Mesenchymal Stem Cell Transition to Tumor-Associated Fibroblasts Contributes to Fibrovascular Network Expansion and Tumor Progression

By Erika L Spaeth, J. Dembinski, A. Sasser, Keri Watson, A. Klopp, B. Hall, Michael Andreeff, F. Marini. PLoS ONE, 2009

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Background 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. Methodology/Principal Findings 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. Conclusions/Significance 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.

Subfields: Genetics, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/31eb6e58de225e43f6dac4647fb8d9d9052f6e0e

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Citations in the corpus

Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of Action of Living, Apoptotic, and Dead MSCs (2019, background): “Human bone marrow-derived MSCs (BM-MSCs) were shown to adopt a CAF-like phenotype with similar functional properties after prolonged exposure to tumorconditioned medium (100, 101).”
Targeting cancer stem cell pathways for cancer therapy (2020, background): “502 The possible mechanism is related to the spontaneous fusion between cancer cells and MSCs.”
The biology of ovarian cancer: new opportunities for translation (2009, background): “Haematopoietic mesenchymal stem cells have been shown to home to ovarian cancer xenografts and differentiate into fibroblasts, contributing to microvascularization, stromal networks and production of tumour-stimulating cytokines (for example, IL-6”
Stroma Cells in Tumor Microenvironment and Breast Cancer (2012, neutral): “The third source of CAFs is malignant tumor cells that undergo EMT changes [3, 16].”
Accessories to the crime: functions of cells recruited to the tumor microenvironment. (2012, positive): “…factor-1 (SDF-1/CXCL12), and a variety of FGFs—with the capability to stimulate cancer cell proliferation (Cirri and Chiarugi, 2011; Erez et al., 2010; Franco et al., 2010; Kalluri and Zeisberg, 2006; Orimo et al., 2005; Rä sä nen and Vaheri, 2010; Rosen and MacDougald, 2006; Spaeth et al., 2009).”
Cancer-related inflammation: common themes and therapeutic opportunities. (2012, background): “TAFs are hought to arise from mesenchymal stem cells [22] but recent data uggest that other bone marrow cells can regulate their activity.”
Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks (2011, background): “It has been shown that MSCs can produce IL6 (9, 10) and can stimulate tumor growth through the paracrine production of secreted IL6 (11).”
Tumor-associated stromal cells as key contributors to the tumor microenvironment (2016, background): “This is primarily due to the recruitment of nearby non-cancerous host stromal cells, including bone-marrow mesenchymal stromal cells (MSCs), adipocytes, and endothelial cells, that secrete a plethora of mediators and growth factors for the tumor that help facilitate tumor progression [3].”
The tumor microenvironment at a glance (2012, background): “CAFs can derive from multiple resident precursors, such as endothelial cells, smooth muscle cells and myoepithelial cells, or mesenchymal stem cells (Brittan et al., 2002; Spaeth et al., 2009; Tomasek et al., 2002; Willis et al., 2006).”
Guidelines for the welfare and use of animals in cancer research (2010, background): “…angiogenic factors (Collado et al, 2007), cancer-associated fibroblasts (Noel et al, 1993; Orimo et al, 2005) or mesenchymal stem cells (Karnoub et al, 2007; Spaeth et al, 2009) can increase tumorigenicity, better recapitulate the human tumour microenvironment and enhance metastatic potential.”