BMC Cancer 2009, 9:251 http://www.biomedcentral.com/1471-2407/9/251 ThFyihgpeueCrrpeylCa3sAiaPe-/a-rmlyicien slipfeonata6n–e8ouwskly develop colonic mucosal The CyCAP-/- mice spontaneously develop colonic mucosal hyperplasia early in life at 6–8 wk. The differ- ence between this hyperplastic mucosa and normal mucosa of the WT mice is inconspicuous by superficial observation, but statistically, the difference is significant (p < 0.0001, T- test) (20 × magnification, H&E). [12], has been shown to reduce the lag period for the appearance of carcinogen-induced neoplastic lesions and to allow their induction with single, subthreshold doses of carcinogen. Our data indicate that the CyCAP mice spontaneously develop thicker and more proliferative mucosa of the colon, which allowed for marked induction of both additional mucosal hyperplasia and mucosal tumors after the treatment with carcinogen and is in agree- ment with previous studies, which have indicated that mucosal hyperplasia has a profound effect upon early car- cinogenesis [67,68]. Intraluminal factors including western-style diet/food were found to produce colonic mucosal hyperplasia in experimental animals [69,70]. However, Delvaux et al. [71] detected an increase in colonic cell proliferation within an excluded colostomy segment. It was also recently demonstrated that serum insulin levels directly correlate with the presence of adenoma and hyperplastic IhFnyigpmuearrnpeyla5estaircl-ylikaedecnhoamngaessawftereazaolsxoypmretsheannte treatment, In many early adenomas after azoxymethane treat- ment, hyperplastic-like changes were also present. Adenomatous changes without (A) and with (B) evidence of cytologic dysplasia and cystically dilated crypts and hyperplas- tic changes in close proximity to muscularis mucosae were found in tumors after azoxymethane treatment (20 × magni- fication, H&E). polyps in the proximal colon of humans [72]. The history of tobacco smoking was also associated with higher inci- dence of hyperplastic polyps [59]. The latter studies sug- gested that extraluminal factors may also play an important role in the regulation of colonic mucosal growth. Immune regulation and host defense may repre- sent one additional extraluminal factor in regulation of TFmhioegenruetdribeoffybe4vraeizoonucxseysbmeienttwthheaennecrWypTt laendgtKh Oandancimryaplts caeftlelrcotnhteetnrteart-e The differences in the crypt length and crypt cell con- tent are more obvious between WT and KO animals after the treatment by azoxymethane. After the treat- ment by azoxymethane, the CyCAP-/- mice develop more extensive mucosal hyperplasia of the colon than WT animals (p < 0.0001, T-test). The mononuclear inflammatory content in the lamina propria is not increased compared to WT ani- mals (20 × magnification, H&E). aSFzpiogexuctyrrmeume6thoafnheistologic changes in KO mice treated by Spectrum of histologic changes in KO mice treated by azoxymethane. Early dysplastic changes were noted in many areas, some of which corresponded to ACF (A). More extensive moderate dysplasia was noted in areas of thickened mucosa (B) and in tumors/adenomas (C). Focal severe dys- plasia/carcinoma in situ changes were also note (D). Page 7 of 11 (page number not for citation purposes)