Abstract 915: Thrombomodulin expression regulates the tumor stroma differentiation of mesenchymal stem cells for controlling tumor growth

Bone marrow-derived mesenchymal stem cells (MSCs) sustain cancer cells by creating a microenvironment favorable for tumor growth. In particular, MSCs have been implicated in gastric cancer development. There is extensive evidence suggesting that Hedgehog signaling regulates tumor growth. However, very little is known regarding the precise roles of Hedgehog signaling and MSCs in tumor development within the stomach. The current study tests that hypothesis that Sonic Hedgehog (Shh), secreted from MSCs, provides a proliferative stimulus for the gastric epithelium in the presence of inflammation. Red fluorescent protein-expressing MSCs transformed in vitro (stMSCs) were transduced with lentiviral constructs containing a vector control (stMSCvect) or short hairpin RNA (shRNA) targeting the Shh gene (stMSCShhKO). Gastric submucosal transplantation of wild-type MSCs (wtMSCs), wild-type MSCs overexpressing Shh (wtMSCShh), stMSCvect, or stMSCShhKO cells in C57BL/6 control (BL/6) or gastrin-deficient (GKO) mice was performed and mice analyzed 30 and 60 days posttransplantation. Compared with BL/6 mice transplanted with wtMSCShh and stMSCvect cells, inflamed GKO mice developed aggressive gastric tumors. Tumor development was not observed in mouse stomachs transplanted with wtMSC or stMSCShhKO cells. Compared with stMSCShhKO-transplanted mice, within the inflamed GKO mouse stomach, Shh-expressing stMSCvect- and wtMSCShh-induced proliferation of CD44-positive cells. CD44-positive cells clustered in gland-like structures within the tumor stroma and were positive for Patched (Ptch) expression. We conclude that Shh, secreted from MSCs, provides a proliferative stimulus for the gastric epithelium that is associated with tumor development, a response that is sustained by chronic inflammation.

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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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Let-7f miRNA regulates SDF-1α- and hypoxia-promoted migration of mesenchymal stem cells and attenuates mammary tumor growth upon exosomal release

Cell Death and Disease ◽

10.1038/s41419-021-03789-3 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Virginia Egea ◽

Kai Kessenbrock ◽

Devon Lawson ◽

Alexander Bartelt ◽

Christian Weber ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Human Mesenchymal Stem Cells ◽

Target Cells ◽

Autophagic Flux ◽

Stromal Cell Derived Factor

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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Close Interactions between Mesenchymal Stem Cells and Neuroblastoma Cell Lines Lead to Tumor Growth Inhibition

PLoS ONE ◽

10.1371/journal.pone.0048654 ◽

2012 ◽

Vol 7 (10) ◽

pp. e48654 ◽

Cited By ~ 12

Author(s):

Giovanna Bianchi ◽

Fabio Morandi ◽

Michele Cilli ◽

Antonio Daga ◽

Chiara Bocelli-Tyndall ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Growth Inhibition ◽

Cell Lines ◽

Neuroblastoma Cell ◽

Tumor Growth Inhibition ◽

Neuroblastoma Cell Lines

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Inhibition of breast tumor growth and abnormal angiogenesis in mice treated with endothelial cells and their progenitor mesenchymal stem cells derived from bone marrow

Neoplasma ◽

10.4149/neo_2016_610 ◽

2016 ◽

Vol 63 (06) ◽

pp. 911-924

Author(s):

M. ADELIPOUR ◽

A. ALLAMEH ◽

S. M. TAVANGAR ◽

Z. M. HASSAN ◽

M. SOLEIMANI

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Endothelial Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Breast Tumor

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727. Gene-Modified Mesenchymal Stem Cells Selectively Engraft in Stroma of Ovarian Carcinomas and Control Tumor Growth

Molecular Therapy ◽

10.1016/j.ymthe.2005.07.267 ◽

2005 ◽

Vol 11 ◽

pp. S282

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Ovarian Carcinomas ◽

Control Tumor Growth ◽

Control Tumor ◽

And Control

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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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The Effects of Mesenchymal Stem Cells on Antimelanoma Immunity Depend on the Timing of Their Administration

Stem Cells International ◽

10.1155/2020/8842659 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Dragana Miloradovic ◽

Dragica Miloradovic ◽

Bojana Simovic Markovic ◽

Aleksandar Acovic ◽

Carl Randall Harrell ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

T Lymphocytes ◽

Tumor Growth ◽

Nk Cells ◽

Plasma Levels ◽

Th17 Cells ◽

Antitumor Immunity ◽

Granzyme B ◽

Lower Plasma

There is still a lively debate about whether mesenchymal stem cells (MSCs) promote or suppress antitumor immune response. Although several possible explanations have been proposed, including different numbers of injected and engrafted MSCs, heterogeneity in phenotype, and function of tumor cells, the exact molecular mechanisms responsible for opposite effects of MSCs in modulation of antitumor immunity are still unknown. Herewith, we used a B16F10 murine melanoma model to investigate whether timing of MSC administration in tumor-bearing mice was crucially important for their effects on antitumor immunity. MSCs, intravenously injected 24 h after melanoma induction (B16F10+MSC1d-treated mice), significantly enhanced natural killer (NK) and T cell-driven antitumor immunity, suppressed tumor growth, and improved survival of melanoma-bearing animals. Significantly higher plasma levels of antitumorigenic cytokines (TNF-α and IFN-γ), remarkably lower plasma levels of immunosuppressive cytokines (TGF-β and IL-10), and a significantly higher number of tumor-infiltrating, IFN-γ-producing, FasL- and granzyme B-expressing NK cells, IL-17-producing CD4+Th17 cells, IFN-γ- and TNF-α-producing CD4+Th1 cells, and CD8+cytotoxic T lymphocytes (CTLs) were observed in B16F10+MSC1d-treated mice. On the contrary, MSCs, injected 14 days after melanoma induction (B16F10+MSC14d-treated mice), promoted tumor growth by suppressing antigen-presenting properties of tumor-infiltrating dendritic cells (DCs) and macrophages and by reducing tumoricidal capacity of NK cells and T lymphocytes. Significantly higher plasma levels of TGF-β and IL-10, remarkably lower plasma levels of TNF-α and IFN-γ, and significantly reduced number of tumor-infiltrating, I-A-expressing, and IL-12-producing macrophages, CD80- and I-A-expressing DCs, granzyme B-expressing CTLs and NK cells, IFN-γ- and IL-17-producing CTLs, CD4+Th1, and Th17 cells were observed in B16F10+MSC14d-treated animals. In summing up, the timing of MSC administration into the tumor microenvironment was crucially important for MSC-dependent modulation of antimelanoma immunity. MSCs transplanted during the initial phase of melanoma growth exerted tumor-suppressive effect, while MSCs injected during the progressive stage of melanoma development suppressed antitumor immunity and enhanced tumor expansion.

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