Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer.
The retinoblastoma gene (Rb) is mutated at significant frequency in various human epithelial tumors, including colorectal cancer, and is strongly associated with metastatic disease. However, sole inactivation of Rb in the mouse has so far failed to yield epithelial cancers. Here, we specifically inactivate Rb and/or p53 in the urogenital epithelium and the intestine. We find that the loss of both tumor suppressors is unable to yield tumors in the transitional epithelium lining the bladder, kidneys and ureters. Instead, these mice develop highly metastatic tumors of neuroendocrine, not epithelial, origin within the urogenital tract to give prostate cancer in the males and vaginal tumors in the females. Additionally, we discovered that the sole inactivation of Rb in the intestine was sufficient to induce formation of metastatic colorectal adenocarcinomas. These tumors closely mirror the human disease in regard to the age of onset, histological appearance, invasiveness and metastatic potential. Like most human colorectal carcinomas, our murine Rb-deficient tumors demonstrate genomic instability and they show activation of β-catenin. Deregulation of the Wnt/β-catenin pathway is specific to the intestinal tumors, as genomic instability but not activation of β-catenin was observed in the neuroendocrine tumors. To date, attempts to generate genetically engineered mouse models of colorectal cancer tumors have yielded mostly cancer of the small intestine, which rarely occurs in humans. Our system provides the opportunity to accurately model and study colorectal cancer in the mouse via a single gene mutation.
Koch Institute for Integrative Cancer Research, Cambridge, MA, USA.
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Parisi
Department of Pathology, Tufts Cummings School of Veterinary Medicine, North Grafton, MA, USA.
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Bronson
Koch Institute for Integrative Cancer Research, Cambridge, MA, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
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D000230:Adenocarcinoma / Q000209:etiology* / Q000378:metabolism / Q000556:secondary; D000818:Animals; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D007414:Intestinal Neoplasms / Q000209:etiology / Q000378:metabolism / Q000556:secondary; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism / Q000556:secondary; D008175:Lung Neoplasms / Q000209:etiology / Q000378:metabolism / Q000556:secondary; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D018358:Neuroendocrine Tumors / Q000209:etiology / Q000378:metabolism / Q000556:secondary; D011471:Prostatic Neoplasms / Q000209:etiology / Q000378:metabolism / Q000556:secondary; D016160:Retinoblastoma Protein / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D060449:Wnt Signaling Pathway
D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53