Abstract
Lysophosphatidic acid (LPA) stimulates growth and invasion of ovarian cancer cells and tumor angiogenesis. Cancer-derived LPA induces differentiation of human adipose tissue-derived mesenchymal stem cells (hASCs) to alpha-smooth muscle actin (alpha-SMA)-positive cancer-associated fibroblasts. Presently, we explored whether cancer-derived LPA regulates secretion of pro-angiogenic factors from hASCs. Conditioned medium (CM) from the OVCAR-3 and SKOV3 ovarian cancer cell lines stimulated secretion angiogenic factors such as stromal-derived factor-1 alpha (SDF-1 alpha) and VEGF from hASCs. Pretreatment with the LPA receptor inhibitor Ki16425 or short hairpin RNA lentiviral silencing of the LPA((1)) receptor abrogated the cancer CM-stimulated expression of alpha-SMA, SDF-1, and VEGF from hASCs. LPA induced expression of myocardin and myocardin-related transcription factor-A, transcription factors involved in smooth muscle differentiation, in hASCs. siRNA-mediated depletion of endogenous myocardin and MRTF-A abrogated the expression of alpha-SMA, but not SDF-1 and VEGF. LPA activated RhoA in hASCs and pretreatment with the Rho kinase inhibitor Y27632 completely abrogated the LPA-induced expression of alpha-SMA, SDF-1, and VEGF in hASCs. Moreover, LPA-induced alpha-SMA expression was abrogated by treatment with the ERK inhibitor U0126 or the phosphoinositide-3-kinase inhibitor LY294002, but not the PLC inhibitor U73122. LPA-induced VEGF secretion was inhibited by LY294002, whereas LPA-induced SDF-1 secretion was markedly attenuated by U0126, U73122, and LY294002. These results suggest that cancer-secreted LPA induces differentiation of hASCs to cancer-associated fibroblasts through multiple signaling pathways involving Rho kinase, ERK, PLC, and phosphoinositide-3-kinase.
Highlights
Tumors are composed of genetically altered malignant cells along with a heterogenous population of non-neoplastic stromal cell components, such as fibroblasts, myofibroblasts, endothelial cells, pericytes, and inflammatory cells, and tumor cells interact with the stromal cells via paracrine signaling (De Wever and Mareel, 2003)
carcinoma-associated fibroblasts (CAFs)-derived stromal-derived factor-1 (SDF-1) increases carcinoma cell growth directly through the CXCR4 receptor displayed on tumor cells, and serves to recruit endothelial progenitor cells into tumors, thereby stimulating neoangiogenesis (Orimo and Weinberg, 2006)
In spite of the functional importance of CAF-derived VEGF and SDF-1 in tumorigenesis, the molecular mechanisms associated with the expression of pro-angiogenic factors in CAFs have not been clarified
Summary
Tumors are composed of genetically altered malignant cells along with a heterogenous population of non-neoplastic stromal cell components, such as fibroblasts, myofibroblasts, endothelial cells, pericytes, and inflammatory cells, and tumor cells interact with the stromal cells via paracrine signaling (De Wever and Mareel, 2003). Carcinoma-associated fibroblasts (CAFs, called as myofibroblasts or cancer stroma), which express α-smooth muscle actin (α-SMA), play important roles during cancer progression and metastasis (Bhowmick et al, 2004; Desmouliere et al, 2004; Orimo and Weinberg, 2006; De Wever et al, 2008) They stimulate tumorigenesis, angiogenesis, and invasion in a variety of solid tumors, including prostate, breast, and ovarian carcinomas (Sappino et al, 1988; Olumi et al, 1999; De Wever and Mareel, 2003; Orimo et al, 2005; Ganss, 2006) by secreting various extracellular matrix proteins, proteases, chemokines, and angiogenic factors (Li et al, 2007). Accumulating evidence suggests that MSCs could have an adverse effect that favors tumor growth
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