| Ovarian cancer-derived lysophosphatidic acid stimulates secretion of VEGF and stromal cell-derived factor-1 alpha from human mesenchymal stem cells. | |
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MedLine Citation:
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PMID: 20177148 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Eun Su Jeon; Soon Chul Heo; Il Hwan Lee; Yoon Ji Choi; Ji Hye Park; Kyung Un Choi; Do Youn Park; Dong Soo Suh; Man Soo Yoon; Jae Ho Kim |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Experimental & molecular medicine Volume: 42 ISSN: 1226-3613 ISO Abbreviation: Exp. Mol. Med. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-29 Completed Date: 2010-09-20 Revised Date: 2010-09-28 |
Medline Journal Info:
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Nlm Unique ID: 9607880 Medline TA: Exp Mol Med Country: Korea (South) |
Other Details:
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Languages: eng Pagination: 280-93 Citation Subset: IM |
Affiliation:
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Medical Research Center for Ischemic Tissue Regeneration, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 626-870, Korea. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Actins
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metabolism Adipose Tissue / cytology Cell Line, Tumor Chemokine CXCL12 / secretion* Culture Media, Conditioned Endothelial Cells / drug effects, metabolism Female Humans Lysophospholipids / pharmacology* Mesenchymal Stem Cells / drug effects*, secretion* Microphthalmia-Associated Transcription Factor / metabolism Neovascularization, Physiologic / drug effects Ovarian Neoplasms / enzymology, metabolism*, pathology Paracrine Communication / drug effects Receptors, Lysophosphatidic Acid / metabolism Signal Transduction / drug effects Vascular Endothelial Growth Factors / secretion* rho-Associated Kinases / metabolism rhoA GTP-Binding Protein / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Actins; 0/Chemokine CXCL12; 0/Culture Media, Conditioned; 0/Lysophospholipids; 0/MITF protein, human; 0/Microphthalmia-Associated Transcription Factor; 0/Receptors, Lysophosphatidic Acid; 0/Vascular Endothelial Growth Factors; 22002-87-5/lysophosphatidic acid; EC 2.7.11.1/rho-Associated Kinases; EC 3.6.5.2/rhoA GTP-Binding Protein |
| Comments/Corrections | |
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