| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1949586 | Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | 2010 | 9 Pages |
Carcinoma-associated fibroblasts play a key role in tumorigenesis and metastasis by providing a tumor-supportive microenvironment. In the present study, we demonstrate that conditioned medium from A549 human lung adenocarcinoma cells induces differentiation of human adipose tissue-derived mesenchymal stem cells (hASCs) to carcinoma-associated fibroblasts expressing α-smooth muscle actin, vascular endothelial growth factor, and stromal cell-derived factor-1. A549 conditioned medium-induced differentiation of hASCs to carcinoma-associated fibroblasts was completely abrogated by treatment of hASCs with Ki16425, a lysophosphatidic acid receptor antagonist, or knockdown of lysophosphatidic acid receptor 1 (LPA1) expression in hASCs with small interfering RNA or lentiviral short hairpin RNA. Using a murine xenograft transplantation model of A549 cells, we showed that co-transplantation of hASCs with A549 cells stimulated growth of A549 xenograft tumor, angiogenesis, and differentiation of hASCs to carcinoma-associated fibroblasts in vivo. Knockdown of LPA1 expression in hASCs abrogated hASCs-stimulated growth of A549 xenograft tumor, angiogenesis, and differentiation of hASCs to carcinoma-associated fibroblasts. Moreover, A549 conditioned medium-treated hASCs stimulated tube formation of human umbilical vein endothelial cells by LPA1-dependent secretion of vascular endothelial growth factor. These results suggest that A549 cells induce in vivo differentiation of hASCs to carcinoma-associated fibroblasts, which play a key role in tumor angiogenesis within tumor microenvironment, through an LPA-LPA1-mediated paracrine mechanism.
Research highlights► Mesenchymal stem cells stimulate growth of A549 xenograft tumor in vivo. ► Mesenchymal stem cells stimulate tumor angiogenesis of A549 xenograft tumor. ► A549 cells stimulate secretion of VEGF from mesenchymal stem cells. ► LPA receptor 1 is involved in the secretion of VEGF from mesenchymal stem cells. ► VEGF stimulates angiogenesis of human umbilical vein endothelial cells in vitro.
