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Application of Mesenchymal Stem Cells for Therapeutic Agent Delivery in Anti-tumor Treatment

Daria S. Chulpanova, Kristina V. Kitaeva, Leysan G. Tazetdinova and 3 more

Frontiers in Pharmacology · 2018 · Review

doi:10.3389/fphar.2018.00259

Abstract

Mesenchymal stem cells (MSCs) are non-hematopoietic progenitor cells, which can be isolated from different types of tissues including bone marrow, adipose tissue, tooth pulp, and placenta/umbilical cord blood. There isolation from adult tissues circumvents the ethical concerns of working with embryonic or fetal stem cells, whilst still providing cells capable of differentiating into various cell lineages, such as adipocytes, osteocytes and chondrocytes. An important feature of MSCs is the low immunogenicity due to the lack of co-stimulatory molecules expression, meaning there is no need for immunosuppression during allogenic transplantation. The tropism of MSCs to damaged tissues and tumor sites makes them a promising vector for therapeutic agent delivery to tumors and metastatic niches. MSCs can be genetically modified by virus vectors to encode tumor suppressor genes, immunomodulating cytokines and their combinations, other therapeutic approaches include MSCs priming/loading with chemotherapeutic drugs or nanoparticles. MSCs derived membrane microvesicles (MVs), which play an important role in intercellular communication, are also considered as a new therapeutic agent and drug delivery vector. Recruited by the tumor, MSCs can exhibit both pro- and anti-oncogenic properties. In this regard, for the development of new methods for cancer therapy using MSCs, a deeper understanding of the molecular and cellular interactions between MSCs and the tumor microenvironment is necessary. In this review, we discuss MSC and tumor interaction mechanisms and review the new therapeutic strategies using MSCs and MSCs derived MVs for cancer treatment.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 24, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Due to their tropism to the tumor niche, mesenchymal stem cells (MSCs) are promising vectors for the delivery of antitumor agents. The isolation of MSCs from adult tissues poses circumvents many of the ethical and safety concerns which surround the use of embryonic or fetal stem cells, as these have been comprehensively discussed elsewhere, this review focuses on the anti-tumor and therapeutic potential of MSCs. It is believed that the migration of MSCs toward the tumor is determined by inflammatory signaling similar to a chronic non-healing wound. It has been shown that MSCs are actively attracted to hepatic carcinoma, breast cancer, glioma and pre-metastatic niches. However, the mechanism and factors responsible for the targeted tropism of MSCs to wounds and tumors microenvironments remain unclear. MSCs can migrate to sites of trauma and injury following the gradient of chemo-attractants in the extracellular matrix (ECM) and peripheral blood and local factors, such as hypoxia, cytokine environment and Toll-like receptors ligands, where upon arrival these local factors promote MSCs to express growth factors that accelerate tissue regeneration.

It is believed, that following accumulation at the sites of tumor formation and growth, MSCs differentiate into pericytes or tumor-associated fibroblasts (TAF) thereby forming a growth supporting microenvironment and secreting such trophic factors as vascular endothelial growth factor (VEGF), interleukin 8 (IL-8), transforming growth factor β (TGF-β), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF).. For example, it has been shown that MSCs stimulate tumor growth and vascularization within the colorectal cancer xenograft model in vivo and can also induce activation of Akt and ERK in endothelial cells, thereby increasing their recruitment and angiogenic potential. Whilst in co-culture in vitro experiments, MSCs stimulated the invasion and proliferation of breast cancer cells.

However, besides tumor progression, MSCs can also supress tumor growth by cell cycle arrest and inhibition of proliferation, as well as blocking of PI3K/AKT pathway and tumor suppressor gene expression. Anti-tumor properties are described for MSCs isolated from various sources in experiments both in vitro and in vivo of various tumor models (different tumor models are discussed in. For instance, MSCs injected into an in vivo model of Kaposi’s sarcoma suppressed tumor growth. Similar results have been reported for hepatoma, pancreatic cancer, prostate cancer and melanoma in both in vitro and in vivo models.

Thus, there are contradictory reports about the role of MSCs in tumor formation and development. The differences in the anticancer activity of MSCs reported by different group might be due to their activation status, which is discussed elsewhere. Nevertheless, there is a consensus that MSCs have enhanced tropism toward tumors which make them ideal vector candidates for targeted anti-tumor therapy.

MSCs Migrate Toward Irradiated Tumors

Mesenchymal stem cells migration in the context of radiation therapy may also be very promising for cancer therapy. In fact, MSCs migrate better to irradiated 4T1 mouse mammary tumor cells in comparison to non-irradiated 4T1 cells. Irradiated 4T1 cells are characterized by increased expression levels of TGF-β1, VEGF, and PDGF-BB. The activation of chemokine receptor CCR2 in MSCs interacting with irradiated 4T1 cells was also observed, as well as higher expression of MCP-1/CCL2 in the tumor parenchyma of 4T1 mice. Thus, MCP-1/CCL2/CCR2 signaling is important in the attraction of MSCs to irradiated tumor cells. Furthermore, CCR2 inhibition resulted in a significant decrease in MSC migration in vitro. In irradiated glioma cells reported increased IL-8 expression, which led to an upregulation of IL-8 receptor by MSCs and an increase in their migration potential and tropism to glioma cells.

