Tejada Max L, Yu Lanlan, Dong Jianying, Jung Kenneth, Meng Gloria, Peale Franklin V, Frantz Gretchen D, Hall Linda, Liang XiaoHuan, Gerber Hans-Peter, Ferrara Napoleone
Department of Molecular Oncology, Pathology, Genentech, Inc., South San Francisco, California 94080, USA.
Clin Cancer Res. 2006 May 1;12(9):2676-88. doi: 10.1158/1078-0432.CCR-05-1770.
Activated fibroblasts are thought to play important roles in the progression of many solid tumors, but little is known about the mechanisms responsible for the recruitment of fibroblasts in tumors. Using several methods, we identified platelet-derived growth factor A (PDGFA) as the major fibroblast chemoattractant and mitogen from conditioned medium generated by the Calu-6 lung carcinoma cell line. In addition, we showed that Calu-6 tumors express significant levels of PDGFC, and that the levels of expression of these two PDGFRalpha ligands correlate strongly with the degree of stromal fibroblast infiltration into the tumor mass. The most intense expression of PDGFRalpha was observed in fibroblasts in the tumor outer rim. We subsequently showed that disrupting PDGFRalpha-mediated signaling results in significant inhibition of tumor growth in vivo. Furthermore, analysis of a compendium of microarray data revealed significant expression of PDGFA, PDGFC, and PDGFRalpha in human lung tumors. We propose that therapies targeting this stromal cell type may be effective in treating certain types of solid tumors.
活化的成纤维细胞被认为在许多实体瘤的进展中发挥重要作用，但关于肿瘤中负责募集成纤维细胞的机制却知之甚少。我们采用多种方法，从Calu-6肺癌细胞系产生的条件培养基中鉴定出血小板衍生生长因子A（PDGFA）是主要的成纤维细胞趋化因子和促有丝分裂原。此外，我们发现Calu-6肿瘤表达显著水平的PDGFC，并且这两种PDGFRα配体的表达水平与基质成纤维细胞浸润肿瘤块的程度密切相关。在肿瘤外缘的成纤维细胞中观察到PDGFRα的表达最为强烈。我们随后表明，破坏PDGFRα介导的信号传导会导致体内肿瘤生长受到显著抑制。此外，对一组微阵列数据的分析显示，PDGFA、PDGFC和PDGFRα在人肺肿瘤中显著表达。我们提出，针对这种基质细胞类型的疗法可能对治疗某些类型的实体瘤有效。
