Dysregulation of β-Catenin is Common in Canine Sporadic Colorectal Tumors

Abstract

Abstract. Human colorectal tumorigenesis is often initiated by APC (adenomatous polyposis coli) or ␤-catenin (CTNNB1) mutations, which result in dysregulation of ␤-catenin expression, followed by alterations in E-cadherin and/or p53. We examined 32 canine intestinal tumors for expression and intracellular distribution of ␤-catenin, E-cadherin, and p53 using immunohistochemistry. ␤-Catenin in normal mucosal epithelial cells was restricted to lateral cell membranes, but 13/13 (100%) colorectal adenomas had intense cytoplasmic and/ or nuclear reactivity. Three of six (50%) colorectal carcinomas, 2/13 (15%) small intestinal carcinomas, and dysplastic cells in 1/2 focal hyperplastic lesions in the small intestine had a similar pattern of staining; remaining tumors had normal membranous ␤-catenin reactivity. There was a correlation (P ϭ 0.007) between abnormal ␤-catenin and E-cadherin staining with 11/13 (85%) colorectal adenomas, 3/6 (50%) colorectal carcinomas, and 3/13 (23%) small intestinal carcinomas showing decreased membranous reactivity compared with normal mucosal epithelium. E-cadherin staining was reduced more often in adenomas than in carcinomas (P ϭ 0.04). There were two patterns of nuclear p53 staining: Ͼ60% of nuclei in 2/26 (8%) carcinomas (one colorectal, one small intestinal) were strongly labeled, whereas three colorectal adenomas and one small intestinal carcinoma had fainter staining in 10-20% of cells. Dysregulation of ␤-catenin appears to be as important in canine colorectal tumorigenesis as it is in the human disease and could be due to analogous mutations. Malignant progression in canine intestinal tumors does not appear to be dependent on loss of E-cadherin or ␤-catenin expression or strongly associated with overexpression of nuclear CM1 antibody-reactive p53.

Feline Progressive Histiocytosis

“…These antibodies have been characterized as crossreactive and have been used extensively in veterinary immunohistochemistry. 17,22 Immunohistochemistry Immunohistochemistry was performed as previously described. 1 Cryosections were fixed in acetone, and endogenous peroxidase was quenched with hydrogen peroxide (0.3%) and sodium azide (0.1%) in phosphatebuffered saline (PBS).…”

Fetal Microchimerism in Cancer Protection and Promotion: Current Understanding in Dogs and the Implications for Human Health

“…The tumor suppressor p53 is overexpressed in benign and malignant colonic lesions of dogs. Dysregulation of β-catenin has been demonstrated in sporadic canine colorectal tumors, similar to that seen in human tumors [54]. The clonality of canine colorectal lesions has not been explored, but more polyclonal lesions in humans carry a higher risk of progressing to malignancy [55].…”

“…The presence of microchimerism in the recipient lowers the rate of rejection in humans receiving HLA-haploidentical renal transplants [60]. Human patients who are microchimeric and receive mismatched HSC transplant are more likely to engraft and have less graft vs host disease (GVHD) than patients who are not microchimeric [53][54][55][56][57][58][59][60][61].…”

Review Paper: Cancer Chemopreventive Compounds and Canine Cancer

“…A diversity of scientific literature, including in vitro, animal, ecologic, and epidemiologic studies, supports a role for vitamin D in decreasing colorectal cancer incidence. 62,95 However, despite abundant experimental evidence in support of an inverse association between vitamin D status and breast cancer risk, 90 the available epidemiologic evidence provides, at best, limited support for such an association. 21,28 Similarly, the association between vitamin D status and prostate cancer risk is less clear than that for colorectal cancer, which suggests that not all tissues respond identically to vitamin D. 26,49,70 In veterinary studies, calcitriol (VDR agonist) and other analogs when added to several canine cancer cell lines, including transitional cell carcinoma cells, canine squamous carcinoma cells, and canine adenocarcinoma, inhibited cell growth via induction of cell cycle arrest.…”

“…Pet dogs are becoming more widely recognized as valuable in comparative oncology with a broad range of comparable types of cancers, similar tumor genetics and molecular phenotypes, histologic appearances, disease duration, and responses to conventional therapies. 62,80 Importantly, greater variability in environmental and host genetic factors significantly affects disease expression but deters rapid identification of specific tumorigenic and antitumorigenic factors in animals and humans. Cancers found in dogs include melanoma; non-Hodgkin lymphoma; osteosarcoma; soft tissue sarcomas; and prostate, mammary, lung, and colorectal carcinomas, as well as head and neck squamous cell carcinoma and transitional cell carcinoma of the bladder.…”