Oncogenic transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer survival

AbstractBone marrow-derived human mesenchymal stem cells (hMSCs) are recruited to damaged or inflamed tissues where they contribute to tissue repair. This multi-step process involves chemokine-directed invasion of hMSCs and on-site release of factors that influence target cells or tumor tissues. However, the underlying molecular mechanisms are largely unclear. Previously, we described that microRNA let-7f controls hMSC differentiation. Here, we investigated the role of let-7f in chemotactic invasion and paracrine anti-tumor effects. Incubation with stromal cell-derived factor-1α (SDF-1α) or inflammatory cytokines upregulated let-7f expression in hMSCs. Transfection of hMSCs with let-7f mimics enhanced CXCR4-dependent invasion by augmentation of pericellular proteolysis and release of matrix metalloproteinase-9. Hypoxia-induced stabilization of the hypoxia-inducible factor 1 alpha in hMSCs promoted cell invasion via let-7f and activation of autophagy. Dependent on its endogenous level, let-7f facilitated hMSC motility and invasion through regulation of the autophagic flux in these cells. In addition, secreted let-7f encapsulated in exosomes was increased upon upregulation of endogenous let-7f by treatment of the cells with SDF-1α, hypoxia, or induction of autophagy. In recipient 4T1 tumor cells, hMSC-derived exosomal let-7f attenuated proliferation and invasion. Moreover, implantation of 3D spheroids composed of hMSCs and 4T1 cells into a breast cancer mouse model demonstrated that hMSCs overexpressing let-7f inhibited tumor growth in vivo. Our findings provide evidence that let-7f is pivotal in the regulation of hMSC invasion in response to inflammation and hypoxia, suggesting that exosomal let-7f exhibits paracrine anti-tumor effects.

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Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo

Cancer Letters ◽

10.1016/j.canlet.2011.10.002 ◽

2012 ◽

Vol 315 (1) ◽

pp. 28-37 ◽

Cited By ~ 238

Author(s):

Wei Zhu ◽

Ling Huang ◽

Yahong Li ◽

Xu Zhang ◽

Jianmei Gu ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Human Bone ◽

Human Bone Marrow ◽

Promote Tumor Growth ◽

Marrow Mesenchymal Stem Cells

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Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth

Leukemia ◽

10.1038/sj.leu.2404489 ◽

2006 ◽

Vol 21 (2) ◽

pp. 304-310 ◽

Cited By ~ 256

Author(s):

R Ramasamy ◽

E W-F Lam ◽

I Soeiro ◽

V Tisato ◽

D Bonnet ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Tumor Cells ◽

Proliferation And Apoptosis

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Decidua mesenchymal stem cells migrated toward mammary tumors in vitro and in vivo affecting tumor growth and tumor development

Cancer Gene Therapy ◽

10.1038/cgt.2012.71 ◽

2012 ◽

Vol 20 (1) ◽

pp. 8-16 ◽

Cited By ~ 30

Author(s):

I Vegh ◽

M Grau ◽

M Gracia ◽

J Grande ◽

P de la Torre ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Tumor Development ◽

Mammary Tumors

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Mesenchymal stem cells promote glioma neovascularization in vivo by fusing with cancer stem cells

BMC Cancer ◽

10.1186/s12885-019-6460-0 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 5

Author(s):

