Jeon Eun Su, Lee Il Hwan, Heo Soon Chul, Shin Sang Hun, Choi Yoon Ji, Park Ji Hye, Park Do Youn, Kim Jae Ho
Medical Research Center for Ischemic Tissue Regeneration, Medical Research Institute, Yangsan, Republic of Korea.
Biochim Biophys Acta. 2010 Nov;1801(11):1205-13. doi: 10.1016/j.bbalip.2010.08.003. Epub 2010 Aug 11.
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.
癌相关成纤维细胞通过提供肿瘤支持性微环境在肿瘤发生和转移中起关键作用。在本研究中，我们证明来自人肺腺癌细胞A549的条件培养基可诱导人脂肪组织来源的间充质干细胞（hASC）分化为表达α-平滑肌肌动蛋白、血管内皮生长因子和基质细胞衍生因子-1的癌相关成纤维细胞。用溶血磷脂酸受体拮抗剂Ki16425处理hASC，或用小干扰RNA或慢病毒短发夹RNA敲低hASC中溶血磷脂酸受体1（LPA(1)）的表达，可完全消除A549条件培养基诱导的hASC向癌相关成纤维细胞的分化。使用A549细胞的小鼠异种移植模型，我们发现hASC与A549细胞共移植可刺激A549异种移植瘤的生长、血管生成以及体内hASC向癌相关成纤维细胞的分化。敲低hASC中LPA(1)的表达可消除hASC刺激的A549异种移植瘤的生长、血管生成以及hASC向癌相关成纤维细胞的分化。此外，A549条件培养基处理的hASC通过LPA(1)依赖性分泌血管内皮生长因子刺激人脐静脉内皮细胞形成管腔。这些结果表明，A549细胞通过LPA-LPA(1)介导的旁分泌机制诱导hASC在体内分化为癌相关成纤维细胞，后者在肿瘤微环境中的肿瘤血管生成中起关键作用。
