FCCC LOGO Faculty Publications
Cooper HS , Chang WCL , Coudry R , Gary MA , Everley L , Spittle CS , Wang H , Litwin S , Clapper ML
Generation of a unique strain of multiple intestinal neoplasia (Apc +/Min-FCCC) mice with significantly increased numbers of colorectal adenomas
Molecular Carcinogenesis. 2005 ;44(1) :31-41
Back to previous list
Abstract
The relevance of the Apc+/Min mouse model in the study of human colorectal cancer remains uncertain due to the predominance of small intestinal adenomas and few, if any, colorectal adenomas. A new strain of Apc +/Min mice (Apc+/Min-FCCC) with significantly greater numbers of colorectal adenomas has been generated and characterized. Male C57BL/6J-Apc+/Min mice (the Jackson Laboratory, Bar Harbor, ME) were crossed with wild-type (Apc+/+) C57BL/ 6J females from an independent colony at this institution (offspring =Apc+/Min-FCCC) and 233 animals were evaluated over 20 generations. In order to determine the contribution of genetics to the enhanced colorectal adenoma phenotype, breeding pairs (Apc+/Min male × wild type female C57BL/6J) were purchased from the Jackson Laboratory and offspring (Apc+/Min-JAX) were maintained in our facility under identical conditions (n = 98). Animals were fed Purina Rodent chow (#5013) diet containing 5% fat. The entire intestinal tract was examined histopathologically in both strains. Both the Apc and Pla2g2a (candidate for Mom1) genes were sequenced and found to be identical for both the Apc+/Min-FCCC and Apc+/Min-JAX mouse strains. The multiplicity of colorectal adenomas in the Apc+/Min-FCCC mice was much higher than reported in the literature and significantly greater than the multiplicity of colorectal adenomas in Apc+/Min-JAX mice maintained in our facility (P = 0.01). Apc+/Min-FCCC had a significantly greater incidence of rectal prolapse (P = 0.02) and small intestinal adenocarcinomas (P = 0.001), and multiplicity of small intestinal adenocarcinomas (P = 0.001) compared to Apc+/Min-JAX mice. Male Apc+/Min-FCCC mice had significantly greater numbers of colorectal adenomas compared to female Apc+/Min-FCCC mice (P = 0.0002), as did male Apc+/Min-JAX mice vs. female Apc+/Min-JAX mice (P < 0.0001). These results allow us to conclude: (1) Apc+/Min-FCCC mice are unique in that they develop significantly greater numbers of colorectal adenomas and small intestinal cancers, and a significantly greater incidence of small intestinal cancers and rectal prolapse than Apc+/Min-JAX mice. (2) This study represents the first report of a significant gender difference in multiplicity of colorectal adenomas. (3) Differences between Apc +/Min-FCCC and Apc+/Min-JAX mice in currently undefined genetic modifiers may contribute to the enhanced colorectal phenotype. (4) The Apc+/Min-FCCC strain is highly suited for the investigation of colorectal neoplastic disease and chemoprevention studies. © 2005 Wiley-Liss, Inc.
Notes
08991987 (ISSN) Cited By: 0; Export Date: 25 May 2006; Source: Scopus CODEN: MOCAE; DOI: 10.1002/mc.20114 Language of Original Document: English Correspondence Address: Clapper, M.L.; Division of Population Science; Fox Chase; Cancer Center; 333 Cottman Avenue Philadelphia, PA 19111, United States Molecular Sequence Numbers: GENBANK: NM_007462; Chemicals/CAS: DNA, 9007-49-2 References: Rustgi, A.K., Hereditary gastrointestinal polyposis and non-polyposis syndromes (1994) N Engl J Med, 331, pp. 1694-1702; Grove, E.F.C., Lamlum, H., Crabtree, M., Mutation Cluster Region, Association between germline and somatic mutations and genotype phenotype correlation in upper gastrointestinal familial adenomatous polyposis (2002) Am J Pathol, 160, pp. 2055-2061; Houlston, R., Crabtree, M., Phillips, R., Tomlinson, I., Explaining differences in the severity of familial adenomatous polyposis in the search for modifier genes (2001) Gut, 48, pp. 1-5; Giardello, F.M., Krush, A.J., Petersen, G.M., Phenotypic