. Cancer Sci. 2015;106:959-964.
Not in our library10.1111/cas.12715
264.
Najminejad H., Kalantar S.M., Abdollahpour-Alitappeh M., Karimi M.H., Seifalian A.M., Gholipourmalekabadi M., Sheikhha M.H. Emerging roles of exosomal miRNAs in breast cancer drug resistance. IUBMB Life. 2019;71:1672-1684.
Not in our library10.1002/iub.2116
265.
Uen Y., Wang J.-W., Wang C., Jhang Y., Chung J.-Y., Tseng T., Sheu M., Lee S. Mining of potential microRNAs with clinical correlation-regulation of syndecan-1 expression by miR-122-5p altered mobility of breast cancer cells and possible correlation with liver injury. Oncotarget. 2018;9:28165.
Not in our library10.18632/oncotarget.25589
266.
Fong M.Y., Zhou W., Liu L., Alontaga A.Y., Chandra M., Ashby J., Chow A., O’Connor S.T.F., Li S., Chin A.R. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat. Cell Biol. 2015;17:183-194.
Not in our library10.1038/ncb3094
267.
Jiang L., Gu Y., Du Y., Liu J. Exosomes: Diagnostic biomarkers and therapeutic delivery vehicles for cancer. Mol. Pharm. 2019;16:3333-3349.
Not in our library10.1021/acs.molpharmaceut.9b00409
268.
Kim J.-H., Kim E., Lee M.Y. Exosomes as diagnostic biomarkers in cancer. Mol. Cell. Toxicol. 2018;14:113-122.
Not in our library10.1007/s13273-018-0014-4
269.
An T., Qin S., Xu Y., Tang Y., Huang Y., Situ B., Inal J.M., Zheng L. Exosomes serve as tumour markers for personalized diagnostics owing to their important role in cancer metastasis. J. Extracell. Vesicles. 2015;4:27522.
Not in our library10.3402/jev.v4.27522
270.
Jafari R., Rahbarghazi R., Ahmadi M., Hassanpour M., Rezaie J. Hypoxic exosomes orchestrate tumorigenesis: Molecular mechanisms and therapeutic implications. J. Transl. Med. 2020;18:1-14.
Not in our library10.1186/s12967-020-02662-9
271.
Ohnishi Y., Inoue H., Furukawa M., Kakudo K., Nozaki M. Heparin-binding epidermal growth factor-like growth factor is a potent regulator of invasion activity in oral squamous cell carcinoma. Oncol. Rep. 2012;27:954-958.
Not in our library10.3892/or.2011.1616
272.
Exosome-Based Cancer Therapy: Implication for Targeting Cancer Stem Cells · 2017
No notice
273.
Chitadze G., Bhat J., Lettau M., Janssen O., Kabelitz D. Generation of Soluble NKG 2 D Ligands: Proteolytic Cleavage, Exosome Secretion and Functional Implications. Scand. J. Immunol. 2013;78:120-129.
Not in our library10.1111/sji.12072
274.
Prostate Tumor-Derived Exosomes Down-Regulate NKG2D Expression on Natural Killer Cells and CD8+ T Cells: Mechanism of Immune Evasion · 2014
No notice
275.
Andaloussi S.E., Lakhal S., Mäger I., Wood M.J. Exosomes for targeted siRNA delivery across biological barriers. Adv. Drug Deliv. Rev. 2013;65:391-397.
Not in our library10.1016/j.addr.2012.08.008
276.
Ruzzo A., Graziano F., Loupakis F., Santini D., Catalano V., Bisonni R., Ficarelli R., Fontana A., Andreoni F., Falcone A. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Pharm. J. 2008;8:278-288.
Not in our library10.1038/sj.tpj.6500463
277.
Harries M., Gore M. Part I: Chemotherapy for epithelial ovarian cancer–treatment at first diagnosis. Lancet Oncol. 2002;3:529-536.
Not in our library10.1016/s1470-2045(02)00846-x
278.
Vaupel P., Mayer A. Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev. 2007;26:225-239.
Not in our library10.1007/s10555-007-9055-1
279.
Vaupel P., Schmidberger H., Mayer A. The Warburg effect: Essential part of metabolic reprogramming and central contributor to cancer progression. Int. J. Radiat. Biol. 2019;95:912-919.
Not in our library10.1080/09553002.2019.1589653
280.
Flemming A. PD1 makes waves in anticancer immunotherapy. Nat. Rev. Drug Discov. 2012;11:601.
Not in our library10.1038/nrd3806
281.
Haanen J.B., Robert C. Immune checkpoint inhibitors. Immuno-Oncol. 2015;42:55-66.
Not in our library10.1159/000437178
282.
Mechanisms of resistance to immune checkpoint inhibitors · 2018
No notice
283.
Chafe S.C., McDonald P.C., Saberi S., Nemirovsky O., Venkateswaran G., Burugu S., Gao D., Delaidelli A., Kyle A.H., Baker J.H. Targeting Hypoxia-Induced Carbonic Anhydrase IX Enhances Immune-Checkpoint Blockade Locally and SystemicallyCAIX Inhibition Enhances Immune-Checkpoint Blockade. Cancer Immunol. Res. 2019;7:1064-1078.
Not in our library10.1158/2326-6066.cir-18-0657
284.
Elinav E., Garrett W.S., Trinchieri G., Wargo J. The cancer microbiome. Nat. Rev. Cancer. 2019;19:371-376.
