Immunotherapy by mesenchymal stromal cell delivery of oncolytic viruses for treating metastatic tumors
2022; Elsevier BV; Volume: 25; Linguagem: Inglês
10.1016/j.omto.2022.03.008
ISSN2372-7705
AutoresA‐Rum Yoon, Cosette M. Rivera‐Cruz, Jeffrey M. Gimble, Chae‐Ok Yun, Marxa L. Figueiredo,
Tópico(s)Cancer Research and Treatments
ResumoOncolytic viruses (OVs) have emerged as a very promising anti-cancer therapeutic strategy in the past decades. However, despite their pre-clinical promise, many OV clinical evaluations for cancer therapy have highlighted the continued need for their improved delivery and targeting. Mesenchymal stromal cells (MSCs) have emerged as excellent candidate vehicles for the delivery of OVs due to their tumor-homing properties and low immunogenicity. MSCs can enhance OV delivery by protecting viruses from rapid clearance following administration and also by more efficiently targeting tumor sites, consequently augmenting the therapeutic potential of OVs. MSCs can function as "biological factories," enabling OV amplification within these cells to promote tumor lysis following MSC-OV arrival at the tumor site. MSC-OVs can promote enhanced safety profiles and therapeutic effects relative to OVs alone. In this review we explore the general characteristics of MSCs as delivery tools for cancer therapeutic agents. Furthermore, we discuss the potential of OVs as immune therapeutics and highlight some of the promising applications stemming from combining MSCs to achieve enhanced delivery and anti-tumor effectiveness of OVs at different pre-clinical and clinical stages. We further provide potential pitfalls of the MSC-OV platform and the strategies under development for enhancing the efficacy of these emerging therapeutics. Oncolytic viruses (OVs) have emerged as a very promising anti-cancer therapeutic strategy in the past decades. However, despite their pre-clinical promise, many OV clinical evaluations for cancer therapy have highlighted the continued need for their improved delivery and targeting. Mesenchymal stromal cells (MSCs) have emerged as excellent candidate vehicles for the delivery of OVs due to their tumor-homing properties and low immunogenicity. MSCs can enhance OV delivery by protecting viruses from rapid clearance following administration and also by more efficiently targeting tumor sites, consequently augmenting the therapeutic potential of OVs. MSCs can function as "biological factories," enabling OV amplification within these cells to promote tumor lysis following MSC-OV arrival at the tumor site. MSC-OVs can promote enhanced safety profiles and therapeutic effects relative to OVs alone. In this review we explore the general characteristics of MSCs as delivery tools for cancer therapeutic agents. Furthermore, we discuss the potential of OVs as immune therapeutics and highlight some of the promising applications stemming from combining MSCs to achieve enhanced delivery and anti-tumor effectiveness of OVs at different pre-clinical and clinical stages. We further provide potential pitfalls of the MSC-OV platform and the strategies under development for enhancing the efficacy of these emerging therapeutics. IntroductionCancer is one of the leading causes of mortality worldwide, accounting for almost 10 million deaths in 2020.1Ferlay J. Ervik M. Lam F. Colombet M. Mery L. Piñeros M. Znaor A. Soerjomataram I. Bray F. Global cancer observatory: cancer today.https://gco.iarc.fr/today/Date: 2020Google Scholar Whereas outstanding advancements in cancer treatment have been made in the past decades, stemming from novel and effective chemotherapeutics, targeted antibodies, and immunotherapeutics,2Shahid K. Khalife M. Dabney R. Phan A.T. Immunotherapy and targeted therapy-the new roadmap in cancer treatment.Ann. Transl. Med. 2019; 7: 595https://doi.org/10.21037/atm.2019.05.58Google Scholar several tumor types still display resistance to available therapies or undergo recurrence following treatment. These challenges to treatment success, along with the late-stage diagnosis of many cancer types, result in limited treatment options and reduced survivability in afflicted