Cancer-derived lysophosphatidic acid stimulates differentiation of human mesenchymal stem cells to myofibroblast-like cells.
Lysophosphatidic acid (LPA) is enriched in ascites of ovarian cancer patients and is involved in growth and invasion of ovarian cancer cells. Accumulating evidence suggests cancer-associated myofibroblasts play a pivotal role in tumorigenesis through secreting stromal cell-derived factor-1 (SDF-1). In the present study, we demonstrate that LPA induces expression of alpha-smooth muscle actin (alpha-SMA), a marker for myofibroblasts, in human adipose tissue-derived mesenchymal stem cells (hADSCs). The LPA-induced expression of alpha-SMA was completely abrogated by pretreatment of the cells with Ki16425, an antagonist of LPA receptors, or by silencing LPA(1) or LPA(2) isoform expression with small interference RNA (siRNA). LPA elicited phosphorylation of Smad2/3, and siRNA-mediated depletion of endogenous Smad2/3 or adenoviral expression of Smad7, an inhibitory Smad, abrogated the LPA induced expression of alpha-SMA and phosphorylation of Smad2/3. LPA-induced secretion of transforming growth factor (TGF)-beta1 in hADSCs, and pretreatment of the cells with SB431542, a TGF-beta type I receptor kinase inhibitor, or anti-TGF-beta1 neutralizing antibody inhibited the LPA-induced expression of alpha-SMA and phosphorylation of Smad2. Furthermore, ascites from ovarian cancer patients or conditioned medium from ovarian cancer cells induced expression of alpha-SMA and phosphorylation of Smad2, and pretreatment of the cells with Ki16425 or SB431542 abrogated the expression of alpha-SMA and phosphorylation of Smad2. In addition, LPA increased the expression of SDF-1 in hADSCs, and pretreatment of the cells with Ki16425 or SB431562 attenuated the LPA-stimulated expression of SDF-1. These results suggest that cancer-derived LPA stimulates differentiation of hADSCs to myofibroblast-like cells and increases SDF-1 expression through activating autocrine TGF-beta1-Smad signaling pathway.
Department of Physiology, School of Medicine, Pusan National University, 1-Ga, Ami-Dong, Suh-Gu, Busan 602-739, Republic of Korea.
Eun Su
ES
Jeon
Hyun Jung
HJ
Moon
Mi Jeong
MJ
Lee
Hae Young
HY
Song
Young Mi
YM
Kim
Mong
M
Cho
Dong-Soo
DS
Suh
Man-Soo
MS
Yoon
Chulhun L
CL
Chang
Jin Sup
JS
Jung
Jae Ho
JH
Kim
D000199:Actins / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D001201:Ascites; D019898:Autocrine Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000473:pathology*; D051381:Rats; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D000199:Actins; D054377:Chemokine CXCL12; D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C032881:lysophosphatidic acid