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

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.

Mesenchymal Stem Cells Selectively Engraft into Tumor Stroma and Produce Potent Antitumor Proteins In Situ.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 352-352
Author(s):  
Michael Andreeff ◽  
Jennifer Dembinski ◽  
Brett M. Hall ◽  
Matus Studeny ◽  
Xiaoyang Ling ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Metastatic Breast ◽  
Firefly Luciferase ◽  
Scid Mice ◽  
Ovarian Tumors ◽  
Renilla Luciferase

Abstract The formation of stroma is essential for tumor growth and involves complex interactions between malignant tumor cells, and non-tumor stromal cells. We have previously demonstrated that mesenchymal stem cells (MSC) integrate into solid tumors as stromal elements (Cancer Res62:3603, 2002; JNCI96:1593, 2004,), suggesting the development of anti-cancer therapies based on the intratumoral production of agents by gene-modified MSC. However, no direct evidence has demonstrated this migration and selective engraftment into the tumor microenvironment. Therefore, we noninvasively visualized MSC using luciferase bioluminescence. MSC were labeled by a fiber modified Ad vector expressing firefly luciferase (AdLux-F/RGD) and these MSC-Lux were injected into normal (healthy) SCID mice or mice bearing established metastatic breast or ovarian tumors. Biodistributed MSC-Lux were imaged utilizing the Xenogen IVIS detection system. In normal mice, human MSC (hMSC) migrated to the lungs where they remained resident for 7–10 days. In animals bearing established metastatic lung tumors, IV injected hMSC again migrated to the lungs. However, in contrast to control mice, the Lux signal remained strong over a 15-day period with only a slight decrease over the first 10 days. After IP injection, hMSC-LUX were detected in the peritoneum, and after 7 days, no hMSC-LUX was detected in normal animals, while strong punctate regions of LUX-activity were observed in ovarian tumors. In contrast to SCID mice injected with hMSC, healthy Balb/C mice injected with Balb/C derived MSC-LUX initially migrated to the lungs and within 2.5 hrs had exited the lungs to remain liver and spleen resident for 5–7 days. When tumor cells were transduced with renilla luciferase constructs, the co-localization and dynamic interactions of firefly luciferase MSC and renilla luciferase tumors could be examined in detail. Mechanisms regulating the MSC-tumor interactions involve TGF-beta, HGF/c-Met, and EGFR and will be discussed. We then examined whether hMSC-producing interferon-beta (IFNb-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 bearing pulmonary metastases of carcinomas or melanomas, tumor growth was significantly inhibited as compared to untreated or vector-control MSC controls (p= 0.007), while recombinant IFNb protein (50,000 IU qod) was ineffective (p=0.14). IV injected IFNb-MSC prolonged the survival of mice bearing metastatic breast carcinomas (p=0.001) Intraperitoneal (IP) injections of IFN-MSC into mice carrying ovarian carcinomas resulted in doubling of survival in SKOV-3, and cures in 70% of mice carrying OVAR-3 tumors. MSC injected into the ipsilateral or contralateral carotid artery were found to localize to glioma xenografts in mice and IFNb-MSC significantly (p<0.05) prolonged survival of these mice. These 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-b 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.

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

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3837-3844 ◽  
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)

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

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.

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

2012 ◽  
Vol 315 (1) ◽  
pp. 28-37 ◽  
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

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

2014 ◽  
Vol 13 (1) ◽  
pp. 20 ◽  
Author(s):  
Juan M Funes ◽  
Stephen Henderson ◽  
Rachel Kaufman ◽  
James M Flanagan ◽  
Mathew Robson ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Growth ◽  
Oncogenic Transformation ◽  
Nrf2 Expression

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

Leukemia ◽  
2006 ◽  
Vol 21 (2) ◽  
pp. 304-310 ◽  
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

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

2012 ◽  
Vol 20 (1) ◽  
pp. 8-16 ◽  
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

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

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
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.

scholarly journals Mesenchymal stem cells induce epithelial proliferation within the inflamed stomach

2014 ◽  
Vol 306 (12) ◽  
pp. G1075-G1088 ◽  
Author(s):  
Jessica M. Donnelly ◽  
Amy Engevik ◽  
Rui Feng ◽  
Chang Xiao ◽  
Gregory P. Boivin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Growth ◽  
Hedgehog Signaling ◽  
Fluorescent Protein ◽  
Tumor Development ◽  
Tumor Stroma ◽  
Gastric Epithelium ◽  
Wild Type

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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