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Jeon ES, Heo SC, Lee IH, Choi YJ, Park JH, Choi KU, Park DY, Suh DS, Yoon MS, Kim JH: Ovarian Cancer-Derived Lysophosphatidic Acid Stimulates Secretion of VEGF and SDF-1a from Human Mesenchymal Stem Cells. Zhong Xi Yi Jie He Xue Bao. 2008 May;6(5):493-7.
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 a-smooth muscle actin (a-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-1a (SDF-1a) and vascular endothelial growth factor (VEGF) from hASCs. Pretreatment with the LPA receptor inhibitor Ki16425 or short hairpin RNA lentiviral silencing of the LPA1 receptor abrogated the cancer CM-stimulated expression of a-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. Small interfering RNA-mediated depletion of endogenous myocardin and MRTF-A abrogated the expression of a-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 a-SMA, SDF-1, and VEGF in hASCs. Moreover, LPA-induced a-SMA expression was abrogated by treatment with the extracellular signal-regulated kinase inhibitor U0126 or the phosphoinositide-3-kinase inhibitor LY294002, but not the phospholipase C 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, extracellular signal-regulated kinase, phospholipase C, and phosphoinositide-3-kinase. |
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