patients.The use of oncolytic viruses (OVs) represents an alternative strategy for the treatment of various cancers. OVs typically are replication-competent viruses that can infect and replicate within tumor but not normal cells.3Kirn D. Oncolytic virotherapy for cancer with the adenovirus dl1520 (Onyx-015): results of phase I and II trials.Expert Opin. Biol. Ther. 2001; 1: 525-538https://doi.org/10.1517/14712598.1.3.525Google Scholar,4Ganly I. Kirn D. Eckhardt G. Rodriguez G.I. Soutar D.S. Otto R. Robertson A.G. Park O. Gulley M.L. Heise C. et al.A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer.Clin. Cancer Res. 2000; 6: 798-806Google Scholar This tumor selectivity can be naturally occurring or achieved by genetic engineering. These genetic manipulations can be performed to enhance the therapeutic efficacy of these viruses, for example, by addition of factors to disrupt cancer-specific pathways or overcome resistance mechanisms encountered at the tumor site. The selective cytopathic effects of these viruses in the tumors can also stimulate the establishment of anti-tumor immunity.5Lawler S.E. Speranza M.C. Cho C.F. Chiocca E.A. Oncolytic viruses in cancer treatment: a review.JAMA Oncol. 2017; 3: 841-849https://doi.org/10.1001/jamaoncol.2016.2064Google ScholarSeveral OVs have shown promise in pre-clinical and clinical studies, including oncolytic herpes simplex type virus (oHSV), oncolytic adenovirus (oAd), and oncolytic measles virus (oMV). Tumor cell lysis by OVs can result in the release of pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and tumor-associated antigens (TAAs) as well as elevated production of various cytokines and chemokines, such as type I interferons (IFNs).6Brown M.C. Holl E.K. Boczkowski D. Dobrikova E. Mosaheb M. Chandramohan V. Bigner D.D. Gromeier M. Nair S.K. Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of dendritic cells and tumor antigen-specific CTLs.Sci. Transl. Med. 2017; 9https://doi.org/10.1126/scitranslmed.aan4220Google Scholar All of these by-products of the oncolytic process can augment various aspects of the anti-tumor immune response (both innate and adaptive), including TAA presentation by antigen-presenting cells (APCs), induction of tumor-specific T cell responses, and immune activation in the tumor microenvironment.7Bommareddy P.K. Shettigar M. Kaufman H.L. Integrating oncolytic viruses in combination cancer immunotherapy.Nat. Rev. Immunol. 2018; 18: 498-513https://doi.org/10.1038/s41577-018-0014-6Google Scholar,8Felt S.A. Grdzelishvili V.Z. Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update.J. Gen. Virol. 2017; https://doi.org/10.1099/jgv.0.000980Google Scholar Further, engineering OVs to express immunomodulatory genes may further augment the potential for these vectors to stimulate anti-tumor immunity. Several immune-stimulatory agents (and their combinations) that can alter the tumor microenvironment and ultimately promise to promote long-lasting clinical therapeutic benefit are under examination. Examples include exploring the expression of IFN-β to increase the immunogenicity of OV-treated tumor cells or delivering interleukin-12 (IL-12) and IL-18 via an OV, which promote potent anti-tumor effects of natural killer (NK) and cytotoxic T cell activity.9Boagni D.A. Ravirala D. Shaun Xiaoliu Z. Current strategies in engaging oncolytic viruses with antitumor immunity.Mol. Ther. Oncolytics. 2021; https://doi.org/10.1016/j.omto.2021.05.002Google Scholar However, despite the highly promising features of OVs, a challenge to their use exists in the rapid clearance of the virions if administered without a vehicle, due to recognition by the immune system or sequestration in off-target sites, leading to poor accumulation at the tumor site and limited therapeutic efficacy.10Zheng M. Huang J. Tong A. Yang H. Oncolytic viruses for cancer therapy: barriers and recent advances.Mol. Ther. Oncolytics. 