Once at the irradiated tumor site, MSCs can suppress immune cell activation directly through cell-cell interactions by binding the membrane protein PD-1 with PD-L1 and PD-L2 ligands on the T-lymphocyte surface. Moreover, MSCs can induce T-lymphocyte agonism by suppressing the expression of CD80 and CD86 on antigen-presenting cells. Thus, the increased MSCs tropism to irradiated tumors may have the opposite effect in cancer therapy.

The described data clearly illustrate the correlation between tissue damage and MSCs recruitment. Due to an increase in tropism to the tumor, genetically modified MSCs can be an effective therapeutic tool. However, such therapeutic strategies can be risky for cancer patients since MSCs can potentially stimulate cancer progression within certain contexts.

MSCs Chemotaxis Mediating Factors

Mesenchymal stem cells migrate to damaged tissue, trauma or sites of inflammation in response to secreted cytokines. Similarly, the tumor environment consists of a large number of immune cells, which alongside tumor cells, secrete soluble factors such as VEGF, PDGF, IL-8, IL-6, basic fibroblast growth factor (bFGF or FGF2), stromal cell-derived factor 1 (SDF-1), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), monocyte chemoattractant protein 1 (MCP1), hepatocyte growth factor (HGF), TGF-β and urokinase-type plasminogen activator receptor (UPAR), attracting MSCs.

Soluble factors CCL21, IL-8, CXC3L1, IL-6, macrophage inflammatory protein 1δ (MIP-1δ) and MIP-3α directly mediate MSCs chemotaxis and recruitment to damaged tissues. IL-6 mediates chemotaxis, which facilitates MSC attraction into the main tumor growth sites. observed the dose-dependent chemotactic activity of bone marrow-derived MSCs in relation to SDF-1α and IL-8. IL-8 dependent recruitment of MSCs was also detected in glioma. A multitude of angiogenic cytokines secreted by glioma cells, including IL-8, actively attract MSCs to tumor tissue. Experiments with conditioned medium from Huh-7 hepatoma cell (Huh-7 CM) showed that MIP-1δ and MIP-3α induced MSC migration. Moreover, after cultivation of MSCs in Huh-7 CM the expression of matrix metalloproteinase 1 (MMP-1), necessary for migration, was significantly increased. It was also shown that PDGF-BB, VEGF and TGF-β1 can induce MSC migration. Experiments using MSCs modified with CXCR4, showed that increased expression of the CXCR4 receptor enhances MSC migration toward tumor cells in both in vitro and in vivo models. In osteosarcoma models, it was described that SDF-1α is involved in MSCs recruitment to tumor areas. MSCs in turn stimulate the migration of osteocarcinoma cells by CCL5/RANTES secretion, thereby promoting tumor invasion and metastatic colonization by providing metastatic osteosarcoma cells with a suitable microenvironment.

Genetically Engineered MSCs With Anticancer Activity

In early studies MSCs genetically modified with interferon β (IFN-β) were injected into human melanoma mouse xenotransplantation models which resulted in decreased tumor growth and increased (2-times) survival of mice in comparison with controls. In addition, it was shown in a melanoma xenograft mouse model that additional loading of IFN-β-modified canine MSCs with low amounts of cisplatin significantly increased the effectiveness of the antitumor therapy.

Currently, besides IFN-β there are several other cytokines and tumor-suppressor genes with anticancer activity which are used for genetic modification of MSCs (Table 1). One of the most promising therapeutic pro-apoptotic cytokines is tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which selectively induces apoptosis in cancer cells. The antitumor effect of TRAIL-modified MSCs has been described for different types of tumors, within which TRAIL has not been found to be cytotoxic for normal mammalian cells and tissues. It is interesting that recombinant TNF-α-activated MSCs in combination with radiation exposure are able to significantly increase expression level of endogenous TRAIL. Long-lasting expression of endogenous TRAIL can also be observed in IFN-γ-modified MSCs. To increase the therapeutic potential of TRAIL-modified MSCs, it has been suggested they could be used in combination with chemotherapeutic agents, such as cisplatin. However, some tumors have mechanism of TRAIL resistance through overexpression of X-linked inhibitory of apoptosis protein (XIAP), which inhibits caspase 3 and 9 activation. Anti-apoptotic properties of XIAP are under control of the second mitochondria-derived activator of caspase (Smac), which prevents physical interaction of XIAP and caspases thereby preventing apoptosis inhibition. used MSCs for the delivery and simultaneous expression of novel cell penetrable forms of Smac and TRAIL. The effectiveness of this approach was shown in TRAIL-resistant breast cancer cell line MCF-7.

Besides IFN-β and TRAIL as anti-tumor agents, interleukins are also under consideration because they regulate inflammation and immune responses For instance, IL-12-modified MSCs decrease metastasis and induce cancer cell apoptosis in mice with melanoma, lung cancer and hepatoma by 75, 83, and 91%, respectively. The activation of immune cells [cytotoxic T-lymphocytes and natural killers (NK)] was also reported. showed that injection of genetically modified amniotic fluid-derived MSCs expressing IL-2 resulted in induction of apoptosis in ovarian cancer cells in an in vivo mouse model.

