EARLY EXPRESSION OF bcl‐2 PROTEIN IN THE ADENOMA–CARCINOMA SEQUENCE OF COLORECTAL NEOPLASIA

Abstract

bcl-2 was originally identified as an oncogene involved in follicular lymphomas as a result of chromosomal translocation (14;18). It is now believed that bcl-2 is implicated in the regulation of cell death by inhibiting apoptosis and that its expression is not restricted to haematopoietic cells, but is also present in many epithelial and mesenchymal tissues. Recent studies have analysed the expression of this molecule in a variety of non-lymphoid malignancies including lung, breast, prostate, and nasopharyngeal carcinomas and neuroblastoma. In the present study, 50 colorectal adenomas, 10 hyperplastic polyps, and 142 carcinomas, including 25 arising from pre-existing adenomas, were examined using an antibody detecting the bcl-2 protein product. In non-neoplastic mucosa, bcl-2 was expressed in the crypt cells only, whilst the more differentiated surface epithelial cells lacked any demonstrable bcl-2. Forty-one of the 50 adenomas (82 per cent) and 48 of the 142 carcinomas were positive for bcl-2 expression. All hyperplastic polyps were negative. A reciprocal relationship was found between bcl-2 reactivity and p53 overexpression, as detected by DO7 antibody, in approximately 65 per cent of the cases. The bcl-2-positive/p53-negative subgroup showed a strong correlation (P = 0.0056) with negative lymph node status (Dukes' A and B), implying a less aggressive pathway of neoplastic transformation.

Bcl-2 protein expression: association with p53 and prognosis in colorectal cancer

“…Other reports have shown that p53 can down-regulate bcl-2 gene expression (Miyashita et al, 1994) and in a breast cell line bcl-2 was down-regulated by overexpression of a mutant p53 (Halder et al, 1994). In a previous study (Kaklamanis et al, 1996), carcinomas arising from adenomas showed loss of bcl-2 (85% positive adenomas compared with 25% positive carcinomas), implying that during the adenomacarcinoma progression, at the time when p53 mutations usually take place, bcl-2 expression is down-regulated.…”

“…Bcl-2 detection in these neoplasms seems to be correlated with favourable clinicopathological parameters and better prognosis (Hague et al, 1994;Ofner et al, 1995;Baretton et al, 1996;Kaklamanis et al, 1996;Watson et al, 1996;Manne et al, 1997;Pereira et al, 1997), although the latter has been controversial (Bosari et al, 1995;Sinicrope et al, 1995;Mosnier et al, 1996). Recently, it was shown that bcl-2 expression did not influence response to chemotherapy for advanced or metastatic disease (Sneider et al, 1997).…”

“…In a recent study in tissues with a rapid turnover, such as colorectal mucosa, bcl-2 was found only in the crypt cells of the colonic pits and was not present in hyperplastic polyps. In the neoplastic counterpart, bcl-2 was detected in the majority of adenomas (85%) but in only 25-30% of the invasive carcinomas, reflecting a possible down-regulation (Kaklamanis et al, 1996).…”

Bcl-2 expression in rectal cancer

“…The observation that bcl-2 is not only restricted to hematopoietic cells, but also expressed in a variety of epithelial and nonepithelial tissues, led to an increasing on research directed to clarify the role of this molecule in the pathogenesis and prognosis of several malignancies (10) . There is a hypothesis that expression of bcl-2 predisposes to the development of colorectal neoplasms since it may extend survival of cells exposed to carcinogenic agents (21) .…”

Germline BCL-2 sequence variants and inherited predisposition to prostate cancer

“…39 Similarly, increased bcl-2 expression has been reported in colorectal adenomas, cervical intraepithelial neoplasia and other precancerous lesions, suggesting that bcl-2 plays an oncogenic role during the early stages of carcinogenesis in cells other than prostate epithelial cells. 17,33,40,41 We are aware of various limitations in the current study. For instance, we did not consider the interaction between variations in the BCL-2 gene and other targets that may regulate or modulate apoptosis, including: (1) oncogenes/tumour suppressor genes such as p53, myc, ras, abl, raf, jun and the bcl-2 family (i.e., other prosurvival and prodeath); (2) hormones (i.e., androgen/androgen receptor), cytokines and growth factor/ growth factor receptors (e.g., tumour necrosis factor-á/ Fas and tumour growth factor-b (TGF-b)/TGF-b receptor), endothelial growth factor/endothelial growth factor receptor and (3) extracellular matrix regulators/cell adhesion molecules.…”