Ovarian cancer-derived lysophosphatidic acid stimulates secretion of VEGF and stromal cell-derived factor-1 alpha from human mesenchymal stem cells.
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.
Jeon
Eun Su
ES
Medical Research Center for Ischemic Tissue Regeneration, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 626-870, Korea.
Heo
Soon Chul
SC
Lee
Il Hwan
IH
Choi
Yoon Ji
YJ
Park
Ji Hye
JH
Choi
Kyung Un
KU
Park
Do Youn
DY
Suh
Dong Soo
DS
Yoon
Man Soo
MS
Kim
Jae Ho
JH
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
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