variability of familial adenomatous polyposis in eleven unrelated families with identical Apc gene mutation (1994) Gastro-enterology, 106, pp. 1542-1547; Heinimann, K., Mulhaupt, B., Weber, W., Phenotypic differences in familial adenomatous polyposis based on APC gene mutation status (1998) Gut, 43, pp. 675-679; Rozen, P., Samuel, Z., Shomrat, R., Legum, C., Notable intrafamilial phenotypic variation in a kindred with familial adenomatous polyposis and an APC mutation in exon 9 (1999) Gut, 45, pp. 827-833; Smits, R., Vanderhouvenvanoordt, W., Luz, A., Apc 1638N: A mouse model for familial adenomatous polyposis-associated desmoid tumors and cutaneous cysts (1998) Gastroenterology, 114, pp. 275-283; Fodde, R., Smits, R., Clevers, H., Apc, signal transduction and genetic instability in colorectal cancer (2001) Nat Rev, 1, pp. 55-67; Oshima, M., Oshima, H., Kitagawa, K., Kobayashi, M., Itakura, C., Taketo, M., Loss of Apc heterozygosity in abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene (1995) Proc Natl Acad, 92, pp. 4482-4486; Oshima, H., Oshima, M., Kobayashi, M., Tsutsumi, M., Taketo, A.M., Morphological and molecular process of polyp formation in Apc ?/716 knockout mice (1997) Cancer Res, 57, pp. 1644-1649; Yang, K., Edelman, N.W., Lau, K., A mouse model of human familial adenomatous polyposis (1997) J Exp Zool, 277, pp. 245-254; Moser, A.R., Pitot, H.C., Dove, W.F., Dominant mutation that predisposes multiple intestinal neoplasia in the mouse (1990) Science, 247, pp. 322-324; Shoemaker, R., Gould, K.A., Luongo, C., Moser, A.R., Dove, W.F., Studies of neoplasia in the Min mouse (1997) Biochemica et Biophysica Acta, 1332, pp. F25-F48; Gould, K.A., Dove, W.F., Localized gene action controlling ntestinal neoplasia in mice (1997) Proc Natl Acad Sci, 94, pp. 5848-5853; Cormier, R.T., Bilger, A., Lillich, A.J., The MOM1AKR intestinal tumor resistance region consists of pla2g2a and a locus distal to D4Mit64 (2000) Oncogene, 19, pp. 3182-3192; Silverman, K.A., Koratkar, E., Siracusa, L.D., Buchberg, A.M., Identification of the modifier of Min II (MOM 2) locus. A new mutation that influences Apc induced intestinal neoplasia (2002) Genome Res, 12, pp. 88-97; Koratkar, R., Dequignot, E., Hauck, W.W., Siracusa, L.D., The CAST/ Ei strain confers significant protection against Apc (Min) intestinal polyps, independent of the resistant modifier of Min1 (Mom1) locus (2002) Cancer Res, 62, pp. 5413-5417; Czarnomska, A., Krysik, E., Piskorowska, J., Opposite effects of modifiers of the ApcMin mutation in intestine and mammary gland (2003) Cancer Res, 63, pp. 4533-4537; Su, L.K., Kinzler, K.W., Vogelstein, B., Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene (1992) Science, 256, pp. 668-670; Corpet, D.E., Pierre, F., Point: From animal models to prevention of colon cancer. Systematic review of chemoprevention in Min mice and choice of the model system (2003) Cancer Epidemiol Biomarkers Prev, 12, pp. 391-400; Boolbol, S.K., Dannenberg, A.J., Chadburn, N.A., Cyclooxygenase-II overexpression and tumor formation are blocked by Sulindac in a murine model of familial adenomatous polyposis (1996) Cancer Res, 56, pp. 2556-2560; Barnes, C.J., Lee, M., Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin (1998) Gastroenterology, 114, pp. 873-877; Wasan, H.S., Novelli, M., Bee, J., Bodmer, W.F., Dietary fat influences on polyp phenotype in multiple intestinal neoplasia mice (1997) Proc Natl Acad Sci USA, 94, pp. 3308-3313; Jacoby, R.F., Seibert, K., Cole, C.E., Kelloff, G., Lubet, R.A., Cyclooxygenase II inhibitor celecoxib as a preventive and therapeutic agent in the Min mouse model of adenomatous polyposis (2000) Cancer Res, 60, pp. 5040-5044; Pierre, F., Perrin, P., Schamp, M., Bornet, F., Mefla, H.K., Menante, A.U.J., Short chain fructo-oligosaccharides reduces the occurrence of colon tumors and development of gut associated lymphoid tissue in the Min mice (1997) Cancer Res, 57, pp. 225-228; Scott, D.J., Hull, M.A., Cartwright, E.J., Lack of inducible nitric oxide synthatase promotes intestinal tumorigenesis in the ApcMin/+ mouse (2001) Gastroenterology, 121, pp. 889-899; Paulsen, J.E., Steffensen, I.