A “field change” of inhibited apoptosis occurs in colorectal mucosa adjacent to colorectal adenocarcinoma

Abstract

Background: Colorectal cancer is associated with a ''field change'' of increased proliferation throughout the colonic and rectal mucosa. Both proliferation and apoptosis are disrupted during carcinogenesis. Whether altered apoptosis contributes to this field change of microscopic abnormality is, however, unclear. Bcl-xL is an anti-apoptotic protein that inhibits apoptosis by preventing release of cytochrome c, a recognised pathway to cell death. Aim: To determine whether Bcl-xL inhibition of apoptosis is increased in colorectal mucosa adjacent to colorectal adenocarcinoma over that in normal non-neoplastic colorectal mucosa. Patients: Patients undergoing surgical resection for neoplastic (adenocarcinoma) or non-neoplastic disease of the colorectum (rectal prolapse, diverticular disease or volvulus). Methods: Formalin-fixed, paraffin-wax-embedded surgical colorectal resection specimens were immunostained for Bcl-xL protein. Labelling indices were determined by counting the proportion of positively stained cells in mucosal crypts. Results: 85 patients were studied. Bcl-xL immunostaining was most marked in the upper third of mucosal crypts. It occurred in a minority of samples from non-neoplastic colorectal mucosa, but was seen in most mucosal samples adjacent to colorectal adenocarcinoma. Significant increases (p,0.001) were observed in Bcl-xL labelling indices in the mucosa at 1 cm (n = 46, median labelling index 31.8%, interquartile range 8.3-43.9%) and at 10 cm (n = 52, median labelling index 22.0%, interquartile range 0.0-36.3%) from colorectal carcinoma, compared with normal, non-neoplastic colorectal mucosa (n = 22, median labelling index 0.0%, interquartile range 0.0-0.0%). Conclusions: The findings are consistent with a field change of inhibited apoptosis in mucosa adjacent to colorectal carcinoma.

Field defects in progression to gastrointestinal tract cancers

“…Bcl-x L expression increased at 1 cm and 10 cm away from colorectal adenocarcinomas in non-neoplastic colorectal mucosa suggesting the presence of an apoptosis resistant field [53]. A similar finding was also reported for the anti-apoptotic protein Bcl-2 [54].…”

p16INK4a Gene Promoter Hypermethylation in Mucosa as a Prognostic Factor for Patients with Colorectal Cancer

“…The results of the present study, as well as those of previous recent studies (8,9,12,(31)(32)(33)(34)(35), indicate that the use of matching normal-appearing mucosa as control material in CRC may be questioned. Clearly, the colorectal mucosa of patients with CRC differs from that of healthy individuals on several levels.…”

“…The finding indicated that although neoplastic lesions develop in a limited area of the colon, the entire large bowel may be at risk for tumor growth. Several recent studies have shown that the adjacent mucosa is not normal metabolically when compared with mucosa of healthy controls (31)(32)(33)(34). Alterations have been found at different distances from the site of the growing tumor, and may occur in a patch-like manner (31) or as a "fieldchange" surrounding the tumor (34).…”

Minichromosome maintenance protein 2 (MCM2) is a stronger discriminator of increased proliferation in mucosa adjacent to colorectal cancer than Ki-67

“…Proliferation35 or apoptosis36 may have been attenuated in mucosa situated within 1 cm of the colorectal cancer—for example, by the local effects of modulatory factors released from the tumour or by nutrient deprivation of adjacent cells 35. Further studies are needed to determine whether carcinoma-associated proliferation and apoptosis vary with the proximity of adjacent mucosa to the neoplasm.…”