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Carcinoma Associated Fibroblast Like Differentiation of Human Mesenchymal Stem Cells

ABSTRACT: Carcinoma associated fibroblasts (CAFs) have recently been implicated in important aspects of epithelial solid tumor biology such as neoplastic progression, tumor growth, angiogenesis, and metastasis. However, neither the source of CAFs nor the differences between CAFs and fibroblasts from non-neoplastic tissue have been well defined. In this study we demonstrate that human bone marrow-derived mesenchymal stem cells (hMSCs) exposed to tumor-conditioned medium (TCM) over a prolonged period of time assume a CAF-like myofibroblastic phenotype. More importantly, these cells exhibit functional properties of CAFs including sustained expression of stromal derived factor 1 (SDF-1) and the ability to promote tumor cell growth both in vitro and in an in vivo co-implantation model and expression of myofibroblast markers including α-smooth muscle actin and fibroblast surface protein. hMSCs induced to differentiate to a myofibroblast-like phenotype using 5-azacytidine do not promote tumor cells growth as efficiently as hMSCs cultured in tumor-conditioned medium nor do they demonstrate increased SDF-1 expression. Furthermore, gene expression profiling revealed similarities between TCM exposed hMSCs and carcinoma associated fibroblasts. Taken together these data suggest that hMSCs are a source of carcinoma associated fibroblasts and can be used in the modeling of tumor-stroma interactions. To our knowledge this is the first report demonstrating that hMSCs become activated and resemble carcinoma associated myofibroblasts upon prolonged exposure to conditioned medium from MDAMB231 human breast cancer cells. Keywords: differentiation

ORGANISM(S): Homo sapiens

PROVIDER: GSE9764 | GEO | 2008/06/23

SECONDARY ACCESSION(S): PRJNA103695

REPOSITORIES: GEO

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Project description:Disseminated tumor cells (DTCs) in the bone marrow can be detected in patients with solid tumors early on in disease progression. Via interaction with mesenchymal stromal cells (MSCs) these tumor cells may interfere with hematopoiesis. Using appropriate co-culture models, we investigated whether DTCs can change the bone marrow microenvironment by modulating MSC function with a special emphasis on their chemoattractive activity towards hematopoietic stem and progenitor cells (HSPCs). Human bone marrow derived MSCs as well as an immortalised MSC line (SCP-1) were co-cultured with MCF-7, MDA-MB231 breast carcinoma or MCF-10A non-malignant breast epithelial cells or their conditioned medium. Gene expression analysis of SCP-1 cells cultured with MCF-7 conditioned medium revealed SDF-1/CXCL12 as one of the significantly downregulated genes. Both tumor cell lines caused an inhibited SDF-1 promoter activity in SCP-1 cells, whereby MCF-7 medium decreased it to 77% and MDA-MB231 to 47%. Moreover, the SDF-1 mRNA and protein levels were significantly reduced. As a functional consequence of lower SDF-1 levels, we detected a decreased trans-well migration potential of CD34+ HSPC to MSC/tumor cell co-cultures or conditioned medium. The specificity of this chemokine mediated effect was confirmed by blocking studies with the CXCR4 antagonist AMD3100. Downregulation of SP1 transcription factor and increased miR23a levels in MSCs after contact with tumor cell medium as well as an enhanced TGFb1 expression were identified as potential molecular regulators of SDF-1 activity in MSCs. We propose an additional mechanism by which tumor cells affect the niche environment of HSPCs and therefore negatively impact hematopoiesis. Gene expression of human immortalized mesenchymal stromal cells (SCP-1) was investigated after incubation with conditioned medium of the breast carcinoma cell line MCF-7 for 24, 48, and 72 hours. Three independent experiments were performed at each time.

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Carcinoma Associated Fibroblast Like Differentiation of Human Mesenchymal Stem Cells

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