2019; 15: 234-247https://doi.org/10.1016/j.omto.2019.10.007Google ScholarA promising strategy for the delivery of cancer therapeutic agents is the use of mesenchymal stromal cells (MSCs) as vehicles. MSCs are considered potential vehicles for therapeutic payloads (i.e., drugs, OVs, etc.) to solid tumors owing to their tumor tropism and limited immunogenicity. MSCs home to tumors because the tumor microenvironment resembles that of non-healing wounds.11Li P. Gong Z. Shultz L.D. Ren G. Mesenchymal stem cells: from regeneration to cancer.Pharmacol. Ther. 2019; 200: 42-54https://doi.org/10.1016/j.pharmthera.2019.04.005Google Scholar,12Zhang M. Zhang J. Ran S. Sun W. Zhu Z. Polydopamine-assisted decoration of Se nanoparticles on curcumin-incorporated nanofiber matrices for localized synergistic tumor-wound therapy.Biomater. Sci. 2021; https://doi.org/10.1039/d1bm01607eGoogle Scholar These traits render them excellent candidates for the delivery of therapeutic cargo to the tumor site while protecting it from immune clearance.13Cheng S. Nethi S.K. Rathi S. Layek B. Prabha S. Engineered mesenchymal stem cells for targeting solid tumors: therapeutic potential beyond regenerative therapy.J. Pharmacol. Exp. Ther. 2019; 370: 231-241https://doi.org/10.1124/jpet.119.259796Google Scholar,14Hmadcha A. Martin-Montalvo A. Gauthier B.R. Soria B. Capilla-Gonzalez V. Therapeutic potential of mesenchymal stem cells for cancer therapy.Front. Bioeng. Biotechnol. 2020; 8: 43https://doi.org/10.3389/fbioe.2020.00043Google Scholar In addition, in the case of OVs, cellular vehicles such as MSCs also can act as biological factories for these therapeutic agents, as this vehicle platform allows for replication of the OV cargo.15Yoon A.R. Hong J. Li Y. Shin H.C. Lee H. Kim H.S. Yun C.O. Mesenchymal stem cell-mediated delivery of an oncolytic adenovirus enhances antitumor efficacy in hepatocellular carcinoma.Cancer Res. 2019; 79: 4503-4514https://doi.org/10.1158/0008-5472.Can-18-3900Google Scholar Importantly, the combination of all of these properties indicates that MSC delivery of OVs may enable high accumulation of OVs at tumors while maintaining a low toxicity profile to patients.In this review, we explore the emergence and evolution of MSCs as a cellular vehicle for delivering various cancer therapeutics. Among the many possible MSC cargoes, we mainly focus on OVs and discuss the advances and present understanding of OV-mediated immunity and oncolysis. We review the promise of using MSCs as delivery vehicles for OVs in both the pre-clinical and the clinical landscape. This review also further discusses the key challenges to the clinical use of the MSC-OV platform, as well as groundbreaking innovations that have been made recently to further improve MSC-mediated therapy.Rationale for using MSCs as a cellular delivery vehicleMSC types and their characteristicsMSCs are a heterogeneous population of multipotent cells of mesenchymal origin that are of interest for several clinical applications, from tissue regeneration to cancer therapeutics, because of their ability to home toward sites of injury, differentiate into multiple lineages, and participate in tissue repair and immunomodulation.16Rodríguez-Fuentes D.E. Fernández-Garza L.E. Samia-Meza J.A. Barrera-Barrera S.A. Caplan A.I. Barrera-Saldaña H.A. Mesenchymal stem cells current clinical applications: a systematic review.Arch. Med. Res. 2021; 52: 93-101https://doi.org/10.1016/j.arcmed.2020.08.006Google ScholarAlthough the term "mesenchymal stem cell" was not adopted until 1991,17Caplan A.I. Mesenchymal stem cells.J. Orthop. Res. 1991; 9: 641-650https://doi.org/10.1002/jor.1100090504Google Scholar this population was first described as a subpopulation of bone marrow cells with osteogenic potential by Friedenstein and co-workers in their seminal studies conducted in the 1960s and 1970s.18Bianco P. Robey P.G. Simmons P.J. Mesenchymal stem cells: revisiting history, concepts, and assays.Cell Stem Cell. 2008; 2: 313-319https://doi.org/10.1016/j.stem.2008.03.002Google Scholar Since then, MSCs have been isolated from several species and from many tissue sources, including the bone marrow, adipose tissue, dental pulp, birth-derived tissues, peripheral blood, synovium, endometrium, and others.19Berebichez-Fridman R. Montero-Olvera P.R. Sources and clinical applications of mesenchymal stem cells: state-of-the-art review.Sultan Qaboos Univ. Med. J. 2018; 18: e264-e277https://doi.org/10.18295/squmj.2018.18.03.002Google Scholar In addition, MSCs also have been effectively produced from induced pluripotent stem cells (iPSCs).20Lian Q. Zhang Y. Zhang J. Zhang H.K. Wu X. Lam F.F. Kang S. Xia J.C. Lai W.H. Au K.W. et al.Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemia in mice.Circulation. 2010; 121: 1113-1123https://doi.org/10.1161/CIRCULATIONAHA.109.898312Google ScholarWhile the terminology "mesenchymal stem cell" was the original denomination and is often used in the literature to describe these cells, the International Society for Cellular Therapy (ISCT) currently recommends the use of the term "mesenchymal stromal cells" to define them. As per the ISCT position statements,21Horwitz E.M. Le Blanc K. Dominici M. Mueller I. Slaper-Cortenbach I. Marini F.C. Deans R.J. Krause D.S. Keating A. Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement.Cytotherapy. 2005; 7: 393-395https://doi.org/10.1080/14653240500319234Google Scholar,22Viswanathan S. Shi Y. Galipeau J. Krampera M. Leblanc K. Martin I. Nolta J. Phinney D.G. Sensebe L. Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy (ISCT®) mesenchymal stromal cell committee position statement on nomenclature.Cytotherapy. 2019; 21: 1019-1024https://doi.org/10.1016/j.jcyt.2019.08.002Google Scholar the former term is recommended to be used to refer to a progenitor cell population with demonstrable functionality of self-renewal and differentiation. The latter is to be used to refer to a bulk population with notable secretory, homing, and immunomodulatory properties, although some mesenchymal stem cells may be present within the MSC population. Furthermore, because of inconsistent definition of the MSC characteristics among investigators, in 2006 the ISCT proposed a set of minimal criteria to distinguish MSCs or multipotent MSCs.23Dominici M. Le Blanc K. Mueller I. Slaper-Cortenbach I. Marini F. Krause D. Deans R. Keating A. Prockop D. Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.Cytotherapy. 2006; 8: 315-317https://doi.org/10.1080/14653240600855905Google Scholar The first criterion is that MSCs must be plastic-adherent when maintained under standard culture conditions. Second, MSCs must meet specific surface-antigen expression profiles, as measured by flow cytometry. The MSC population must express (≥95%) CD105 (endoglin), CD73 (ecto-5′-nucleotidase), and CD90 (THY-1) and lack expression of (≤2%) CD45 (leukocyte common antigen), CD34 (hematopoietic progenitor cell antigen CD34), CD14 (monocyte differentiation antigen CD14) or CD11b (integrin subunit αM), CD79α (B cell antigen receptor complex-associated protein α) or CD19 (B lymphocyte surface antigen B4), and human leukocyte antigen (HLA) class II. Last, MSCs must be able to differentiate at a minimum into osteoblasts, adipocytes, and chondroblasts under standard in vitro differentiation conditions. Nevertheless, how to more thoroughly define MSCs remains an area of continued investigation, and additional phenotypical and functional properties, such as immune functionality, are being explored as alternative metrics to identify this population.24Galipeau J. Krampera M. Barrett J. Dazzi F. Deans R.J. DeBruijn J. Dominici M. Fibbe W.E. Gee A.P. Gimble J.M. et al.International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials.Cytotherapy. 2016; 18: 151-159https://doi.org/10.1016/j.jcyt.2015.11.008Google Scholar Of note, the established minimal identification criteria likely best fit in vitro-expanded MSCs and may need to be carefully revised for tissue-resident or freshly isolated MSCs, as recent evidence suggests some altered MSC characteristics may develop upon in vitro expansion. For example, whereas CD34 is typically included as a negative marker, its expression can be detected in tissue-resident MSCs, suggesting that its expression is lost during in vitro cultivation.25Lin C.S. Ning H. Lin G. Lue T.F. Is CD34 truly a negative marker for mesenchymal stromal cells?.Cytotherapy. 2012; 14: 1159-1163https://doi.org/10.3109/14653249.2012.729817Google Scholar,26Kaiser S. Hackanson B. Follo M. Mehlhorn A. Geiger K. 