Lysophosphatidic acid in malignant ascites stimulates migration of human mesenchymal stem cells.
Lysophosphatidic acid (LPA) is elevated in ascites of ovarian cancer patients and is involved in growth and invasion of ovarian cancer cells. Accumulating evidence suggests a pivotal role of mesenchymal stem cells (MSCs) or stromal cells in tumorigenesis. In the present study, we demonstrated that ascites from ovarian cancer patients and LPA increased migration of human MSCs. The migration of MSCs induced by LPA and malignant ascites was completely abrogated by pretreatment with Ki16425, an antagonist of LPA receptors, and by silencing of endogenous LPA(1), but not LPA(2), with small interference RNA, suggesting a key role of LPA played in the malignant ascites-induced migration. LPA induced activation of ERK through pertussis toxin-sensitive manner, and pretreatment of MSCs with U0126, a MEK inhibitor, or pertussis toxin attenuated the LPA-induced migration. Moreover, LPA induced activation of RhoA in MSCs, and pretreatment of the cells with Y27632, a Rho kinase inhibitor, markedly inhibited the LPA-induced migration. In addition, LPA and malignant ascites increased intracellular concentration of calcium in MSCs, and Ki16425 completely inhibited the elevation of intracellular calcium. These results suggest that LPA is a crucial component of the malignant ascites which induce the migration of MSCs and elevation of intracellular calcium.
Lee
Mi Jeong
MJ
Medical Research Center for Ischemic Tissue Regeneration of Pusan National University, Medical Research Institute, Busan 602-739, Republic of Korea.
Jeon
Eun Su
ES
Lee
Jung Sub
JS
Cho
Mong
M
Suh
Dong-Soo
DS
Chang
Chulhun L
CL
Kim
Jae Ho
JH
D001201:Ascites; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000473:pathology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D008246:Lysophospholipids; D020742:rhoA GTP-Binding Protein; C032881:lysophosphatidic acid; D002118:Calcium