p27 expression in inflammatory bowel disease-associated neoplasia. Further evidence of a unique molecular pathogenesis

Abstract

The cyclin-dependent kinase inhibitor p27 is a negative regulator of the transition from G1 to S phase of the cell cycle, protects against inflammatory injury and promotes epithelial differentiation. Because p27 protein has been shown to be abnormally expressed both in dysplasia associated with Barrett's esophagus and in sporadic colorectal adenomas, we used immunohistochemistry to evaluate p27 expression in inflammatory bowel disease (IBD)-associated dysplasia and carcinomas. Normal, inflamed, and transitional mucosa, sporadic adenomas, and sporadic colonic carcinomas were studied as controls. In normal colonic epithelium p27 expression was restricted to the superficial, terminally differentiated cells. In colitic and inflamed diverticular mucosa p27 was expressed in the base of the crypts in 86 and 70% of cases, respectively. Similarly, in transitional mucosa adjacent to sporadic carcinomas p27 was expressed in the base of the crypts in all cases. Strong p27 expression extended more frequently from the base of the crypts to superficial cells in IBD-associated dysplasia than in sporadic adenomas (P < 0.007). Twenty of 20 (100%) IBD-associated carcinomas showed low p27 expression (<50% nuclei positive) compared to 6 of 20 (30%) stage-matched sporadic colorectal carcinomas (P < 0.001). We conclude (i) aberrant p27 protein expression in inflamed and IBD-associated nondysplastic mucosa is indistinguishable from that found in transitional mucosa adjacent to sporadic carcinomas; (ii) p27 is overexpressed in dysplastic lesions, perhaps as an attempt to counterbalance proliferative stimuli; and (iii) IBD-associated colorectal carcinomas have significantly lower p27 expression, commonly associated with poor prognosis, than stage-matched sporadic colorectal carcinomas. These findings further substantiate the existence of divergent molecular pathogenetic pathways between these types of carcinomas and suggest an intrinsically more aggressive behavior of IBD-associated colon carcinomas compared to sporadic ones.

Figure 1.

a: Normal colonic mucosa, H&E stain. b: Nuclear p27 protein expression in terminally differentiated epithelial cells in the uppermost one-third of crypts. Lymphocytes in the lamina propria also show nuclear staining. c: IBD-associated nondysplastic epithelium, H&E stain. d: Strong nuclear and cytoplasmic p27 protein expression at the base of the crypts in the putative stem cells. Inset: Transitional mucosa adjacent to a sporadic carcinoma showing p27 protein expression at the base of crypts.

Figure 2.

a: Sporadic colorectal adenoma, H&E stain. b: p27 protein expression limited to the lowest one-third of crypts in this sporadic colorectal adenoma. c: IBD-associated dysplasia, H&E stain. d: Strong p27 protein expression throughout crypts.

Figure 3.

a: Sporadic colorectal carcinoma, H&E stain. b: Strong nuclear expression of p27 protein in tumor cells. c: IBD-associated adenocarcinoma, H&E stain. d: Tumor is negative for p27 protein expression. Note positively reactive lymphocytes surrounding tumor cells.

Figure 4.

Hypothesis of colonic carcinogenesis with respect to p27 expression in normal colonic mucosa and inflammatory bowel disease. p27 is localized in superficially differentiated cells in normal colonic epithelium. Both in transitional mucosa adjacent to tumor and in nondysplastic mucosa from patients with IBD, p27 is expressed in the basal stem cells (and it is both nuclear and cytoplasmic), but not in terminally differentiated superficial colonocytes. In sporadic adenomas and in IBD-associated dysplasia, p27 is overexpressed throughout the crypt epithelium in a transcriptionally controlled manner to counterbalance proliferative stimuli. Invasive adenocarcinomas, which are more frequently exophytic in sporadic cancers, express p27 in >50% of cells in 70% of cases whereas all cases of IBD-associated tumors express low levels of p27. Targeted degradation of p27, which is ubiquitin-proteasome-dependent, appears to be responsible for loss of p27 in tumors. In addition, IBD-associated cancers tend to invade the submucosa earlier, skipping an exophytic growth phase. Finally, the initial molecular alterations in sporadic (APC, ras, bcl-2) and IBD-associated cancers (p53, TGFβRII, p16) appear to be distinctly different. Thus, p27 protein expression appears to underscore the different tumor progression occurring in IBD-associated cancers with respect to sporadic carcinomas.