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Samia-Meza J.A. Barrera-Barrera S.A. Caplan A.I. Barrera-Saldaña H.A. Mesenchymal stem cells current clinical applications: a systematic review.Arch. Med. Res. 2021; 52: 93-101https://doi.org/10.1016/j.arcmed.2020.08.006Google Scholar,31Lalu M.M. McIntyre L. Pugliese C. Fergusson D. Winston B.W. Marshall J.C. Granton J. Stewart D.J. Canadian Critical Care Trials GroupSafety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials.PLoS One. 2012; 7: e47559https://doi.org/10.1371/journal.pone.0047559Google ScholarBenefits of MSCs as delivery agents for anti-tumor therapiesSeveral of the functional properties of MSCs have rendered them a potential candidate for use in the delivery of anti-cancer therapeutics.14Hmadcha A. Martin-Montalvo A. Gauthier B.R. Soria B. Capilla-Gonzalez V. Therapeutic potential of mesenchymal stem cells for cancer therapy.Front. Bioeng. Biotechnol. 2020; 8: 43https://doi.org/10.3389/fbioe.2020.00043Google Scholar Similar to the observed behavior of MSCs in response to signals produced at sites of injury, MSCs are recruited to tumor sites.32Kidd S. Spaeth E. Dembinski J.L. Dietrich M. Watson K. Klopp A. Battula V.L. Weil M. Andreeff M. Marini F.C. Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging.Stem Cells. 2009; 27: 2614-2623https://doi.org/10.1002/stem.187Google Scholar This, in conjunction with the immune-evasive status of these cells, renders them a potential vehicle for the delivery of therapeutic payloads such as chemotherapeutics,33Layek B. Sadhukha T. Panyam J. Prabha S. Nano-engineered mesenchymal stem cells increase therapeutic efficacy of anticancer drug through true active tumor targeting.Mol. Cancer Ther. 2018; 17: 1196-1206https://doi.org/10.1158/1535-7163.MCT-17-0682Google Scholar therapeutic antibodies,34Zhang X. Yang Y. 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Mesenchymal stem cell-mediated delivery of an oncolytic adenovirus enhances antitumor efficacy in hepatocellular carcinoma.Cancer Res. 2019; 79: 4503-4514https://doi.org/10.1158/0008-5472.Can-18-3900Google Scholar and lung42Rincón E. Cejalvo T. Kanojia D. Alfranca A. Rodríguez-Milla M. Gil Hoyos R.A. Han Y. Zhang L. Alemany R. Lesniak M.S. García-Castro J. Mesenchymal stem cell carriers enhance antitumor efficacy of oncolytic adenoviruses in an immunocompetent mouse model.Oncotarget. 2017; 8: 45415-45431https://doi.org/10.18632/oncotarget.17557Google Scholar cancers and others (Figure 1). Although the mechanisms of MSC tumor homing are not fully understood, several molecules and receptors have been identified as implicated in this process.In studies assessing MSC migration toward lung and breast cancer cell lines, macrophage migration inhibitory factor (MIF) was identified as a key chemoattractant during MSC recruitment to tumors.43Lourenco S. Teixeira V.H. Kalber T. Jose R.J. Floto R.A. Janes S.M. Macrophage migration inhibitory factor-CXCR4 is the dominant chemotactic axis in human mesenchymal stem cell recruitment to tumors.J. Immunol. 2015; 194: 3463-3474https://doi.org/10.4049/jimmunol.1402097Google Scholar MIF was shown to interact physically with the receptors C-X-C motif chemokine receptor (CXCR) 2, CXCR4, and CD74 (HLA class II histocompatibility antigen γ chain) in MSCs, yet MIF/CXCR4 was identified as the main axis driving MSC tumor homing. While the stromal cell-derived factor 1 (SDF-1)/CXCR4 axis is one of the most studied in MSC homing to injury sites, in this study, SDF-1 was not detected at significant levels within the molecules secreted by the cancer cell lines examined. Nonetheless, SDF-1 has been reported by others as being important in MSC migration toward tumors.44Gao H. Priebe W. Glod J. Banerjee D. Activation of signal transducers and activators of transcription 3 and focal adhesion kinase by stromal cell-derived factor 1 is required for migration of human mesenchymal stem cells in response to tumor cell-conditioned medium.Stem Cells. 