Genetic and expression analysis of MET, MACC1 and HGF in metastatic colorectal cancer: Response to Met inhibition in patient xenografts and pathological correlations
Articolo
Data di Pubblicazione:
2011
Abstract:
PURPOSE:
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.
EXPERIMENTAL DESIGN:
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.
RESULTS:
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.
CONCLUSIONS:
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.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
HEPATOCYTE GROWTH-FACTOR; PRIMARY COLON-CANCER; LIVER METASTASES; KINASE INHIBITORS; BREAST-CANCER; AMPLIFICATION; IDENTIFICATION; PROTOONCOGENE; , CHEMOTHERAPY; SENSITIVITY
Elenco autori:
Francesco Galimi; Davide Torti; Francesco Sassi; Claudio Isella; Davide Corà; Stefania Gastaldi; Dario Ribero; Andrea Muratore; Paolo Massucco; Dimitrios Siatis; Gianluca Paraluppi; Federica Gonella; Francesca Maione; Alberto Pisacane; Ezio David; Bruno Torchio; Mauro Risio; Mauro Salizzoni; Lorenzo Capussotti; Tim Perera; Enzo Medico; M.F. Di Renzo; Paolo M. Comoglio; Livio Trusolino*; Andrea Bertotti* (*Co-Senior Authors)
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