Gastroenterology Division, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):11026-31. doi: 10.1073/pnas.0914295107. Epub 2010 Jun 1.
Squamous cell cancers comprise the most common type of human epithelial cancers. One subtype, esophageal squamous cell carcinoma (ESCC), is an aggressive cancer with poor prognosis due to late diagnosis and metastasis. Factors derived from the extracellular matrix (ECM) create an environment conducive to tumor growth and invasion. Specialized cancer-associated fibroblasts (CAFs) in the ECM influence tumorigenesis. We have shown previously that the nature and activation state of fibroblasts are critical in modulating the invasive ability of ESCC in an in vivo-like organotypic 3D cell culture, a form of human tissue engineering. Dramatic differences in invasion of transformed esophageal epithelial cells depended on the type of fibroblast in the matrix. We hypothesize that CAFs create an environment primed for growth and invasion through the secretion of factors. We find that fibroblast secretion of hepatocyte growth factor (HGF) fosters the ability of transformed esophageal epithelial cells to invade into the ECM, although other unidentified factors may cooperate with HGF. Genetic modifications of both HGF in fibroblasts and its receptor Met in epithelial cells, along with pharmacologic inhibition of HGF and Met, underscore the importance of this pathway in ESCC invasion and progression. Furthermore, Met activation is increased upon combinatorial overexpression of epidermal growth factor receptor (EGFR) and p53(R175H), two common genetic mutations in ESCC. These results highlight the potential benefit of the therapeutic targeting of HGF/Met signaling in ESCC and potentially other squamous cancers where this pathway is deregulated.
鳞状细胞癌包括最常见的人类上皮癌。其中一种亚型，食管鳞状细胞癌（ESCC）是一种侵袭性癌症，由于诊断和转移较晚，预后较差。细胞外基质（ECM）中的因子创造了有利于肿瘤生长和侵袭的环境。ECM 中的专门的癌症相关成纤维细胞（CAFs）影响肿瘤发生。我们之前已经表明，成纤维细胞的性质和激活状态对于在类似于体内的器官样 3D 细胞培养物（一种人类组织工程形式）中调节 ESCC 的侵袭能力非常重要。转化的食管上皮细胞的侵袭能力存在显著差异，这取决于基质中成纤维细胞的类型。我们假设 CAFs 通过分泌因子来创造有利于生长和侵袭的环境。我们发现，成纤维细胞分泌的肝细胞生长因子（HGF）促进了转化的食管上皮细胞向 ECM 中侵袭的能力，尽管其他未识别的因子可能与 HGF 合作。对成纤维细胞中的 HGF 和上皮细胞中的其受体 Met 进行遗传修饰，以及对 HGF 和 Met 的药理学抑制，强调了该途径在 ESCC 侵袭和进展中的重要性。此外，在 EGFR 和 p53（R175H）的组合过表达时，Met 的激活增加，这两种基因突变为 ESCC 中的常见遗传突变。这些结果突出了针对 HGF/Met 信号通路的治疗靶向在 ESCC 中的潜在益处，并且在该途径失调的其他鳞状癌中也可能具有潜在益处。