PTEN (phosphatase and tensin homolog deleted on chromosome 10) is one of the main human tumor-suppressors. showed that PTEN expressing MSCs are able to migrate toward DBTRG (brain glioblastoma) tumor cells in vitro. PTEN-modified MSCs anti-cancer activity in co-culture with U251 glioma cells in vitro was also described. MSC-mediated delivery and anti-tumor properties were described for other proteins (IFN-α, IFN-γ, CX3CL1, apoptin, PEDF) and ncRNAs (miR-124 and miR-145) (Table 1). Modification of MSCs for the co-expression of several therapeutic proteins can increase their anti-cancer potential. It was shown that TRAIL and herpes simplex virus thymidine kinase (HSV-TK) modified MSCs in the presence of ganciclovir (GCV) significantly reduced tumor growth and increased survival of mice with highly malignant glioblastoma multiform (GBM).

The effect of direct administration of many of these agents in cancer treatment is often limited due to their short half-life in the body and pronounced toxicity in relation to normal, non-cancerous cells. The use of MSCs for delivery of the above mentioned therapeutic proteins can help to minimize such problems because MSCs can selectively migrate to tumor sites and exert therapeutic effects locally thereby significantly increasing the concentration of the agent in the tumor and reducing its systemic toxicity.

Another promising approach is delivery of oncolytic viruses with MSCs. For instance, used MSCs as a vector for the delivery of oncolytic herpes simplex virus (oHSV) [approved by Food and Drug Administration (FDA) for melanoma treatment] in human brain melanoma metastasis models in immunodeficient and immunocompetent mice. Authors noted that the introduced MSCs-oHSV migrated to the site of tumor formation and significantly prolonged the survival of mice. In the immunocompetent model a combination of MSCs-oHSV and PD-L1 blockade increases IFNγ-producing CD8+ tumor-infiltrating T lymphocytes and results in a significant increase of the median survival of treated animals.

MSCs Primed With Anticancer Drugs

Mesenchymal stem cells relative resistance to cytostatic and cytotoxic chemotherapeutic drugs and migration ability opens new ways to use them for targeted delivery of therapeutic drugs directly to tumor sites. showed that SR4987 BDF/1 mouse bone marrow stromal cells can be a reservoir for doxorubicin (DOX) which can subsequently be released not only in the form of DOX metabolites but also in its original form. It was further shown that MSCs efficiently absorb and release paclitaxel (PTX) in an active form, DOX, and gemcitabine (GCB), all having an inhibitory effect on tongue squamous cell carcinoma (SCC154) cells growth in vitro.

found that the maximum concentration of PTX which did not affect MSC viability was 10 000 ng/mL. The concentration is sufficient to decrease the viability of certain types of tumor cells, for example, human leukemia cells. In vivo investigations show that PTX-primed MSCs (MSCs-PTX) demonstrate strong antitumor activity inhibiting the growth of tumor cells and vascularization of the tumor in a MOLT-4 (leukemia) xenograft mouse model. The anti-tumor activity of primed MSCs is currently being investigated on the different types of tumor cells. For instance, showed that MSCs-PTX suppress the proliferation of human myeloma cells RPMI 8226 in in vitro 3D dynamic culture system. The anti-cancer activity of MSCs-PTX has been further shown in relation to pancreatic carcinoma cells in vitro.

showed that cisplatin (CDDP) had no significant effect on cell morphology, adhesion or induction of apoptosis in MSCs, nor does it affect their immunophenotype or differentiation potential of MSCs once primed with CDDP. This has been confirmed using CDDP at concentrations of 2.5 μg/ml and 5.0 μg/ml. Thus, MSCs are promising vectors for CDDP delivery toward the tumor sites.

Beside chemical drugs in soluble form, MSCs can absorb nanomaterials containing chemotherapeutic agents. For instance, MSCs primed with silica nanoparticle-encapsulated DOX promoted a significant increase in the apoptosis of U251 glioma cells in vivo.

in their work used MSCs from two sources: dog adipose tissue and bone marrow, to study MSCs-PTX antitumor activity on human glioma cells (T98G and U87MG). The investigation once again showed the pronounced antitumor effect of MSCs-PTX and opens new perspectives for oncological disease therapy not only in humans but also in animals.

MSC-Derived Microvesicles

Extracellular vesicles (EVs) [microvesicles (MVs) and exosomes] released by a large number of cells play an important role in intercellular communication. MVs from different cell types contain biologically active functional proteins, and nucleic acids including mRNA and microRNA. It was shown that MSC-derived MVs can promote progression of various types of tumors. For instance, MSC-derived MVs have been found to facilitate the migration of MCF7 breast cancer cells by activating the Wnt signaling pathway, promote the progression of nasopharyngeal carcinoma cells and increase the proliferation and metastatic potential of gastric cancer cells. MSC-derived MVs can also increase tumor cell resistance to drugs. For example, MSC-derived MVs can induce resistance to 5-fluorouracil in gastric cancer cells by activating the CaM-Ks/Raf/MEK/ERK pathway. showed that a possible cause of increased resistance to chemotherapy are micro-RNAs which are included in MVs, such as miR-222/223, which support the resistance of the breast cancer cells in the bone marrow. However, there are conflicting results, for example reported that MVs isolated from bone marrow and cord blood-derived MSCs suppressed division and induced apoptosis in glioblastoma cells. However, MVs isolated from adipose tissue-derived MSCs showed the opposite effect and stimulated tumor cell proliferation. As mentioned above, such differences might be explained by activation status of parental MSCs from which the MVs are generated.

