Genetic and Expression Analysis of MET, MACC1, and HGF in Metastatic Colorectal Cancer: Response to Met Inhibition in Patient Xenografts and Pathologic Correlations

Autor: Maria Flavia Di Renzo, Mauro Salizzoni, Lorenzo Capussotti, Stefania Gastaldi, Enzo Medico, Livio Trusolino, Timothy Perera, Alberto Pisacane, Davide Corà, Davide Torti, Gianluca Paraluppi, Paolo Massucco, Dimitrios Siatis, Andrea Bertotti, Francesco Galimi, Francesca Maione, Mauro Risio, Claudio Isella, Dario Ribero, Ezio David, Federica Gonella, Bruno Torchio, Paolo M. Comoglio, Andrea Muratore, Francesco Sassi
Rok vydání: 2011
Předmět:
Male
Cancer Research
Colorectal cancer
HEPATOCYTE GROWTH-FACTOR
Mice
SCID
PRIMARY COLON-CANCER
Nod
Biomarkers
Pharmacological
Mice
Mice
Inbred NOD
LIVER METASTASES
KINASE INHIBITORS
BREAST-CANCER
AMPLIFICATION
IDENTIFICATION
PROTOONCOGENE
CHEMOTHERAPY
SENSITIVITY
Medicine
Neoplasm Metastasis
Aged
80 and over
Hepatocyte Growth Factor
Middle Aged
Proto-Oncogene Proteins c-met
Gene Expression Regulation
Neoplastic
Real-time polymerase chain reaction
Oncology
Female
Hepatocyte growth factor
Colorectal Neoplasms
medicine.drug
In silico
Antineoplastic Agents
Downregulation and upregulation
Biomarkers
Tumor
Animals
Humans
Receptors
Growth Factor
Protein Kinase Inhibitors
Aged
Messenger RNA
business.industry
Gene Expression Profiling
Carcinoma
Cancer
medicine.disease
Xenograft Model Antitumor Assays
Immunology
Trans-Activators
Cancer research
business
Transcription Factors
Zdroj: Clinical Cancer Research. 17:3146-3156
ISSN: 1557-3265
1078-0432
Popis: 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. Clin Cancer Res; 17(10); 3146–56. ©2011 AACR.
Databáze: OpenAIRE
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