Ovarian cancer-derived lysophosphatidic acid stimulates secretion of VEGF and stromal cell-derived factor-1alpha from human mesenchymal stem cells.
10.3858/emm.2010.42.4.027
- Author:
Eun Su JEON
1
;
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
Author Information
1. Medical Research Center for Ischemic Tissue Regeneration, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 626-870, Korea. jhkimst@pusan.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
carcinoma;
fibroblasts;
lysophosphatidic acid;
ovarian neoplasms;
receptors, lysophosphatidic acid;
rho-associated kinases;
vascular endothelial growth factor A
- From:Experimental & Molecular Medicine
2010;42(4):280-293
- CountryRepublic of Korea
- Language:English
-
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-1alpha (SDF-1alpha) and 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 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.
