Laboratories of Molecular Pharmacology, Institute for Cancer Research and Treatment IRCC, Candiolo, Italy.
Clin Cancer Res. 2011 May 15;17(10):3146-56. doi: 10.1158/1078-0432.CCR-10-3377. Epub 2011 Mar 29.
We determined the gene copy numbers for MET, for its transcriptional activator MACC1 and for its ligand hepatocyte growth factor (HGF) in liver metastases from colorectal carcinoma (mCRC). We correlated copy numbers with mRNA levels and explored whether gain and/or overexpression of MET and MACC1 predict response to anti-Met therapies. Finally, we assessed whether their genomic or transcriptional deregulation correlates with pathologic and molecular parameters of aggressive disease.
One hundred three mCRCs were analyzed. Copy numbers and mRNA were determined by quantitative PCR (qPCR). Thirty nine samples were implanted and expanded in NOD (nonobese diabetic)/SCID (severe combined immunodeficient) mice to generate cohorts that were treated with the Met inhibitor JNJ-38877605. In silico analysis of MACC1 targets relied on genome-wide mapping of promoter regions and on expression data from two CRC datasets.
No focal, high-grade amplifications of MET, MACC1, or HGF were detected. Chromosome 7 polysomy and gain of the p-arm were observed in 21% and 8% of cases, respectively, and significantly correlated with higher expression of both Met and MACC1. Met inhibition in patient-derived xenografts did not modify tumor growth. Copy number gain and overexpression of MACC1 correlated with unfavorable pathologic features better than overexpression of Met. Bioinformatic analysis of putative MACC1 targets identified elements besides Met, whose overexpression cosegregated with aggressive forms of colorectal cancer.
Experiments in patient-derived xenografts suggest that mCRCs do not rely on Met genomic gain and/or overexpression for growth. On the basis of pathologic correlations and bioinformatic analysis, MACC1 could contribute to CRC progression through mechanisms other than or additional to Met transcriptional upregulation.
我们测定了来自结直肠癌肝转移（mCRC）的肝转移灶中 MET、其转录激活因子 MACC1 及其配体肝细胞生长因子（HGF）的基因拷贝数。我们将拷贝数与 mRNA 水平相关联，并探索 MET 和 MACC1 的扩增和/或过表达是否预测抗-Met 治疗的反应。最后，我们评估它们的基因组或转录失调是否与侵袭性疾病的病理和分子参数相关。
分析了 103 例 mCRC。通过定量 PCR（qPCR）测定拷贝数和 mRNA。39 个样本被植入 NOD（非肥胖型糖尿病）/SCID（严重联合免疫缺陷）小鼠中进行扩增，以生成接受 Met 抑制剂 JNJ-38877605 治疗的队列。MACC1 靶基因的计算分析依赖于启动子区域的全基因组图谱和来自两个 CRC 数据集的表达数据。
未检测到 MET、MACC1 或 HGF 的局灶性、高级别扩增。7 号染色体多倍体和 p 臂获得分别在 21%和 8%的病例中观察到，并且与 Met 和 MACC1 的表达均升高显著相关。在患者来源的异种移植模型中，Met 抑制并未改变肿瘤生长。MACC1 的拷贝数扩增和过表达与不良的病理特征相关性优于 Met 的过表达。对推定的 MACC1 靶基因的计算分析除了 Met 之外，还鉴定了与结直肠癌侵袭性形式共分离的元素。
患者来源的异种移植实验表明，mCRC 不依赖于 Met 基因组扩增和/或过表达来生长。基于病理相关性和计算分析，MACC1 可能通过除 Met 转录上调之外或除其之外的其他机制促进 CRC 的进展。