-L., Loberg, E.M., Husoy, T., Namork, E., Alexander, J., Qualitative and quantitative relationship between dysplastic aberrant crypt foci and tumorigenesis in the Min/+ mouse (2001) Cancer Res, 61, pp. 5010-5015; Cormier, T., Dove, W.F., Dnmt1N/+ reduces the net growth rate and multiplicity of intestinal adenomas in C57BL/6J multiple intestinal neoplasia (Min)/+ mice independently of p53 but demonstrates strong synergy with the modifier of Min/AKR resistant allele (2000) Cancer Res, 60, pp. 3965-3970; Davis, C.D., Zeng, H., Finley, J.W., Selenium-enriched broccoli decreases intestinal tumorigenesis in multiple intestinal neoplasia mice (2002) J Nutr, 132, pp. 307-309; LeFebvre, A.M., Chen, I., Desreumaux, P., Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57 BL/6J-/Apc Min/positive mice (1998) Nat Med, 4, pp. 1053-1057; Jacoby, R.F., Marshall, D.J., Newton, M.A., Novakovic, K., Tutch, K., Cole, C.E., Lubetr, A., (...), Dove, W.F., Chemoprevention of spontaneous intestinal adenomas in the APC Min mouse model by the non-steroidal antiinflammatory drug Piroxicam (1996) Cancer Res, 56, pp. 710-714; Watson, S.A., Smith, A.N., Hypergastrinemia promotes adenoma progression in the/Apc Min -/+ mouse model of familial adenomatous polyposis (2001) Cancer Res, 61, pp. 625-631; Ritland, S.R., Leighton, J.A., Hirsch, R.E., Morrow, J.D., Weaver, A.L., Gendler, S.J., Evaluation of 5 aminosalicylic acid (5-ASA) for cancer chemoprevention: Lack of efficacy against adenomatous polyps in the ApcMin mouse (1999) Clin Cancer Res, 5, pp. 855-863; Van Kranen, H.J., Van Ierselp, W.C., Rijnkels, J.M., Beems, D.B., Alink, G.M., Van Kreijl, C.F., Effects of dietary fat in vegetable fruit mixture in the development of intestinal neoplasia in the Apc Min mouse (1998) Carcinogenesis, 19, pp. 1597-1601; Lal, G., Ash, C., Hay, K., Suppressed intestinal polyps in the Msh2-deficient and non-Msh2 deficient multiple intestinal neoplasia mice by a specific cyclo-oxygenase-2 inhibitor and by a dual cyclo-oxygenase 1/2 inhibitor (2001) Cancer Res, 61, pp. 6131-6136; Roose, J., Huls, G., Van Brest, M., Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1 (1999) Science, 285, pp. 1923-1926; Kennedy, A.R., Beazer-Barclay, Y., Kinzler, K.W., Newburne, P.M., Suppression of carcinogenesis in the intestines of Min mice by the soybean derived Bowman-Birk inhibitor (1996) Cancer Res, 56, pp. 679-682; Paulsen, J.E., Steffensen, I.-L., Andrassen, A., Vikse, R., Alexander, J., Neonatal exposure to food mutagen 2-amino-1 methyl-6-phenylimidazol [4,5,6] pyridine via breast milk or directly induces intestinal tumors in multiple intestinal neoplasia mice (1999) Carcinogenesis, 20, pp. 1277-1282; Song, J., Medline, A., Mason, J.B., Gallinger, S., Kim, Y.I., Effects of dietary folate on intestinal tumorigenesis in the Apc Min mouse (2000) Cancer Res, 60, pp. 5434-5440; Novelli, M.R., Wasan, H., Rosewel, I., Tumor burden and clonality in multiple intestinal neoplasia mouse/normal mouse aggregation chimeras (1999) Proc Natl Acad Sci, 96, pp. 12553-12558; Perkins, S., Vershoyl, E., Hill, K., Chemopreventive efficacy and pharmakinetics of curcumin in the Min /+ mouse model of familial adenomatous polyposis (2002) Cancer Epidemiol Biomarkers Prev, 11, pp. 535-540; Kakuni, M., Morimura, K., Wanibuchi, A., Food restriction inhibits the growth in intestinal polyps in multiple intestinal neoplasia mouse (2002) JPN J Cancer Res, 93, pp. 236-241; Saez, E., Tibtibez, P., Nelson, M.C., Activators of the nuclear receptor PPAR Gamma enhanced colon polyp formation (1998) Nat Med, 4, pp. 1058-1061; Boivin, G.P., Washington, K., Yang, K., Pathology of mouse models of intestinal cancer: Consensus report and