One of the possible approaches to use MSCs-isolated MVs in therapy is via the priming/loading of these structures with therapeutic agents. demonstrated that the antitumor activity of MSCs-PTX may be due to the release of a large number of MVs by the MScs. Loaded with PTX MSCs demonstrate vacuole-like structures and accumulation of MVs in extracellular space without significant change in cell morphology. Presence of PTX in MVs was confirmed by Fourier spectroscopy. The release of PTX containing MVs were found to exert anti-cancer activity which was confirmed using the human pancreatic adenocarcinoma cell line CFPAC-1 in vitro. This finding was supported by the recent studies of which showed antitumor activity of MVs derived from MSCs-PTX and MSCs-GCB on pancreatic cancer cells in vitro.

investigated antitumor activity of MSC-derived MVs carrying recombinant TRAIL (rTRAIL) on their surface. Cultivation of M231 breast cancer cells in the presence of MVs led to the induction of apoptosis in cancer cells. At the same time, MVs did not induce apoptosis in normal human bronchial epithelial cells (HBECs). The use of MSC-derived MVs bearing rTRAIL on their surface proved to be more effective than using pure rTRAIL.

developed bioluminescent EVs using Renilla luciferase (Rluc)-expressing MSCs (EV-MSC/Rluc) and showed that these vesicles migrate at tumor sites in the Lewis lung carcinoma (LLC) model in vivo. Significant cytotoxic effect of EV-MSC/Rluc on LLC and 4T1 cells in vitro was also noticed. Moreover, EV-MSC/Rluc inhibited LLC tumor growth in vivo.

Conclusion

Tumor development and response to therapy depends not only on tumor cells, but also on different cell types which form the stroma and microenvironment. These include immune cells, vascular endothelial cells and tumor-associated stromal cells such as TAF and MSCs. Due to tropism to the tumor microenvironment, MSCs can be considered as promising vectors for the delivery of antitumor agents (Figure 1). To date, there are large number of experimental studies that confirm the anti-oncogenic potential of MSCs modified with therapeutic genes and/or loaded with chemotherapeutic drugs. Thus, the approach of therapeutic agent delivery to the tumor sites using MSCs is promising. However, since it is known that native MSCs can exhibit not only anticancer but also pro-oncogenic properties, further research is needed to improve the safety of this approach. An alternative to using intact MSCs to deliver anti-tumor agents, is the use of MSC-derived MVs which can also be loaded with the same antitumor agents. Further research is needed to evaluate the safety and efficiency of the different therapeutic approaches described in this review to harness the promising potential of MSCs as therapeutic vectors.

Author Contributions

DC wrote the manuscript and made the table. KK and VJ collected the data of homing of MSCs. LT collected the information of MSCs priming. KK made the figure. DC, VS, and AR conceived the idea and edited the manuscript, figure, and table.

Conflict of Interest Statement

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

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    Klopp A. H. Spaeth E. L. Dembinski J. L. Woodward W. A. Munshi A. Meyn R. E. (2007 ). Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res. 67 11687–11695.

    Not in our library10.1158/0008-5472.can-07-1406

  46. 46.

    Kucerova L. Altanerova V. Matuskova M. Tyciakova S. Altaner C. (2007 ). Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res. 67 6304–6313.

    Not in our library10.1158/0008-5472.can-06-4024

  47. 47.

    Kucerova L. Matuskova M. Pastorakova A. Tyciakova S. Jakubikova J. Bohovic R. (2008 ). Cytosine deaminase expressing human mesenchymal stem cells mediated tumour regression in melanoma bearing mice. J. Gene Med. 10 1071–1082.

    Not in our library10.1002/jgm.1239

  48. 48.

    Lathrop M. J. Sage E. K. Macura S. L. Brooks E. M. Cruz F. Bonenfant N. R. (2015 ). Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma. Cancer Gene Ther. 22 44–54.

    Not in our library10.1038/cgt.2014.68

  49. 49.
  50. 50.

    Lejmi E. Perriraz N. Clement S. Morel P. Baertschiger R. Christofilopoulos P. (2015 ). Inflammatory chemokines MIP-1delta and MIP-3alpha are involved in the migration of multipotent mesenchymal stromal cells induced by hepatoma cells. Stem Cells Dev. 24 1223–1235.

    Not in our library10.1089/scd.2014.0176

  51. 51.

    Li L. Guan Y. Liu H. Hao N. Liu T. Meng X. (2011 ). Silica nanorattle-doxorubicin-anchored mesenchymal stem cells for tumor-tropic therapy. ACS Nano 5 7462–7470.