2009; 27: 857-865https://doi.org/10.1002/stem.23Google Scholar,45Menon L.G. Picinich S. Koneru R. Gao H. Lin S.Y. Koneru M. Mayer-Kuckuk P. Glod J. Banerjee D. Differential gene expression associated with migration of mesenchymal stem cells to conditioned medium from tumor cells or bone marrow cells.Stem Cells. 2007; 25: 520-528https://doi.org/10.1634/stemcells.2006-0257Google Scholar In these reports, SDF-1 was shown to be upregulated in MSCs exposed to tumor cell-conditioned medium,34Zhang X. Yang Y. Zhang L. Lu Y. Zhang Q. Fan D. Zhang Y. Zhang Y. Ye Z. Xiong D. Mesenchymal stromal cells as vehicles of tetravalent bispecific Tandab (CD3/CD19) for the treatment of B cell lymphoma combined with Ido pathway inhibitor D-1-methyl-tryptophan.J. Hematol. Oncol. 2017; 10: 56https://doi.org/10.1186/s13045-017-0397-zGoogle Scholar and exposure of MSCs to recombinant SDF-1 led to activation of the Janus kinase 2/signal transducer and activator of transcription 3 (Jak2/STAT3) and mitogen-activated protein kinase/extracellular-signal-regulated kinase (MEK/ERK) signaling pathways, which in turn promoted MSC migration,33Layek B. Sadhukha T. Panyam J. Prabha S. Nano-engineered mesenchymal stem cells increase therapeutic efficacy of anticancer drug through true active tumor targeting.Mol. Cancer Ther. 2018; 17: 1196-1206https://doi.org/10.1158/1535-7163.MCT-17-0682Google Scholar suggesting that SDF-1 acts in an autocrine manner to prepare MSCs to home toward the tumor microenvironment.Other cytokines and their receptors also have been implicated in MSC tumor homing. The C-X-C motif chemokine ligand (CXCL) 16/CXCR6 axis has been shown to play an important role in the recruitment of MSCs to prostate tumors.46Jung Y. Kim J.K. Shiozawa Y. Wang J. Mishra A. Joseph J. Berry J.E. McGee S. Lee E. Sun H. et al.Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis.Nat. Commun. 2013; 4: 1795https://doi.org/10.1038/ncomms2766Google Scholar Signaling through the IL-6/IL-6 receptor axis has been identified as being important for the migration to hypoxic breast cancer tumor cells.47Rattigan Y. Hsu J.M. Mishra P.J. Glod J. Banerjee D. Interleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu.Exp. Cell Res. 2010; 316: 3417-3424https://doi.org/10.1016/j.yexcr.2010.07.002Google Scholar Monocyte chemotactic protein-1 has been reported to have a role in the recruitment of MSCs to primary breast tumors.48Dwyer R.M. Potter-Beirne S.M. Harrington K.A. Lowery A.J. Hennessy E. Murphy J.M. Barry F.P. O'Brien T. Kerin M.J. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells.Clin. Cancer Res. 2007; 13: 5020-5027https://doi.org/10.1158/1078-0432.CCR-07-0731Google Scholar Additional examples of factors involved in MSC migration include IL-8,49Kim S.M. Kim D.S. Jeong C.H. Kim D.H. Kim J.H. Jeon H.B. Kwon S.J. Jeun S.S. Yang Y.S. Oh W. Chang J.W. CXC chemokine receptor 1 enhances the ability of human umbilical cord blood-derived mesenchymal stem cells to migrate toward gliomas.Biochem. Biophys. Res. Commun. 2011; 407: 741-746https://doi.org/10.1016/j.bbrc.2011.03.093Google Scholar fibroblast growth factor 2,50Ritter E. Perry A. Yu J. Wang T. Tang L. Bieberich E. Breast cancer cell-derived fibroblast growth factor 2 and vascular endothelial growth factor are chemoattractants for bone marrow stromal stem cells.Ann. Surg. 2008; 247: 310-314https://doi.org/10.1097/SLA.0b013e31816401d5Google Scholar vascular endothelial growth factor,50Ritter E. Perry A. Yu J. Wang T. Tang L. Bieberich E. Breast cancer cell-derived fibroblast growth factor 2 and vascular endothelial growth factor are chemoattractants for bone marrow stromal stem cells.Ann. Surg. 2008; 247: 310-314https://doi.org/10.1097/SLA.0b013e31816401d5Google Scholar cyclophilin B,51Lin S.Y. Yang J. Everett A.D. Clevenger C.V. Koneru M. Mishra P.J. Kamen B. Banerjee D. Glod J. The isolation of novel mesenchymal stromal cell chemotactic factors from the conditioned medium of tumor cells.Exp. Cell Res. 2008; 314: 3107-3117https://doi.org/10.1016/j.yexcr.2008.07.028Google Scholar and hepatoma-derived growth factor.51Lin S.Y. Yang J. Everett A.D. Clevenger C.V. Koneru M. Mishra P.J. Kamen B. Banerjee D. Glod J. The isolation of novel mesenchymal stromal cell che
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