Abstract
BackgroundTumor 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 FindingsWe 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/SignificanceOur 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.
Highlights
Tumor cells are not self-sustaining entities, but interact via paracrine and juxtacrine signaling with the microenvironment
We postulated that mesenchymal stem cells (MSC), like other bone marrow-resident cells, have the capacity to differentiate within the tumor microenvironment into fibroblastic-like cells that have been variably referred to as; myofibroblasts, tumor-associatedfibroblasts (TAF), carcinoma-associated fibroblasts (CAF), fibrocytes or pericytes [6]
Tumor associated fibroblasts (TAF) are characterized by the presence of four qualifying factors: (1) fibroblast markers fibroblast-specific protein (FSP) and fibroblast activating protein (FAP); (2) genes associated with an increase of tumor aggression, including stromelysin-1 (SL-1), thrombospondin-1 (Tsp-1) and tenascin-C (Tn-C); (3) myofibroblast/provascularizing potential including desmin, alpha-smooth muscle actin (a-SMA), and vascular endothelial growth factor (VEGF) [10]; and lastly, (4) growth factors, transforming growth factor-beta (TGF-b), hepatocyte growth factor (HGF)/ scatter factor (SF), basic fibroblast growth factor and epidermal growth factor (EGF)
Summary
Tumor cells are not self-sustaining entities, but interact via paracrine and juxtacrine signaling with the microenvironment. We postulated that mesenchymal stem cells (MSC), like other bone marrow-resident cells, have the capacity to differentiate within the tumor microenvironment into fibroblastic-like cells that have been variably referred to as; myofibroblasts, tumor-associated (myo)fibroblasts (TAF), carcinoma-associated fibroblasts (CAF), fibrocytes or pericytes [6]. The presence of fibroblast populations within human tumors is associated with poor outcome and an increase in metastatic potential [7,8] These TAF are associated with expression of factors involved in degradation of matrix proteins, angiogenesis and promotion of cell growth: matrix metalloproteinases (MMP), plasminogen activator inhibitor-1, vascular endothelial growth factor (VEGF), insulin growth factor (IGF-2) and hepatocyte growth factor (HGF) [9]. There are several suggested origins of the TAF including tissue-resident, circulating, and epithelial-to-mesenchymal-transitioned cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