    Not in our library10.1021/nn202399w

  52. 52.

    Li L. Li F. Tian H. Yue W. Li S. Chen G. (2014 ). Human mesenchymal stem cells with adenovirus-mediated TRAIL gene transduction have antitumor effects on esophageal cancer cell line Eca-109. Acta Biochim. Biophys. Sin. 46 471–476.

    Not in our library10.1093/abbs/gmu024

  53. 53.

    Li X. Lu Y. Huang W. Xu H. Chen X. Geng Q. (2006 ). In vitro effect of adenovirus-mediated human Gamma Interferon gene transfer into human mesenchymal stem cells for chronic myelogenous leukemia. Hematol. Oncol. 24 151–158.

    Not in our library10.1002/hon.779

  54. 54.

    Lin R. Wang S. Zhao R. C. (2013 ). Exosomes from human adipose-derived mesenchymal stem cells promote migration through Wnt signaling pathway in a breast cancer cell model. Mol. Cell. Biochem. 383 13–20.

    Not in our library10.1007/s11010-013-1746-z

  55. 55.

    Ling X. Marini F. Konopleva M. Schober W. Shi Y. Burks J. (2010 ). Mesenchymal stem cells overexpressing IFN-beta inhibit breast cancer growth and metastases through Stat3 signaling in a syngeneic tumor model. Cancer Microenviron. 3 83–95.

    Not in our library10.1007/s12307-010-0041-8

  56. 56.

    Liu S. Ginestier C. Ou S. J. Clouthier S. G. Patel S. H. Monville F. (2011 ). Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res. 71 614–624.

    Not in our library10.1158/0008-5472.can-10-0538

  57. 57.
  58. 58.

    Marini I. Siegemund M. Hutt M. Kontermann R. E. Pfizenmaier K. (2017 ). Antitumor activity of a mesenchymal stem cell line stably secreting a tumor-targeted TNF-related apoptosis-inducing ligand fusion protein. Front. Immunol. 8:536.

    Not in our library10.3389/fimmu.2017.00536

  59. 59.

    Martinez-Quintanilla J. Bhere D. Heidari P. He D. Mahmood U. Shah K. (2013 ). Therapeutic efficacy and fate of bimodal engineered stem cells in malignant brain tumors. Stem Cells 31 1706–1714.

    Not in our library10.1002/stem.1355

  60. 60.

    Matuskova M. Hlubinova K. Pastorakova A. Hunakova L. Altanerova V. Altaner C. (2010 ). HSV-tk expressing mesenchymal stem cells exert bystander effect on human glioblastoma cells. Cancer Lett. 290 58–67.

    Not in our library10.1016/j.canlet.2009.08.028

  61. 61.

    Mohammadpour H. Pourfathollah A. A. Nikougoftar Zarif M. Shahbazfar A. A. (2016 ). Irradiation enhances susceptibility of tumor cells to the antitumor effects of TNF-alpha activated adipose derived mesenchymal stem cells in breast cancer model. Sci. Rep. 6:28433.

    Not in our library10.1038/srep28433

  62. 62.

    Mohr A. Lyons M. Deedigan L. Harte T. Shaw G. Howard L. (2008 ). Mesenchymal stem cells expressing TRAIL lead to tumour growth inhibition in an experimental lung cancer model. J. Cell Mol. Med. 12 2628–2643.

    Not in our library10.1111/j.1582-4934.2008.00317.x

  63. 63.

    Nakamura K. Ito Y. Kawano Y. Kurozumi K. Kobune M. Tsuda H. (2004 ). Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther. 11 1155–1164.

    Not in our library10.1038/sj.gt.3302276

  64. 64.

    NguyenThai Q. A. Sharma N. Luong do H. Sodhi S. S. Kim J. H. Kim N. (2015 ). Targeted inhibition of osteosarcoma tumor growth by bone marrow-derived mesenchymal stem cells expressing cytosine deaminase/5-fluorocytosine in tumor-bearing mice. J. Gene Med. 17 87–99.

    Not in our library10.1002/jgm.2826

  65. 65.

    Nicolay N. H. Lopez Perez R. Ruhle A. Trinh T. Sisombath S. Weber K. J. (2016 ). Mesenchymal stem cells maintain their defining stem cell characteristics after treatment with cisplatin. Sci. Rep. 6:20035.

    Not in our library10.1038/srep20035

  66. 66.

    Nwabo Kamdje A. H. Kamga P. T. Simo R. T. Vecchio L. Seke Etet P. F. Muller J. M. (2017 ). Mesenchymal stromal cells’ role in tumor microenvironment: involvement of signaling pathways. Cancer Biol. Med. 14 129–141.

    Not in our library10.20892/j.issn.2095-3941.2016.0033

  67. 67.

    Otsu K. Das S. Houser S. D. Quadri S. K. Bhattacharya S. Bhattacharya J. (2009 ). Concentration-dependent inhibition of angiogenesis by mesenchymal stem cells. Blood 113 4197–4205.

    Not in our library10.1182/blood-2008-09-176198

  68. 68.

    Pascucci L. Cocce V. Bonomi A. Ami D. Ceccarelli P. Ciusani E. (2014 ). Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery. J. Control. Release 192 262–270.

