BMC Cancer 2009, 9:251 http://www.biomedcentral.com/1471-2407/9/251 and cyclin D1, and Ki-67 [78,79]. This pathway also has a critical role in Paneth cell differentiation [80]. We have not observed any morphological or immunohistochemi- cal evidence of increase or aberrant localization of Paneth cells in the colon specimens of the CyCAP knockout mice. Also, no abnormalities of Paneth cells were identified in the small intestine of the CyCAP KO mice. While β-cat- enin was not detected in the nuclei of the colonocytes in either WT or KO mice and there were no definite differ- ence in expression of the c-myc and cyclin D1, KO mice had increased membranous β-catenin expression com- pared to their matched WT control and strong expression of β-catenin was also detected in all segments of the colonic crypts including the base indicating that prolifer- ative zone shows β-catenin phenotype that is seen only on the colonic plate of normal mice. Since one way by which cytoplasmic β-catenin is prevented from returning to the nucleus is by being locked by the emerging E-cadherin into adherens junctions which link the cell to prolifera- tively shut-down functioning cells moving up and out of the crypt, the finding of overexpressed membranous β-cat- enin in proliferative compartment of the hyperplastic mucosa may represent a significant abnormality; how- ever, it needs to be further evaluated in future studies. Conclusion CyCAP knockout mice develop mucosal hyperprolifera- tion and mucosal hyperplasia early in life without expo- sure to carcinogen and as such they represent the first known model of spontaneous colonic hyperplasia. When challenged by a carcinogen, CyCAP knockout mice also develop significantly more hyperplasia and more tumors than wild-type mice, indicating that their mucosa is more proliferative than in WT animals. Therefore, our results link an early premalignant change in murine colorectal mucosa to deficiency of a glycoprotein with a role in mod- ulation of endotoxin signalling. Further studies are neces- sary to elucidate if this multifunctional glycoprotein may also have a role in human preneoplastic hyperplasia, the pathogenesis of which is largely unknown. Competing interests The authors declare that they have no competing interests. Authors' contributions EET participated in the design of the study, carried out morphometric and immunoassays, participated in statis- tical analysis, and drafted the manuscript. VK helped with animal experiments. CW participated in the histological analyses. HJL participated in the design of the study and the statistical analysis. LAL evaluated and quantitated Ki- 67 proliferation fraction. SL conceived of the study, per- formed experiments with laboratory animals, participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final man- uscript. Acknowledgements Supported by grants from the Cancer Research Society Inc., Canadian Insti- tutes of Health Research (FRN 11185) and an RUH Foundation Grant (G00005255) This project was performed in part using azoxymethane provided by the National Cancer Institute's Chemical Carcinogen Reference Standards Repository operated under contract by Midwest Research Institute, NO, N02-CB-07008. References 1. Weir HK, Thun MJ, Hankey BF, Ries LA, Howe HL, Wingo PA, et al.: Annual report to the nation on the status of cancer, 1975– 2000 featuring the uses of surveillance data for cancer pre- vention and control. J Natl Cancer Inst 2003, 95:1276-99. 2. Jass JR: Classification of colorectal cancer based on correla- tion of clinical, morphological and molecular features. His- topathology 2007, 50:113-30. 3. Levine JS, Ahnen DJ: Adenomatous polyps of the colon. N Engl J Med 2006, 355:2551-57. 4. Longacre TA, Fenoglio-Preiser CM: Mixed hyperplastic adenom- atous polyps/serrated adenomas. A distinct form of colorec- tal neoplasia. Am J Surg Pathol 1990, 14:524-37. 5. Torlakovic E, Skovlund E, Snover CD, Torlakovic G, Nesland JM: Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 2003, 27:65-81. 6. Torlakovic E, Snover DC: Sessile serrated adenoma: a brief his- tory and current status. Crit Rev Oncog 2006, 12:27-39. 7. Estrada RG, Spjut HJ: Hyperplastic polyps of the large bowel. Am J Surg Pathol 1980, 4:127-33. 8. Shamsuddin AK, Weiss L, Phelps PC, Trump BF: Colon epithelium. IV. Human colon carcinogenesis. Changes in human colon mucosa adjacent to and remote from carcinomas of the colon. J Natl Cancer Inst 1981, 66:413-9. 9. Surawicz CM, Haggitt RC, Husseman M, McFarland LV: Mucosal biopsy diagnosis of colitis: acute self-limited colitis and idio- pathic inflammatory bowel disease. Gastroenterology 1994, 107:755-63. 10. Torlakovic E, Snover DC: Serrated adenomatous polyposis in humans. Gastroenterology 1996, 110:748-55. 11. Higuchi T, Sugihara K, Jass JR: Demographic and pathological characteristics of serrated polyps of colorectum. Histopathol- ogy 2005, 47:32-40. 12. Weinstein IB, Troll W: National cancer workshop on tumor promotion and carcinogenesis. Cancer Res 1977, 37:3461-63. 13. Miller EC, Miller JA: Mechanisms of chemical carcinogenesis. Cancer 1981, 47(Suppl 5):1055-64. 14. Sandgren EP, Luetteke NC, Palmiter RD, Brinster RL, Lee DC: Over- expression of TGF alpha in transgenic mice: induction of epi- thelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 1990, 61:1121-35. 15. Thorup I: Histomorphological and immunohistochemical characterization of colonic aberrant crypt foci in rats: rela- tionship to growth factor expression. Carcinogenesis 1997, 18:465-72. 16. Huang F, Sauma S, Yan Z, Friedman E: Colon absorptive epithelial cells lose proliferative response to TGF alpha as they differ- entiate. Exp Cell Res 1995, 219:8-14. 17. Sauma S, Huang F, Winawer S, Friedman E: Colon goblet cells lose proliferative response to TGF alpha as they differentiate. Int J Cancer 1995, 61:848-53. 18. Cartlidge SA, Elder JB: Transforming growth factor alpha and epidermal growth factor levels in normal human gastroin- testinal mucosa. Br J Cancer 1989, 60:657-60. 19. Kuniyasu H, Ohmori H, Sasaki T, Sasahira T, Yoshida K, Kitadai Y, Fidler IJ: Production of interleukin 15 by human colon cancer cells is associated with induction of mucosal hyperplasia, angiogenesis, and metastasis. Clin Cancer Res 2003, 9:4802-10. 20. Spring KJ, Zhao ZZ, Karamatic R, Walsh MD, Whitehall VL, Pike T, Simms LA, Young J, James M, Montgomery GW, Appleyard M, Hewett D, Togashi K, Jass JR, Leggett BA: High prevalence of sessile ser- rated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy. Gastroenterology 2006, 131:1400-7. Page 9 of 11 (page number not for citation purposes)