title: Ovarian cancer-derived lysophosphatidic acid stimulates secretion of VEGF and stromal cell-derived factor-1 alpha from human mesenchymal stem cells.
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.
authors.affiliation: Medical Research Center for Ischemic Tissue Regeneration, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 626-870, Korea.
authors.forename: Eun Su
authors.initials: ES
authors.lastname: Jeon
authors.forename: Soon Chul
authors.initials: SC
authors.lastname: Heo
authors.forename: Il Hwan
authors.initials: IH
authors.lastname: Lee
authors.forename: Yoon Ji
authors.initials: YJ
authors.lastname: Choi
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Park
authors.forename: Kyung Un
authors.initials: KU
authors.lastname: Choi
authors.forename: Do Youn
authors.initials: DY
authors.lastname: Park
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Suh
authors.forename: Man Soo
authors.initials: MS
authors.lastname: Yoon
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000199:Actins / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D017077:Culture Media, Conditioned; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication / Q000187:drug effects; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D054377:Chemokine CXCL12; D017077:Culture Media, Conditioned; D008246:Lysophospholipids; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D049368:Receptors, Lysophosphatidic Acid; D042442:Vascular Endothelial Growth Factors; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; C032881:lysophosphatidic acid