Not in our library10.1038/s41568-019-0155-3
285.
Schmidt E.V. Developing combination strategies using PD-1 checkpoint inhibitors to treat cancer. Proceedings of the Seminars in Immunopathology. 2019;21-30.
Not in our library10.1007/s00281-018-0714-9
286.
Decazes P., Bohn P. Immunotherapy by immune checkpoint inhibitors and nuclear medicine imaging: Current and future applications. Cancers. 2020;12:371.
Not in our library10.3390/cancers12020371
287.
Grywalska E., Pasiarski M., Góźdź S., Roliński J. Immune-checkpoint inhibitors for combating T-cell dysfunction in cancer. OncoTargets Ther. 2018;11:6505.
Not in our library10.2147/ott.s150817
288.
Sharma P., Allison J.P. The future of immune checkpoint therapy. Science. 2015;348:56-61.
Not in our library10.1126/science.aaa8172
289.
Xue L.J., Mao X.B., Ren L.L., Chu X.Y. Inhibition of CXCL12/CXCR4 axis as a potential targeted therapy of advanced gastric carcinoma. Cancer Med. 2017;6:1424-1436.
Not in our library10.1002/cam4.1085
290.
Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy · 2021
No notice
291.
Perdih A., Sollner Dolenc M. Small molecule antagonists of integrin receptors. Curr. Med. Chem. 2010;17:2371-2392.
Not in our library10.2174/092986710791698558
292.
Keely P.J. Mechanisms by which the extracellular matrix and integrin signaling act to regulate the switch between tumor suppression and tumor promotion. J. Mammary Gland Biol. Neoplasia. 2011;16:205-219.
Not in our library10.1007/s10911-011-9226-0
293.
Gehler S., Ponik S.M., Riching K.M., Keely P.J. Bi-directional signaling: Extracellular matrix and integrin regulation of breast tumor progression. Crit. Rev. Eukaryot. Gene Expr. 2013;23:139-157.
Not in our library10.1615/critreveukargeneexpr.2013006647
294.
Tentori L., Dorio A.S., Muzi A., Lacal P.M., Ruffini F., Navarra P., Graziani G. The integrin antagonist cilengitide increases the antitumor activity of temozolomide against malignant melanoma. Oncol. Rep. 2008;19:1039-1043.
Not in our library10.3892/or.19.4.1039
295.
Unruh A., Ressel A., Mohamed H.G., Johnson R.S., Nadrowitz R., Richter E., Katschinski D.M., Wenger R.H. The hypoxia-inducible factor-1α is a negative factor for tumor therapy. Oncogene. 2003;22:3213-3220.
Not in our library10.1038/sj.onc.1206385
296.
Hypoxia-Inducible Factor 1α Determines Gastric Cancer Chemosensitivity via Modulation of p53 and NF-κB · 2010
No notice
297.
Estrella V., Chen T., Lloyd M., Wojtkowiak J., Cornnell H.H., Ibrahim-Hashim A., Bailey K., Balagurunathan Y., Rothberg J.M., Sloane B.F. Acidity Generated by the Tumor Microenvironment Drives Local InvasionAcid-Mediated Invasion. Cancer Res. 2013;73:1524-1535.
Not in our library10.1158/0008-5472.can-12-2796
298.
Kraus M., Wolf B. Implications of acidic tumor microenvironment for neoplastic growth and cancer treatment: A computer analysis. Tumor Biol. 1996;17:133-154.
Not in our library10.1159/000217977
299.
Chen Q., Feng L., Liu J., Zhu W., Dong Z., Wu Y., Liu Z. Intelligent albumin–MnO2 nanoparticles as pH-/H2O2-responsive dissociable nanocarriers to modulate tumor hypoxia for effective combination therapy. Adv. Mater. 2016;28:7129-7136.
Not in our library10.1002/adma.201601902
300.
Saggar J.K., Tannock I.F. Activity of the hypoxia-activated pro-drug TH-302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy. Int. J. Cancer. 2014;134:2726-2734.
Not in our library10.1002/ijc.28595
301.
Hajj C., Russell J., Hart C.P., Goodman K.A., Lowery M.A., Haimovitz-Friedman A., Deasy J.O., Humm J.L. A combination of radiation and the hypoxia-activated prodrug evofosfamide (TH-302) is efficacious against a human orthotopic pancreatic tumor model. Transl. Oncol. 2017;10:760-765.
Not in our library10.1016/j.tranon.2017.06.010
302.
Wouters B.G., Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat. Rev. Cancer. 2008;8:851-864.
Not in our library10.1038/nrc2501
303.
Feldman D.E., Chauhan V., Koong A.C. The unfolded protein response: A novel component of the hypoxic stress response in tumors. Mol. Cancer Res. 2005;3:597-605.
Not in our library10.1158/1541-7786.mcr-05-0221
304.
Xiao Y., Yu D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol. Ther. 2021;221:107753.
Not in our library10.1016/j.pharmthera.2020.107753
305.
The updated landscape of tumor microenvironment and drug repurposing · 2020
No notice
306.
Najafi M., Goradel N.H., Farhood B., Salehi E., Solhjoo S., Toolee H., Kharazinejad E., Mortezaee K. Tumor microenvironment: Interactions and therapy. J. Cell. Physiol. 2019;234:5700-5721.
Not in our library10.1002/jcp.27425

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