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Cancer-derived lysophosphatidic acid stimulates differentiation of human mesenchymal stem cells to myofibroblast-like cells
- Source :
- Stem cells (Dayton, Ohio). 26(3)
- Publication Year :
- 2007
-
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 α-smooth muscle actin (α-SMA), a marker for myofibroblasts, in human adipose tissue-derived mesenchymal stem cells (hADSCs). The LPA-induced expression of α-SMA was completely abrogated by pretreatment of the cells with Ki16425, an antagonist of LPA receptors, or by silencing LPA1 or LPA2 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 α-SMA and phosphorylation of Smad2/3. LPA-induced secretion of transforming growth factor (TGF)-β1 in hADSCs, and pretreatment of the cells with SB431542, a TGF-β type I receptor kinase inhibitor, or anti-TGF-β1 neutralizing antibody inhibited the LPA-induced expression of α-SMA and phosphorylation of Smad2. Furthermore, ascites from ovarian cancer patients or conditioned medium from ovarian cancer cells induced expression of α-SMA and phosphorylation of Smad2, and pretreatment of the cells with Ki16425 or SB431542 abrogated the expression of α-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-β1-Smad signaling pathway. Disclosure of potential conflicts of interest is found at the end of this article.
- Subjects :
- Adult
Stromal cell
Cellular differentiation
Smad2 Protein
Biology
medicine.disease_cause
Transforming Growth Factor beta1
chemistry.chemical_compound
Lysophosphatidic acid
medicine
Adipocytes
Animals
Humans
Smad3 Protein
Receptors, Lysophosphatidic Acid
Autocrine signalling
Aged
Ovarian Neoplasms
Stem Cells
Ascites
Cell Differentiation
Mesenchymal Stem Cells
Cell Biology
Fibroblasts
Middle Aged
Actins
Chemokine CXCL12
Cell biology
Rats
Autocrine Communication
chemistry
Molecular Medicine
Phosphorylation
lipids (amino acids, peptides, and proteins)
Female
biological phenomena, cell phenomena, and immunity
Signal transduction
Stem cell
Lysophospholipids
Carcinogenesis
Developmental Biology
Subjects
Details
- ISSN :
- 15494918
- Volume :
- 26
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Stem cells (Dayton, Ohio)
- Accession number :
- edsair.doi.dedup.....435fb1c6f105bb63826503fdaa91e9a5