Cancer-derived lysophosphatidic acid stimulates differentiation of human mesenchymal stem cells to myofibroblast-like cells.

Abstract

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.

• Authors: Eun Su Jeon, Hyun Jung Moon, Mi Jeong Lee, Hae Young Song, Young Mi Kim, Mong Cho, Dong-Soo Suh, Man-Soo Yoon, Chulhun L Chang, Jin Sup Jung, Jae Ho Kim
• Journal: Stem cells (Dayton, Ohio) (Stem Cells) Vol. 26 Issue 3 Pg. 789-97 (Mar 2008) ISSN: 1549-4918 [Electronic] England
• PMID: 18065393 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Chemokine CXCL12
• Lysophospholipids
• Receptors, Lysophosphatidic Acid
• SMAD2 protein, human
• SMAD3 protein, human
• Smad2 Protein
• Smad3 Protein
• Transforming Growth Factor beta1
• lysophosphatidic acid

Topics

• Actins (metabolism)
• Adipocytes (cytology, drug effects, metabolism)
• Adult
• Aged
• Animals
• Ascites
• Autocrine Communication (drug effects)
• Cell Differentiation (drug effects)
• Chemokine CXCL12 (biosynthesis, genetics)
• Female
• Fibroblasts (cytology, drug effects)
• Humans
• Lysophospholipids (pharmacology)
• Mesenchymal Stem Cells (cytology, drug effects)
• Middle Aged
• Ovarian Neoplasms (pathology)
• Rats
• Receptors, Lysophosphatidic Acid (metabolism)
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Stem Cells (cytology, drug effects, metabolism)
• Transforming Growth Factor beta1 (pharmacology)