Chao Sun ◽

Xingliang Dai ◽

Dongliang Zhao ◽

Haiyang Wang ◽

Xiaoci Rong ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Tumor Growth ◽

Glioma Cells ◽

Stem Cell Markers ◽

Xenograft Tumor ◽

Angiogenic Effect

Abstract Background and objective Tumor angiogenesis is vital for tumor growth. Recent evidence indicated that bone marrow-derived mesenchymal stem cells (BMSCs) can migrate to tumor sites and exert critical effects on tumor growth through direct and/or indirect interactions with tumor cells. However, the effect of BMSCs on tumor neovascularization has not been fully elucidated. This study aimed to investigate whether fusion cells from glioma stem cells and BMSCs participated in angiogenesis. Methods SU3-RFP cells were injected into the right caudate nucleus of NC-C57Bl/6 J-GFP nude mice, and the RFP+/GFP+ cells were isolated and named fusion cells. The angiogenic effects of SU3-RFP, BMSCs and fusion cells were compared in vivo and in vitro. Results Fusion cells showed elevated levels of CD31, CD34 and VE-Cadherin (markers of VEC) as compared to SU3-RFP and BMSCs. The MVD-CD31 in RFP+/GFP+ cell xenograft tumor was significantly greater as compared to that in SU3-RFP xenograft tumor. In addition, the expression of CD133 and stem cell markers Nanog, Oct4 and Sox2 were increased in fusion cells as compared to the parental cells. Fusion cells exhibited enhanced angiogenic effect as compared to parental glioma cells in vivo and in vitro, which may be related to their stem cell properties. Conclusion Fusion cells exhibited enhanced angiogenic effect as compared to parental glioma cells in vivo and in vitro, which may be related to their stem cell properties. Hence, cell fusion may contribute to glioma angiogenesis.

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Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals

Blood ◽

10.1182/blood-2003-04-1193 ◽

2003 ◽

Vol 102 (10) ◽

pp. 3837-3844 ◽

Cited By ~ 788

Author(s):

Farida Djouad ◽

Pascale Plence ◽

Claire Bony ◽

Philippe Tropel ◽

Florence Apparailly ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Side Effects ◽

Tumor Growth ◽

Tumor Model ◽

Bone Morphogenetic Protein 2 ◽

Melanoma Tumor ◽

Immunocompetent Mice

Abstract Mesenchymal stem cells (MSCs) are largely studied for their potential clinical use. Recently, they have gained further interest after demonstration of an immunosuppressive role. In this study, we investigated whether in vivo injection of MSCs could display side effects related to systemic immunosuppression favoring tumor growth. We first showed in vitro that the murine C3H10T1/2 (C3) MSC line and primary MSCs exhibit immunosuppressive properties in mixed lymphocyte reaction. We demonstrated that this effect is mediated by soluble factors, secreted only on “activation” of MSCs in the presence of splenocytes. Moreover, the immunosuppression is mediated by CD8+ regulatory cells responsible for the inhibition of allogeneic lymphocyte proliferation. We then demonstrated that the C3 MSCs expressing the human bone morphogenetic protein 2 (hBMP-2) differentiation factor were not rejected when implanted in various allogeneic immunocompetent mice and were still able to differentiate into bone. Importantly, using a murine melanoma tumor model, we showed that the subcutaneous injection of B16 melanoma cells led to tumor growth in allogeneic recipients only when MSCs were coinjected. Although the potential side effects of immunosuppression induced by MSCs have to be considered in further clinical studies, the usefulness of MSCs for various therapeutic applications still remains of great interest. (Blood. 2003;102:3837-3844)

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Mesenchymal stem cells selectively engraft into tumor stroma and produce potent antitumor proteins in situ

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3025 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3025-3025

Author(s):