    Not in our library10.1016/j.jconrel.2014.07.042

  69. 69.

    Pessina A. Cocce V. Pascucci L. Bonomi A. Cavicchini L. Sisto F. (2013 ). Mesenchymal stromal cells primed with Paclitaxel attract and kill leukaemia cells, inhibit angiogenesis and improve survival of leukaemia-bearing mice. Br. J. Haematol. 160 766–778.

    Not in our library10.1111/bjh.12196

  70. 70.

    Pessina A. Piccirillo M. Mineo E. Catalani P. Gribaldo L. Marafante E. (1999 ). Role of SR-4987 stromal cells in the modulation of doxorubicin toxicity to in vitro granulocyte-macrophage progenitors (CFU-GM). Life Sci. 65 513–523.

    Not in our library10.1016/s0024-3205(99)00272-6

  71. 71.

    Pinilla S. Alt E. Abdul Khalek F. J. Jotzu C. Muehlberg F. Beckmann C. (2009 ). Tissue resident stem cells produce CCL5 under the influence of cancer cells and thereby promote breast cancer cell invasion. Cancer Lett. 284 80–85.

    Not in our library10.1016/j.canlet.2009.04.013

  72. 72.

    Pokharel D. Wijesinghe P. Oenarto V. Lu J. F. Sampson D. D. Kennedy B. F. (2016 ). Deciphering cell-to-cell communication in acquisition of cancer traits: extracellular membrane vesicles are regulators of tissue biomechanics. OMICS 20 462–469.

    Not in our library10.1089/omi.2016.0072

  73. 73.

    Ponte A. L. Marais E. Gallay N. Langonne A. Delorme B. Herault O. (2007 ). The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells 25 1737–1745.

    Not in our library10.1634/stemcells.2007-0054

  74. 74.

    Qiao L. Xu Z. Zhao T. Zhao Z. Shi M. Zhao R. C. (2008 ). Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model. Cell Res. 18 500–507.

    Not in our library10.1038/cr.2008.40

  75. 75.

    Ramdasi S. Sarang S. Viswanathan C. (2015 ). Potential of mesenchymal stem cell based application in cancer. Int. J. Hematol. Oncol. Stem Cell Res. 9 95–103.

    Not in our library

  76. 76.

    Rattigan Y. Hsu J. M. Mishra P. J. Glod J. Banerjee D. (2010 ). Interleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu. Exp. Cell Res. 316 3417–3424.

    Not in our library10.1016/j.yexcr.2010.07.002

  77. 77.

    Ren C. Kumar S. Chanda D. Chen J. Mountz J. D. Ponnazhagan S. (2008a ). Therapeutic potential of mesenchymal stem cells producing interferon-alpha in a mouse melanoma lung metastasis model. Stem Cells 26 2332–2338.

    Not in our library10.1634/stemcells.2008-0084

  78. 78.

    Ren C. Kumar S. Chanda D. Kallman L. Chen J. Mountz J. D. (2008b ). Cancer gene therapy using mesenchymal stem cells expressing interferon-beta in a mouse prostate cancer lung metastasis model. Gene Ther. 15 1446–1453.

    Not in our library10.1038/gt.2008.101

  79. 79.

    Ringe J. Strassburg S. Neumann K. Endres M. Notter M. Burmester G. R. (2007 ). Towards in situ tissue repair: human mesenchymal stem cells express chemokine receptors CXCR1, CXCR2 and CCR2, and migrate upon stimulation with CXCL8 but not CCL2. J. Cell. Biochem. 101 135–146.

    Not in our library10.1002/jcb.21172

  80. 80.

    Rivera-Cruz C. M. Shearer J. J. Figueiredo Neto M. Figueiredo M. L. (2017 ). The immunomodulatory effects of mesenchymal stem cell polarization within the tumor microenvironment niche. Stem Cells Int. 2017:4015039.

    Not in our library10.1155/2017/4015039

  81. 81.

    Rustad K. C. Gurtner G. C. (2012 ). Mesenchymal stem cells home to sites of injury and inflammation. Adv. Wound Care 1 147–152.

    Not in our library10.1089/wound.2011.0314

  82. 82.

    Ryu C. H. Park S. H. Park S. A. Kim S. M. Lim J. Y. Jeong C. H. (2011 ). Gene therapy of intracranial glioma using interleukin 12-secreting human umbilical cord blood-derived mesenchymal stem cells. Hum. Gene Ther. 22 733–743.

    Not in our library10.1089/hum.2010.187

  83. 83.

    Sage E. K. Kolluri K. K. McNulty K. Lourenco Sda S. Kalber T. L. Ordidge K. L. (2014 ). Systemic but not topical TRAIL-expressing mesenchymal stem cells reduce tumour growth in malignant mesothelioma. Thorax 69 638–647.

    Not in our library10.1136/thoraxjnl-2013-204110

  84. 84.

    Sasaki M. Abe R. Fujita Y. Ando S. Inokuma D. Shimizu H. (2008 ). Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J. Immunol. 180 2581–2587.

    Not in our library10.4049/jimmunol.180.4.2581

  85. 85.

