Kammula Udai S, Kuntz Eleanor J, Francone Todd D, Zeng Zhaoshi, Shia Jinru, Landmann Ron G, Paty Philip B, Weiser Martin R
Surgery Branch, National Cancer Institute, Bethesda, MD, USA.
Cancer Lett. 2007 Apr 18;248(2):219-28. doi: 10.1016/j.canlet.2006.07.007. Epub 2006 Sep 1.
INTRODUCTION/HYPOTHESIS: Over-expression of the c-Met receptor tyrosine kinase has been described in a variety of cancers and implicated in tumor progression. Unlike some solid tumors, current evidence indicates that c-Met activation in colon cancer is unrelated to gene mutation, is ligand dependent, and occurs via a paracrine fashion. We hypothesize that over-expression of the c-Met receptor and its ligand, hepatocyte growth factor (HGF) in the tumor microenvironment is associated with tumor progression and metastases.
Primary tumor c-Met and HGF mRNA expression was analyzed in 60 colon adenocarcinomas. Receptor and ligand expression was analyzed for correlation and association with clinicopathologic features and outcome.
Compared to adjacent normal mucosa, 69% and 48% of tumors showed a greater than 2- and greater than 10-fold elevation in c-Met mRNA, respectively. Elevated HGF mRNA was noted in 47% of tumors with 19% having a greater than 10-fold increase. Tumor c-Met expression was correlated with HGF expression, and a cohort of 33 patients could be defined with both low c-Met and HGF expression. Compared with the 27 tumors with either high c-Met or HGF, the cohort with low c-Met and HGF expression had fewer nodal and distant metastases as well as improved overall survival (HR=2.3, p<0.05).
Evaluation of the c-Met receptor in context of ligand, HGF, allows identification of a metastatic phenotype that correlates with advanced stage and poor survival. c-Met and HGF co-expression in the tumor microenvironment could be useful in the molecular staging of colon cancer and viable therapeutic targets.
引言/假设：c-Met受体酪氨酸激酶的过表达已在多种癌症中被描述，并与肿瘤进展有关。与一些实体瘤不同，目前的证据表明，结肠癌中c-Met的激活与基因突变无关，是配体依赖性的，并且通过旁分泌方式发生。我们假设肿瘤微环境中c-Met受体及其配体肝细胞生长因子（HGF）的过表达与肿瘤进展和转移相关。
分析了60例结肠腺癌中原发性肿瘤的c-Met和HGF mRNA表达。分析受体和配体表达与临床病理特征及预后的相关性和关联性。
与相邻正常黏膜相比，分别有69%和48%的肿瘤c-Met mRNA升高超过2倍和10倍。47%的肿瘤中观察到HGF mRNA升高，其中19%升高超过10倍。肿瘤c-Met表达与HGF表达相关，并且可以确定一组33例患者c-Met和HGF表达均低。与27例c-Met或HGF高表达的肿瘤相比，c-Met和HGF低表达的一组患者的淋巴结转移和远处转移较少，总生存期也有所改善（HR=2.3，p<0.05）。
在配体HGF的背景下评估c-Met受体，可以识别与晚期和不良生存相关的转移表型。肿瘤微环境中c-Met和HGF的共表达可能有助于结肠癌的分子分期和确定可行的治疗靶点。