M. Andreeff ◽

J. Dembinski ◽

M. Studeny ◽

X. Ling ◽

T. McQueen ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Metastatic Breast ◽

Tumor Stroma ◽

Firefly Luciferase ◽

Scid Mice ◽

Renilla Luciferase ◽

Immunocompetent Mice

3025 Background: The formation of stroma is essential for tumor growth and involves complex interactions between malignant cells and non-tumor stromal cells. We have previously demonstrated that IV injected bone marrow derived mesenchymal stem cells (MSC) integrate into solid tumors as stromal elements (Cancer Res 62:3603, 2002; JNCI 96:1593, 2004). Methods: MSC were labeled by a fiber modified Ad vector expressing firefly luciferase (AdLux-F/RGD), injected into normal or tumor-bearing SCID mice, and biodistributed MSC-Lux were imaged utilizing the Xenogen IVIS system. Results: After IP injection, no hMSC-LUX were detected in normal animals after 7 days, while strong punctate regions of LUX-activity were observed in ovarian tumors. Tumor cells transduced with renilla luciferase constructs co- localized with firefly luciferase MSC. Next, we examined whether hMSC-producing interferon-beta (IFNβ-MSC) could inhibit the growth of metastatic tumors in the lungs of SCID mice. When injected IV (4 doses of 106 MSC/week) into SCID mice with pulmonary metastases of carcinomas or melanomas, tumor growth was significantly inhibited as compared with untreated or vector-control MSC controls (p= 0.007). IV injected IFNb-MSC prolonged the survival of mice bearing metastatic breast carcinomas (p=0.001). In an orthotopic, chemoresistant breast cancer model in syngeneic immunocompetent mice, MSC producing IFN-β completely abrograted tumor growth. Localized low-dose XRT to tumors significantly increased the number of tumor-resident MSC. Conclusions: The data suggest that systemically administered gene-modified MSC selectively engraft into the tumor microenvironment and remain resident as part of the tumor architecture. MSC-expressing IFN-β inhibit the growth of melanomas, gliomas, metastatic breast and ovarian cancers in vivo and prolong the survival of mice bearing established tumors. Clinical trials are in preparation. No significant financial relationships to disclose.

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Extracellular vesicle mimics made from iPS cell-derived mesenchymal stem cells improve the treatment of metastatic prostate cancer

Stem Cell Research & Therapy ◽

10.1186/s13287-020-02097-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Qingguo Zhao ◽

Bo Hai ◽

Jack Kelly ◽

Samuel Wu ◽

Fei Liu

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Cancer Cells ◽

Tumor Cells ◽

Mouse Models ◽

Metastatic Prostate Cancer ◽

Prostate Cancer Cells

Abstract Background Extracellular vesicles (EVs) and their mimics from mesenchymal stem cells (MSCs) are promising drug carriers to improve cancer treatment, but their application is hindered by donor variations and expansion limitations of conventional tissue-derived MSCs. To circumvent these issues, we made EV-mimicking nanovesicles from standardized MSCs derived from human induced pluripotent stem cells (iPSCs) with a theoretically limitless expandability, and examined the targeting capacity of these nanovesicles to prostate cancer. Methods Nanovesicles are made from intact iPSC-MSCs through serial extrusion. The selective uptake of fluorescently labeled nanovesicles by prostate cancer cells vs. non-tumor cells was examined with flow cytometry. For in vivo tracing, nanovesicles were labeled with fluorescent dye DiR or renilla luciferase. In mice carrying subcutaneous or bone metastatic PC3 prostate cancer, the biodistribution of systemically infused nanovesicles was examined with in vivo and ex vivo imaging of DiR and luminescent signals. A chemotherapeutic drug, docetaxel, was loaded into nanovesicles during extrusion. The cytotoxicities of nanovesicle-encapsulated docetaxel on docetaxel-sensitive and -resistant prostate cancer cells and non-tumor cells were examined in comparison with free docetaxel. Therapeutic effects of nanovesicle-encapsulated docetaxel were examined in mice carrying subcutaneous or bone metastatic prostate cancer by monitoring tumor growth in comparison with free docetaxel. Results iPSC-MSC nanovesicles are more selectively taken up by prostate cancer cells vs. non-tumor cells in vitro compared with EVs, membrane-only EV-mimetic nanoghosts and liposomes, which is not affected by storage for up to 6 weeks. In mouse models of subcutaneous and bone metastatic PC3 prostate cancer, systemically infused nanovesicles accumulate in tumor regions with significantly higher selectivity than liposomes. The loading of docetaxel into nanovesicles was efficient and did not affect the selective uptake of nanovesicles by prostate cancer cells. The cytotoxicities of nanovesicle-encapsulated docetaxel are significantly stronger on docetaxel-resistant prostate cancer cells and weaker on non-tumor cells than free docetaxel. In mouse models of subcutaneous and bone metastatic prostate cancer, nanovesicle-encapsulated docetaxel significantly decreased the tumor growth and toxicity to white blood cells compared with free docetaxel. Conclusions Our data indicate that EV-mimicking iPSC-MSC nanovesicles are promising to improve the treatment of metastatic prostate cancer.