    Schar M. O. Diaz-Romero J. Kohl S. Zumstein M. A. Nesic D. (2015 ). Platelet-rich concentrates differentially release growth factors and induce cell migration in vitro. Clin. Orthop. Relat. Res. 473 1635–1643.

    Not in our library10.1007/s11999-015-4192-2

  86. 86.

    Sharif S. Ghahremani M. H. Soleimani M. (2017 ). Delivery of exogenous miR-124 to glioblastoma multiform cells by Wharton’s jelly mesenchymal stem cells decreases cell proliferation and migration, and confers chemosensitivity. Stem Cell Rev.

    Not in our library10.1007/s12015-017-9788-3

  87. 87.

    Shi S. Zhang Q. Xia Y. You B. Shan Y. Bao L. (2016 ). Mesenchymal stem cell-derived exosomes facilitate nasopharyngeal carcinoma progression. Am. J. Cancer Res. 6 459–472.

    Not in our library

  88. 88.

    Smith C. L. Chaichana K. L. Lee Y. M. Lin B. Stanko K. M. O’Donnell T. (2015 ). Pre-exposure of human adipose mesenchymal stem cells to soluble factors enhances their homing to brain cancer. Stem Cells Transl. Med. 4 239–251.

    Not in our library10.5966/sctm.2014-0149

  89. 89.

    Son B. R. Marquez-Curtis L. A. Kucia M. Wysoczynski M. Turner A. R. Ratajczak J. (2006 ). Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells 24 1254–1264.

    Not in our library10.1634/stemcells.2005-0271

  90. 90.

    Sordi V. Malosio M. L. Marchesi F. Mercalli A. Melzi R. Giordano T. (2005 ). Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood 106 419–427.

    Not in our library10.1182/blood-2004-09-3507

  91. 91.

    Srinivasula S. M. Hegde R. Saleh A. Datta P. Shiozaki E. Chai J. (2001 ). A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature 410 112–116.

    Not in our library10.1038/35065125

  92. 92.

    Studeny M. Marini F. C. Champlin R. E. Zompetta C. Fidler I. J. Andreeff M. (2002 ). Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res. 62 3603–3608.

    Not in our library

  93. 93.

    Su H. Li J. Osinska H. Li F. Robbins J. Liu J. (2013 ). The COP9 signalosome is required for autophagy, proteasome-mediated proteolysis, and cardiomyocyte survival in adult mice. Circ. Heart Fail. 6 1049–1057.

    Not in our library10.1161/circheartfailure.113.000338

  94. 94.

    Szegezdi E. O’Reilly A. Davy Y. Vawda R. Taylor D. L. Murphy M. (2009 ). Stem cells are resistant to TRAIL receptor-mediated apoptosis. J. Cell Mol. Med. 13 4409–4414.

    Not in our library10.1111/j.1582-4934.2008.00522.x

  95. 95.

    Tsukamoto S. Honoki K. Fujii H. Tohma Y. Kido A. Mori T. (2012 ). Mesenchymal stem cells promote tumor engraftment and metastatic colonization in rat osteosarcoma model. Int. J. Oncol. 40 163–169.

    Not in our library10.3892/ijo.2011.1220

  96. 96.

    Uchibori R. Okada T. Ito T. Urabe M. Mizukami H. Kume A. (2009 ). Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy. J. Gene Med. 11 373–381.

    Not in our library10.1002/jgm.1313

  97. 97.

    Volarevic V. Markovic B. S. Gazdic M. Volarevic A. Jovicic N. Arsenijevic N. (2018 ). Ethical and safety issues of stem cell-based therapy. Int. J. Med. Sci. 15 36–45.

    Not in our library10.7150/ijms.21666

  98. 98.

    Wang G. X. Zhan Y. A. Hu H. L. Wang Y. Fu B. (2012 ). Mesenchymal stem cells modified to express interferon-beta inhibit the growth of prostate cancer in a mouse model. J. Int. Med. Res. 40 317–327.

    Not in our library10.1177/147323001204000132

  99. 99.

    Wang X. J. Xiang B. Y. Ding Y. H. Chen L. Zou H. Mou X. Z. (2017 ). Human menstrual blood-derived mesenchymal stem cells as a cellular vehicle for malignant glioma gene therapy. Oncotarget 8 58309–58321.

    Not in our library10.18632/oncotarget.17621

  100. 100.

    Wu N. Zhang Y. L. Wang H. T. Li D. W. Dai H. J. Zhang Q. Q. (2016 ). Overexpression of hepatocyte nuclear factor 4alpha in human mesenchymal stem cells suppresses hepatocellular carcinoma development through Wnt/beta-catenin signaling pathway downregulation. Cancer Biol. Ther. 17 558–565.

    Not in our library10.1080/15384047.2016.1177675

  101. 101.

    Xia L. Peng R. Leng W. Jia R. Zeng X. Yang X. (2015 ). TRAIL-expressing gingival-derived mesenchymal stem cells inhibit tumorigenesis of tongue squamous cell carcinoma. J. Dent. Res. 94 219–228.

    Not in our library10.1177/0022034514557815

  102. 102.

