Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression

• Published in: PloS one Vol. 4; no. 4; p. e4992
• Main Authors: Spaeth, Erika L, Dembinski, Jennifer L, Sasser, A Kate, Watson, Keri, Klopp, Ann, Hall, Brett, Andreeff, Michael, Marini, Frank
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07-04-2009; Public Library of Science (PLoS)
• Subjects: Actin; Adenocarcinoma; Analysis; Angiogenesis; Animal models; Animals; Bone marrow; Brain cancer; Breast cancer; Cancer; Cell Biology; Cell Division; Cell Lineage; Cell proliferation; Chemokines; Cytokines; Desmin; Development and progression; Disease Progression; Enzymes; Epidermal growth factor; Epidermal growth factors; Female; Fibroblasts; Fibroblasts - cytology; Gene expression; Growth factors; Hematology; Hepatocyte growth factor; Humans; Immunomodulation; Interleukin; Interleukin 6; Interleukins; Mesenchymal stem cells; Mesenchymal Stromal Cells - cytology; Mesenchyme; Metastasis; Motility; Muscle contraction; Muscle proteins; Neovascularization; Oncology; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - pathology; Pancreas; Paracrine signalling; Pathology; Pediatrics; Population; Prostate cancer; Proteins; Recruitment; Rodents; Smooth muscle; Stem cell transplantation; Stem cells; Stromelysin; Transplantation, Heterologous; Tumors; Vascular endothelial growth factor; Xenografts; United States > US; Texas; Ohio
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0004992

Tumor associated fibroblasts (TAF), are essential for tumor progression providing both a functional and structural supportive environment. TAF, known as activated fibroblasts, have an established biological impact on tumorigenesis as matrix synthesizing or matrix degrading cells, contractile cells, and even blood vessel associated cells. The production of growth factors, cytokines, chemokines, matrix-degrading enzymes, and immunomodulatory mechanisms by these cells augment tumor progression by providing a suitable environment. There are several suggested origins of the TAF including tissue-resident, circulating, and epithelial-to-mesenchymal-transitioned cells.
We provide evidence that TAF are derived from mesenchymal stem cells (MSC) that acquire a TAF phenotype following exposure to or systemic recruitment into adenocarcinoma xenograft models including breast, pancreatic, and ovarian. We define the MSC derived TAF in a xenograft ovarian carcinoma model by the immunohistochemical presence of 1) fibroblast specific protein and fibroblast activated protein; 2) markers phenotypically associated with aggressiveness, including tenascin-c, thrombospondin-1, and stromelysin-1; 3) production of pro-tumorigenic growth factors including hepatocyte growth factor, epidermal growth factor, and interleukin-6; and 4) factors indicative of vascularization, including alpha-smooth muscle actin, desmin, and vascular endothelial growth factor. We demonstrate that under long-term tumor conditioning in vitro, MSC express TAF-like proteins. Additionally, human MSC but not murine MSC stimulated tumor growth primarily through the paracrine production of secreted IL6.
Our results suggest the dependence of in vitro Skov-3 tumor cell proliferation is due to the presence of tumor-stimulated MSC secreted IL6. The subsequent TAF phenotype arises from the MSC which ultimately promotes tumor growth through the contribution of microvascularization, stromal networks, and the production of tumor-stimulating paracrine factors.