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Autologous transplantation of mesenchymal stem cells into the portal vein of the miniature pig; a preliminary experiment for NOTES approach

Perspectives in Surgery ◽

10.33699/pis.2019.98.9.350-355 ◽

2019 ◽

Vol 98 (9) ◽

pp. 350-355

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Therapy ◽

Portal Vein ◽

Liver Parenchyma ◽

Miniature Pig ◽

Hepatic Diseases ◽

Study Results

Introduction: There is evidence that mesenchymal stem cells (MSCs) could trans-differentiate into the liver cells in vitro and in vivo and thus may be used as an unfailing source for stem cell therapy of liver disease. Combination of MSCs (with or without their differentiation in vitro) and minimally invasive procedures as laparoscopy or Natural Orifice Transluminal Endoscopic Surgery (NOTES) represents a chance for many patients waiting for liver transplantation in vain. Methods: Over 30 millions of autologous MSCs at passage 3 were transplanted via the portal vein in an eight months old miniature pig. The deposition of transplanted cells in liver parenchyma was evaluated histologically and the trans-differential potential of CM-DiI labeled cells was assessed by expression of pig albumin using immunofluorescence. Results: Three weeks after transplantation we detected the labeled cells (solitary, small clusters) in all 10 samples (2 samples from each lobe) but no diffuse distribution in the samples. The localization of CM-DiI+ cells was predominantly observed around the portal triads. We also detected the localization of albumin signal in CM-DiI labeled cells. Conclusion: The study results showed that the autologous MSCs (without additional hepatic differentiation in vitro) transplantation through the portal vein led to successful infiltration of intact miniature pig liver parenchyma with detectable in vivo trans-differentiation. NOTES as well as other newly developed surgical approaches in combination with cell therapy seem to be very promising for the treatment of hepatic diseases in near future.

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Regeneration of Bone Defects Using Bioactive Glass Combined with Adipose-derived Mesenchymal Stem Cells. An experimental in vivo study

Revista de Chimie ◽

10.37358/rc.19.6.7259 ◽

2019 ◽

Vol 70 (6) ◽

pp. 1983-1987

Author(s):

Cristian Trambitas ◽

Anca Maria Pop ◽

Alina Dia Trambitas Miron ◽

Dorin Constantin Dorobantu ◽

Flaviu Tabaran ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bioactive Glass ◽

Bone Repair ◽

Bone Defects ◽

Calvarial Bone ◽

Specific Protocol ◽

Repair Mechanisms ◽

Male Wistar Rats

Large bone defects are a medical concern as these are often unable to heal spontaneously, based on the host bone repair mechanisms. In their treatment, bone tissue engineering techniques represent a promising approach by providing a guide for osseous regeneration. As bioactive glasses proved to have osteoconductive and osteoinductive properties, the aim of our study was to evaluate by histologic examination, the differences in the healing of critical-sized calvarial bone defects filled with bioactive glass combined with adipose-derived mesenchymal stem cells, compared to negative controls. We used 16 male Wistar rats subjected to a specific protocol based on which 2 calvarial bone defects were created in each animal, one was filled with Bon Alive S53P4 bioactive glass and adipose-derived stem cells and the other one was considered control. At intervals of one week during the following month, the animals were euthanized and the specimens from bone defects were histologically examined and compared. The results showed that this biomaterial was biocompatible and the first signs of osseous healing appeared in the third week. Bone Alive S53P4 bioactive glass could be an excellent bone substitute, reducing the need of bone grafts.

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