    Xie C. Yang Z. Suo Y. Chen Q. Wei D. Weng X. (2017 ). Systemically infused mesenchymal stem cells show different homing profiles in healthy and tumor mouse models. Stem Cells Transl. Med. 6 1120–1131.

    Not in our library10.1002/sctm.16-0204

  103. 103.

    Xin H. Kanehira M. Mizuguchi H. Hayakawa T. Kikuchi T. Nukiwa T. (2007 ). Targeted delivery of CX3CL1 to multiple lung tumors by mesenchymal stem cells. Stem Cells 25 1618–1626.

    Not in our library10.1634/stemcells.2006-0461

  104. 104.

    Xu W. T. Bian Z. Y. Fan Q. M. Li G. Tang T. T. (2009 ). Human mesenchymal stem cells (hMSCs) target osteosarcoma and promote its growth and pulmonary metastasis. Cancer Lett. 281 32–41.

    Not in our library10.1016/j.canlet.2009.02.022

  105. 105.

    Yan C. Song X. Yu W. Wei F. Li H. Lv M. (2016 ). Human umbilical cord mesenchymal stem cells delivering sTRAIL home to lung cancer mediated by MCP-1/CCR2 axis and exhibit antitumor effects. Tumour Biol. 37 8425–8435.

    Not in our library10.1007/s13277-015-4746-7

  106. 106.

    Yan Z. Zhuansun Y. Chen R. Li J. Ran P. (2014a ). Immunomodulation of mesenchymal stromal cells on regulatory T cells and its possible mechanism. Exp. Cell Res. 324 65–74.

    Not in our library10.1016/j.yexcr.2014.03.013

  107. 107.

    Yan Z. Zhuansun Y. Liu G. Chen R. Li J. Ran P. (2014b ). Mesenchymal stem cells suppress T cells by inducing apoptosis and through PD-1/B7-H1 interactions. Immunol. Lett. 162(1 Pt A) 248–255.

    Not in our library10.1016/j.imlet.2014.09.013

  108. 108.

    Yang L. Zhang Y. Cheng L. Yue D. Ma J. Zhao D. (2016 ). Mesenchymal stem cells engineered to secrete pigment epithelium-derived factor inhibit tumor metastasis and the formation of malignant ascites in a murine colorectal peritoneal carcinomatosis model. Hum. Gene Ther. 27 267–277.

    Not in our library10.1089/hum.2015.135

  109. 109.

    Yang X. Du J. Xu X. Xu C. Song W. (2014 ). IFN-gamma-secreting-mesenchymal stem cells exert an antitumor effect in vivo via the TRAIL pathway. J. Immunol. Res. 2014:318098.

    Not in our library10.1155/2014/318098

  110. 110.

    Yang Z. S. Tang X. J. Guo X. R. Zou D. D. Sun X. Y. Feng J. B. (2014 ). Cancer cell-oriented migration of mesenchymal stem cells engineered with an anticancer gene (PTEN): an imaging demonstration. Onco Targets Ther. 7 441–446.

    Not in our library10.2147/ott.s59227

  111. 111.

    You Q. Yao Y. Zhang Y. Fu S. Du M. Zhang G. (2015 ). Effect of targeted ovarian cancer therapy using amniotic fluid mesenchymal stem cells transfected with enhanced green fluorescent protein-human interleukin-2 in vivo. Mol. Med. Rep. 12 4859–4866.

    Not in our library10.3892/mmr.2015.4076

  112. 112.
  113. 113.

    Yuan Z. Kolluri K. K. Sage E. K. Gowers K. H. Janes S. M. (2015 ). Mesenchymal stromal cell delivery of full-length tumor necrosis factor-related apoptosis-inducing ligand is superior to soluble type for cancer therapy. Cytotherapy 17 885–896.

    Not in our library10.1016/j.jcyt.2015.03.603

  114. 114.

    Zhang B. Shan H. Li D. Li Z. R. Zhu K. S. Jiang Z. B. (2012 ). The inhibitory effect of MSCs expressing TRAIL as a cellular delivery vehicle in combination with cisplatin on hepatocellular carcinoma. Cancer Biol. Ther. 13 1175–1184.

    Not in our library10.4161/cbt.21347

  115. 115.

    Zhang J. Hou L. Wu X. Zhao D. Wang Z. Hu H. (2016 ). Inhibitory effect of genetically engineered mesenchymal stem cells with Apoptin on hepatoma cells in vitro and in vivo. Mol. Cell. Biochem. 416 193–203.

    Not in our library10.1007/s11010-016-2707-0

  116. 116.

    Zhao W. H. Cheng J. X. Shi P. F. Huang J. Y. (2011 ). Human umbilical cord mesenchymal stem cells with adenovirus-mediated interleukin 12 gene transduction inhibits the growth of ovarian carcinoma cells both in vitro and in vivo. Nan Fang Yi Ke Da Xue Xue Bao 31 903–907.

    Not in our library

  117. 117.

    Zhu Y. Cheng M. Yang Z. Zeng C. Y. Chen J. Xie Y. (2014 ). Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts. Drug Des. Dev. Ther. 8 2449–2462.

    Not in our library10.2147/dddt.s71466

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