Evidence for reciprocity of bcl-2 and p53 expression in human colorectal adenomas and carcinomas

Abstract

Summary Evidence is accumulating for the failure of apoptosis as an important factor in the evolution of colorectal cancer and its poor response to adjuvant therapy. The proto-oncogene bcl-2 suppresses apoptosis. Its expression could provide an important survival advantage permitting the development of colorectal cancer. The expression of bcl-2 and p53 was determined by immunohistochemistry in 47 samples of histologically normal colonic mucosa, 19 adenomas and 53 adenocarcinomas. Expression of bcl-2 in colonic crypts > 5 cm from the tumours was confined to crypt bases but was more extensive and intense in normal crypts < 5 mm from cancers. A higher proportion of adenomas (63.2%) than carcinomas (36.5%) expressed bcl-2 (P<0.05). A lower proportion of adenomas (31.6%) than carcinomas (62.3%) expressed p53 (P< 0.02). A total of 26.3% of adenomas and 22% of carcinomas expressed both bcl-2 and p53. To determine whether these samples contained cells which expressed both proteins, a dual staining technique for bcl-2 and p53 was used. Only 1/19 adenomas and 2/53 carcinomas contained cells immunopositive for both bcl-2 and p53. Moreover there was evidence of reciprocity of expression of bcl-2 and p53 in these three double staining neoplasms. We suggest that bcl-2 provides a survival advantage in the proliferative compartment of normal crypts and colorectal neoplasms. However, its expression is lost during the evolution from adenoma to carcinoma, whereas p53 expression is increased, an event generally coincident with the expression of stabilised p53, which we presume to represent the mutant form.

Damage-induced apoptosis in intestinal epithelia from bcl-2-null and bax-null mice: investigations of the mechanistic determinants of epithelial apoptosis in vivo

“…Bcl-2 was absent from the murine small intestine by immunohistochemistry (Merritt et al, 1995). Similar results were reported by others, both for mouse and man (Hockenberry et al, 1991;Krajewski et al, 1993;Hague et al, 1994;Watson et al, 1996). In previous studies, we showed that mice rendered homozygously null for bcl-2 demonstrated both increased spontaneous and g-radiation-induced apoptosis in vivo, speci®cally at the site of the presumed colonic stem cells, at the base of the crypt (Merritt et al, 1995).…”

“…This was predictably signi®cant at the base of the colonic crypt (Figure 4c), the focus of bcl-2 expression in both mouse and man (Hockenberry et al, 1991;Krajewski et al, 1993;Hague et al, 1994;Merritt et al, 1995;Watson et al, 1996). However, there was no signi®cant di erence in apoptosis after 24 h (Figure 4b,d).…”

“…The observation of slightly increased levels of apoptosis in the small intestine of homozygously bcl-2-null mice compared with their wild-type counterparts 4.5 h after 5FU administration was somewhat surprising in view of the reported lack of immunohistochemically detectable bcl-2 in this tissue (Krajewski et al, 1993;Hague et al, 1994;Merritt et al, 1995;Watson et al, 1996). However, we previously (Merritt et al, 1995) observed a slightly increased level of apoptosis at this site 3 h after 8 Gy of g-radiation.…”

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

“…We and others have recently shown that bcl-2, although expressed in the majority of colorectal adenomas, is down-regulated in invasive carcinomas and expressed in approximately 25-50% of the cases (Watson et al, 1996;Manne et al, 1997;Sneider et al, 1997). 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).…”

“…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).…”