recommendations (2003) Gastroenterology, 124, pp. 762-777; Rosner, A., Miyoshi, K., Landesman-Bollag, E., Histological differences between ErbB/Ras and Wnt Pathway transgenic mammary tumors (2002) Am J Pathol, 161, pp. 1087-1097; MacPhee, M., Chepenik, K.D., Liddell, R.A., Nelson, K.K., Siracusa, L.D., Buchberg, A.M., The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major-modifier of ApcMin-induce intestinal neoplasia (1995) Cell, 81, pp. 957-966; Hioki, K., Shivapuka, R.N., Oshima, H., Alibaster, O., Oshima, M., Taketo, M.M., Suppression of intestinal polyp development by low fat high fiber diet in Apc?/716 knockout mice (1997) Carcinogenesis, 18, pp. 1863-1865; Spiro, L., Olschwang, S., Groden, J., Alleles of the APC gene: An attenuated form of familial polyposis (1993) Cell, 75, pp. 951-957; Friedl, W., Meuschel, S., Caspari, R., Attenuated familial adenomatous polyposis due to a mutation in the 3 prime part of the APC gene. A clue from understanding the function of the APC protein (1996) Hum Genet, 97, pp. 579-584; Dove, W.F., Clipson, L., Gould, K.A., Intestinal neoplasia in the Apc Min mouse: Independence from the microbial and natural killer (Beige Locus) status (1997) Cancer Res, 57, pp. 812-814; Clark, J.C., Collan, Y., Edie, T.J., Prevalence of polyps in an autopsy series from areas with varying incidence of large bowel cancers (1985) In J Cancer, 36, pp. 179-180; Coode, P.E., Chan, K.W., Chan, Y.T., Polyps and diverticula of the large intestine: A necropsy survery in Hong Kong (1985) Gut, 26, pp. 1045-1048; Weyant, M.J., Carothers, A.M., Mahmoud, N.N., Reciprocal expression of ER alpha and ER beta is associated with estrogen mediated modulation of intestinal tumorigenesis (2001) Cancer Res, 61, pp. 2547-2551; Woodson, K., Lanza, E., Tangrea, J.A., Hormone replacement therapy in colorectal adenoma recurrence among women in the polyp prevention trial (2001) J NCI, 93, pp. 1799-1805; Martinez, N.E., Hormone replacement therapy and adenoma recurrence: Implications for its role in colorectal cancer risk (2001) J NCI, 93, pp. 1764-1765; Grodstein, F., Newcomb, A., Stampfer, M.J., Post-menopausal hormone therapy and the risk of colorectal cancer: A review and meta-analysis (1999) Am J Med, 106, pp. 574-582; Chen, M.J., Longnecker, M.P., Morganstern, H., Lee, E.R., Frankl, H.D., Hailer, W., Recent use of hormone replacement therapy in the prevalence of colorectal adenomas (1998) Cancer Epidemiol Biomarkers Prev, 7, pp. 227-230; Potter, J.D., Bostick, R.M., Grandits, G.A., Hormone replacement therapy is associated with lower risk of adenomatous polyps of the large bowel: Minnesota cancer prevention research unit case control study (1996) Cancer Epidemiol Biomarkers Prev, 5, pp. 779-784; Peipins, L.A., Newman, B., Sandler, R.S., Reproductive history, use of exogenous hormones, risk of colorectal adenomas (1997) Cancer Epidemiol Biomarkers Prev, 6, pp. 671-675; Cooper, H.S., Everley, L., Chan, W.C., The role of mutant Apc in the development of dysplasia and cancer in the mouse model of dextran sulfate sodium induced colitis (2001) Gastroenterology, 121, pp. 1407-1416; Yamada, Y., Hata, K., Hirose, Y., Mori Microadenomatous lesions involving loss of Apc heterozygosity in the colon of adult ApcMin/+ mice (2002) Cancer Res, 62, pp. 6367-6370; Luongo, C., Moser, A.R., Gledhill, S., Dove, W.F., Loss of Apc+ in intestinal adenomas from Min mice (1994) Cancer Res, 54, pp. 5947-5952; Levy, D.B., Smith, K.J., Beazer-Barclay, Y., Hamilton, S.R., Vogelstein, B., Kinzler, K.W., IInactivation of both APC alleles in human and mouse tumors (1994) Cancer Res, 54, pp. 5953-5958; Powell, S.M., Zilz, N., Beazer-Barclay, Y., Apc mutations occur early during colorectal carcinogenesis (1992) Nature, 359, pp. 235-237; Miyoshi, Y., Nagase, H., Ando, H., Somatic mutations of the Apc gene in colorectal tumors; mutation cluster region in the APC gene (1992) Hum Mol Genet, 1, pp. 229-233.