Genes mediating programmed cell death: an immunohistochemical study of bcl-2, c-myc and p53 expression in colorectal neoplasia

Abstract

Aims-To describe the expression of three genes involved in the regulation of cell proliferation and programmed cell death (apoptosis) in normal, dysplastic and malignant large bowel epithelium, and to relate any alterations to important biological and clinical variables. Methods-Immunohistochemistry was used to assess bcl-2, c-myc and p53 gene expression in 70 colorectal carcinomas, 36 adenomas and three samples of normal mucosa. Results-Bcl-2 and c-myc protein were detected in all samples of normal mucosa and most adenomas. P53 was never found in normal mucosa and was expressed in only 5% of adenomas. Sixty nine of 70 carcinomas expressed c-myc protein; p53 was found in 46% and bcl-2 was present in 35%. Bcl-2 expression correlated with a higher degree of tumour differentiation whereas the opposite was true for c-myc. Strong staining for c-myc protein predicted survival in univariate analysis. No correlation was found between p53 and bcl-2 expression. Conclusions-While c-myc and bcl-2 proteins are overexpressed at an early stage of the large bowel adenoma-carcinoma sequence, alterations to the p53 protein level only occur as a late event in large, highly dysplastic adenomas and carcinomas. Bcl-2 may therefore protect the growing adenoma against excessive programmed cell death and mutated p53 may play a similar role in carcinomas. In vitro there is a reciprocal relation between p53 and bcl-2 expression. This could not be confirmed in vivo. Similarly, there was no relation between bcl-2 and c-myc status, despite evidence that these proteins cooperate to cause neoplastic transformation. C-myc may be a prognostic indicator in large bowel cancer. There is no evidence in the present series that bcl-2 status will affect survival.

Proliferation and apoptosis in proliferative lesions of the colon and rectum

“…Hague et al [28] and Sinicrope et al [14] reported bcl-2 staining in over 60% of colorectal carcinomas. Our data, which have already been reported [17], are in agreement with those of Scott et al [29] and Kaklamanis et al [30] and indicate that relative to colorectal adenomas, colorectal carcinomas show a reduction in bcl-2 expression. Given the function of bcl-2 as apoptosis suppressor and the decreased rate of apoptosis in colorectal carcinomas this paradox is not easy to explain.…”

“…It has become clear, however, that the regulation of apoptosis is complex and involves not only bcl-2 but also a variety of other members of this gene family [11,12], in addition to other regulating genes, including p53 and c-myc. This might imply that carcinomas acquire other genetic lesions, which render bcl-2 redundant [29]. Bcl-2 expression was not correlated with p53 expression, as reported previously [29].…”

“…This might imply that carcinomas acquire other genetic lesions, which render bcl-2 redundant [29]. Bcl-2 expression was not correlated with p53 expression, as reported previously [29]. When adenomas and carcinomas were taken together, a strong negative correlation was found between proliferative activity and bcl-2 expression.…”

“…There was a trend for apoptosis to be increased in p53-positive carcinomas but this was not statistically significant. Bcl-2 expression in colorectal adenomas and carcinomas has been previously reported [9,10,14,17,[28][29][30][31]. Hague et al [28] and Sinicrope et al [14] reported bcl-2 staining in over 60% of colorectal carcinomas.…”

Down-regulation of Fas gene expression in colon cancer is not a result of allelic loss or gene rearrangement

“…Resistance of colonocytes to apoptosis may allow hyperproliferation, accumulation of oncogenic mutations and prevent deletion of malignant cells by chemotherapeutic agents. Abnormal expression of the apoptosis-related genes p53 and bcl-2 has been reported in both benign and malignant colon tumours (Sinicrope et al, 1995;Scott et al, 1996), however other molecular mediators of resistance to apoptosis remain to be identified.…”