In 2008, colorectal cancer (CRC) was the fifth most prevalent cancer in the USA accounting for 149,800 new cases and the second most deaths, ~49,000. Progression of CRC normally occurs over decades and involves a combination of selection and the accumulation of "selective" gene alterations. A large body of work examining gene mutations in human colorectal tumor specimens strongly suggests that progression from a normal epithelial cell to a metastatic adenocarcinoma is a multistep process requiring multiple mutations in genes such as APC, K-RAS and TP53. However, the constellation of gene mutations varies considerably and a single combination is not seen in all colorectal cancers. This variability in cancer "genotypes" confounds interpretations because simple progression models although instructive fail to fit all tumors. Certain key questions remain unanswered: "What is the minimal combination of gene mutations sufficient for propelling a normal epithelial cell into a malignant adenocarcinoma? "Does the overall order of mutation accumulation matter or can some mutations occur at random? Ideally, one would like to take a prospective approach and engineer different stage tumors in an intact organism. This is one goal of the present proposal, using genetically engineered mice. Unlike many models in which the mouse is heterozygous for a given mutation or the gene is conditionally mutated in all cells within the target tissue, we will model intestinal tumorigenesis by stochastic, somatic alteration of one or more "cancer" genes in widely separated cells in vivo. We developed a highly versatile stochastic Cre/lox system to target specific gene mutations to individual cells in the mouse. Cre activation occurs by spontaneous frameshift reversion, can be modulated by DNA mismatch repair status and occurs in individual cells surrounded by unaltered (normal) tissue, mimicking spontaneous cancer causing mutations. Cell lineages that experience Cre activation also now express 2-galactosidase, therefore illuminating the consequences of tumor suppressor gene inactivation and oncogene activation. As one primary goal, we will study the short-term and longer-term consequences of individual tumor suppressor gene or oncogene alterations with our stochastic system. As a second goal, with our system we will study mice with multiple gene targets to define the minimal gene (pathway) disruption(s) that are sufficient for invasive intestinal adenocarcinomas. Tumors arising in mice with different target combinations will be analyzed in some detail to provide additional information on the intestinal tumorigenesis pathway(s). These studies are intended to provide a better system for modeling and thereby understanding human colorectal cancer pathway(s).
Colon cancer, which accounted for ~49,000 deaths in the U.S. in 2008, requires the accumulation of multiple gene mutations. We will use a novel mouse model system to define better the most important gene mutations and, therefore, contribute to our understanding of how colon cancers form. This information should aid in better diagnoses and treatments of this deadly disease.
|Fischer, Jared M; Schepers, Arnout G; Clevers, Hans et al. (2014) Occult progression by Apc-deficient intestinal crypts as a target for chemoprevention. Carcinogenesis 35:237-46|
|Fischer, J M; Miller, A J; Shibata, D et al. (2012) Different phenotypic consequences of simultaneous versus stepwise Apc loss. Oncogene 31:2028-38|
|Tsao, Jen-Lan; Dudley, Sandra; Kwok, Brian et al. (2002) Diet, cancer and aging in DNA mismatch repair deficient mice. Carcinogenesis 23:1807-10|
|Baross-Francis, A; Makhani, N; Liskay, R M et al. (2001) Elevated mutant frequencies and increased C : G-->T : A transitions in Mlh1-/- versus Pms2-/- murine small intestinal epithelial cells. Oncogene 20:619-25|
|Yao, X; Buermeyer, A B; Narayanan, L et al. (1999) Different mutator phenotypes in Mlh1- versus Pms2-deficient mice. Proc Natl Acad Sci U S A 96:6850-5|
|Buermeyer, A B; Wilson-Van Patten, C; Baker, S M et al. (1999) The human MLH1 cDNA complements DNA mismatch repair defects in Mlh1-deficient mouse embryonic fibroblasts. Cancer Res 59:538-41|
|Winter, D B; Phung, Q H; Umar, A et al. (1998) Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2. Proc Natl Acad Sci U S A 95:6953-8|
|Baker, S M; Harris, A C; Tsao, J L et al. (1998) Enhanced intestinal adenomatous polyp formation in Pms2-/-;Min mice. Cancer Res 58:1087-9|
|Fritzell, J A; Narayanan, L; Baker, S M et al. (1997) Role of DNA mismatch repair in the cytotoxicity of ionizing radiation. Cancer Res 57:5143-7|
|Baker, S M; Plug, A W; Prolla, T A et al. (1996) Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Nat Genet 13:336-42|
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