The retention of BCL-2 expression in the carcinomas and lymph node metastases may explain the resistance of colorectal tumours to chemotherapeutic treatment.
Here we have investigated bcl-2 expression in a model of epithelial tumours represented by the spectrum of carcinomas arising from the follicular epithelium of the human thyroid gland.
LOH at the bcl-2 locus was detected in 24% (4/17) of gastric and 60% (6/10) of colonic carcinomas, all of which were well differentiated adenocarcinomas, whereas LOH was not seen in poorly differentiated ones.
However, a significant inverse correlation was seen between Bcl-2 expression and histological grade, Bcl-2 being absent in the majority of T1 undifferentiated tumors (grade-III carcinomas).
The expression of bcl-2 protein has been observed in most follicular lymphomas and in approximately 25% of high-grade non-Hodgkin's lymphomas, as well as in solid tumors such as carcinomas of the lung, prostate, and nasopharynx.
Cytoplasmic expression of the bcl-2 protein was detected in 72 (66%) of 110 carcinomas, and a high level of expression was significantly correlated with diploid DNA content (P = 0.02) and low proliferative activity (P = 0.005). bcl-2 was not associated with nuclear p53 expression.
The Bcl-XL protein is a recently discovered member of the bcl-2 family which has been shown to protect cells from some forms of programmed cell death, but has not yet been implicated in the genesis of human carcinomas.
We compared our findings with conventional clinicopathological indicators [menopausal status, number of axillary nodes, histological grade, tumor size and type, estrogen receptor (ER), and progesterone receptor] and with p53 protein expression. bcl-2 protein was present in 65% of the carcinomas (117/180) and it was significantly associated with ER and progesterone receptor and inversely associated with p53 in both the groups of patients treated with adjuvant chemotherapy and tamoxifen.
We postulate (1) increased bcl-2 expression in epithelium adjacent to tumors represents an inherent change in the morphologically normal epithelium because it occurs without the corresponding high proliferative state seen in the normal crypt-regenerative compartment, (2) heterogeneity may provide a mechanistic explanation for chemotherapeutic resistance in tumors since cells having high bcl-2 but low proliferative activity would have prolonged survival and might show resistance to chemotherapeutic agents, and (3) the increased proliferative state in histologically inactive ulcerative colitis may provide a partial explanation for the increased risk of colon carcinomas in these patients.
These results indicate that Bcl-2 may be predominantly expressed at an early stage in gastric carcinomas, possibly in negative association with p53 gene abnormalities.
Whereas in normal mucosa bcl-2 immunoreactivity was restricted to the basal-cell layer, in 9 out of 15 severe squamous dysplasias and in 7 out of 14 carcinomas in situ bcl-2 staining was detected in all epithelial layers.
In addition, the proportion of tumors in which the Bcl-2 immunointensity was more than or equal to that of normal colonic mucosa was significantly lower in carcinomas than adenomas (5 of 30 versus 15 of 24, respectively; P < 0.001), suggesting that decreases in Bcl-2 expression represent a later event associated with the progression of colorectal cancers.
Our results suggest that in tumours of the follicular epithelium p53 and bcl-2 protein abnormalities are associated with more advanced carcinomas and especially with undifferentiated carcinomas, while they are only rarely altered in tumours of the parafollicular C cells.
Expression of Bcl-2 is associated with resistance to hormone therapy and recurrence in prostate carcinomas, whereas in lung and breast carcinomas it is associated with a better prognosis.
We have evaluated 10 cases of apocrine metaplasia, 3 cases of in situ apocrine carcinoma and 10 cases of invasive apocrine carcinomas using immunostaining method for steroid hormone receptors (estrogen, progesterone, androgen), p53, bcl-2 and BRST-2.
To clarify whether changes in bcl-2 protein (bcl-2) expression are directly linked to differentiation, an immunohistochemical investigation was carried out on areas of squamous differentiation within 38 endometrial carcinomas (25 grade 1 and 13 grade 2 cases) as well as eight grade 1 carcinomas after progesterone therapy.
The expression of Bcl-2, a suppressor of apoptotic cell death, was investigated in 52 invasive carcinomas of the breast using reverse transcription-polymerase chain reaction and immunohistochemical methods.
Moderate to strong Bcl-2 immunointensity in more than 30% of cells was found in 32 (34.8%) of 92 carcinomas, with a clear link to favorable clinicopathological features, such as a high differentiation grade (P = 0.0084), an early stage (P = 0.0432) and limited invasion into the myometrium (P = 0.0084).
Expression of bcl-2 was found in 79 of 82 (96%) normal ductal epithelial cells, in 50 of 63 (79%) intraductal carcinomas, and in 62 of 137 (45%) invasive carcinomas, respectively.
On the other hand, two anaplastic and one insular carcinomas showed marked increase in apoptosis along with intense p53 positivity and bcl-2 negativity.