title: Mesenchymal stem cells stimulate angiogenesis in a murine xenograft model of A549 human adenocarcinoma through an LPA1 receptor-dependent mechanism.
abstract: 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 (LPA(1)) 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 LPA(1) 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 LPA(1)-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-LPA(1)-mediated paracrine mechanism.
authors: Medical Research Center for Ischemic Tissue Regeneration, Medical Research Institute, Yangsan, Republic of Korea.
authors: Eun Su
authors: ES
authors: Jeon
authors: Il Hwan
authors: IH
authors: Lee
authors: Soon Chul
authors: SC
authors: Heo
authors: Sang Hun
authors: SH
authors: Shin
authors: Yoon Ji
authors: YJ
authors: Choi
authors: Ji Hye
authors: JH
authors: Park
authors: Do Youn
authors: DY
authors: Park
authors: Jae Ho
authors: JH
authors: Kim
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology
chemical_list: D049368:Receptors, Lysophosphatidic Acid