As compared with the sub-cellular distribution of β-catenin in normal colonic mucosa, neoplastic cells demonstrated a distinct shift from a membranous locali-zation to a more widespread distribution (membranous, cytoplasmic, and nuclear) in cancer lesions. This is in line with previous reports describing β-catenin expression in cancer cells with this type of altered pattern[14,15
]. For example, Wong et al[16
] observed no nuclear β-catenin accumulation in normal tissues, whereas it was present in 8% of polyps, 92% of adenomas, and 100% of carcinomas. In the present series, nuclear expression or accumulation was observed in 48% of the cancer samples, which is in line with several other reports[7,17
]. Interestingly, in 13% of the cases with nuclear expre-ssion, β-catenin was expressed by the tumour cells at the invasion fronts, a figure very similar to the 9% reported by Ougolkov et al[7
We did not find significant correlations between the three β-catenin expression patterns (MI, CI, and NI) and most of the clinical variables recorded (age, sex, grade, and stage), except for tumor localization. Accordingly, β-catenin expression, both CI and NI, was more intense in carcinomas of the descending colon and rectum as compared with lesions localized in the ascending and transverse colon. Similar observations have been reported by previous studies[18–20
]. There is increasing evidence to suggest that molecular mechanisms and molecular phenotypes differ in carcinomas arising in the proximal and distal segments of the large bowel[21
]. The involvement of different molecular pathways in colorectal carcinogenesis is exemplified by the fact that cancers of “mutator” phenotypes preferentially occur in the proximal (right side) colon, whereas the adenoma-carcinoma sequence phenotype is characteristic of carcinomas in the distal (left side) colon and rectum[22,23
]. Corresponding differences have also been shown in association with other potential prognosticators[24
Interestingly, a marginally significant relation was observed between the NI and MI and response to treatment. Accordingly, the patients who did not respond to treatment had a NI above the median, whereas patients who had a high MI responded better to treatment. The significance of these observations remains to be elucidated in a larger study. There is an obvious need to identify novel molecular targets for cancer therapeutics, and in this respect, the recent data showing that suppression of β-catenin can inhibit the neoplastic growth of APC-mutant colorectal cancer are of interest[25
The correlation between β-catenin expression pattern and clinical outcome is a controversial subject. Some studies reported that cytoplasmic rather than nuclear accumulation of β-catenin is significantly related to metastasis-free survival in CRC[6
]. The same was reported regarding the potential prognostic value of nuclear expression. There are studies reporting that positive nuclear expression at the invasive front of the tumor predicts shorter survival[7,19
]. However, other workers failed to find any correlation between nuclear expression and survival in CRC[17,26
]. In contrast, our data show that nuclear expression is a significant predictor of more favorable DSS and DFS (Figures and ). We also analyzed our samples using the same system as originally described by Ougolkov et al[7
]. In our study, however, this special grading system did not confirm the original observation that nuclear expression at the invasive front of the tumor predicts a shorter survival[7
There are multiple explanations for the inconsistent and, in part, discrepant results reported in different studies[6,7,17,19,26
]. Such potential confounding factors might include the size of tissue samples, intrinsic tumor heterogeneity, lack of standardization in the evaluation of positive and negative results, and different immunohistochemical staining and grading methods with varying degree of sensitivity. In addition, our patients represent advanced CRC, with the majority of patients having stage IV disease, as compared with the Ougolkov study, where the majority of patients had stage II CRC. Also, the type of treatment may have played a role in the detected relationships.
Cell-cell adhesion molecules are believed to participate in the processes of invasion, migration and metastasis[27–29
]. In this regard, the E-cadherin and β-catenin complex plays a critical role in cell-cell adhesion. E-cadherin is a member of the cadherin family that mediates calcium-dependent adhesion to ensure the maintenance of a normal phenotype of epithelial cells[1,30
]. β-catenin binds directly to the cytoplasmic domain of E-cadherin and to the actin microfilament network of the cellular cytoskeleton. This binding is essential for stable cell-cell adhesion[31
It can be reasoned that altered expression of β-catenin (i.e., the shift from membranous to cytoplas-mic and nuclear sites) might compromise the integrity of the E-cadherin/β-catenin complex and result in weaker cell-cell adhesion in cancer cells. Thus, it seems feasible to assess whether altered co-expression patterns of these two markers is of any predictive value in CRC. For that purpose, we combined both the membranous and cytoplasmic E-cadherin expression with membranous and cytoplasmic β-catenin expression to compare normal (MI/MI) and abnormal (CI/CI) co-expression, respectively, of these two markers as previously analysed in CRC[13
]. To our disappointment, however, neither the membranous nor the cytoplasmic E-cadherin/β-catenin index (analyzed in two different modes) provided any useful information as to DFS or DSS. Thus, no added value can be obtained with analyzing E-cadherin expression together with β-catenin expression as compared to the analysis of the latter alone (Figures and ).
Taken together, the present results confirm that β-catenin expression is markedly altered in the vast majority of colorectal cancers. This shift from normal membranous expression to the cytoplasmic (CI) and nuclear (NI) patterns seems to bear some association with the localization of the primary tumour, being most pronounced in lesions of the descending colon and rectum. Although the association of CI and NI to treatment response remains unclear, NI seems to provide some prognostic value in predicting more favourable DFS and also DSS, when dichotomized as NI+/NI- expression. Many of the issues still remain unanswered, however, and additional clinical and experimental studies are needed to fully elucidate the role of β-catenin in colorectal carcinogenesis and its potential usefulness as an independent predictor of disease outcome.