β Catenin is a multifunctional protein that is both an integral component of cell adhesion molecules and a pivotal member of a signal transduction pathway.1,2
The activation of β catenin to an oncogenic state is a consequence of the inactivation of the tumour suppressor APC, by direct mutation of the β catenin gene, or by the activation of other Wnt signalling molecules.3,4
β Catenin is currently thought to be involved in the development of colorectal cancer,2–3,14
which is the second leading cause of cancer deaths in Western countries.2–4
Because detection and treatment at an early stage can dramatically improve survival, there has been great interest in developing diagnostic and prognostic factors that can help to detect asymptomatic colorectal carcinoma, as well as its precursor, colorectal adenoma, and to predict the outcome of this cancer accurately.15,16
However, there is no consensus among researchers on the diagnostic and prognostic potential of β catenin in patients with colorectal carcinoma,15–17
and its expression and possible roles in patients with colorectal adenoma11,18
Our study is the first to investigate its prognostic and diagnostic potential and to clarify its expression in adenomas and polyps extensively by selecting patients with simultaneously occurring carcinomas, adenomas, and polyps. Our results clearly showed that the expression of nuclear β catenin increased significantly during the progression from normal to carcinoma stages for both group 1 and 2 specimens. This reaffirms β catenin as a key oncogenic factor in colorectal carcinogenesis.14
Moreover, for the first time we have shown that the expression of nuclear β catenin is significantly higher in adenomas with synchronous carcinomas than in pure adenomas alone, providing evidence that high expression of nuclear β catenin is associated with a higher cancer risk. This hypothesis was further explored by studying nuclear β catenin expression in 19 patients with adenoma who later developed carcinoma. We found that the expression of nuclear β catenin was much higher in those 19 patients. The presence of nuclear β catenin in adenomas is in line with the results of Herter et al
but contrasts with those of Kobayashi et al
who found no nuclear signals in the adenomas studied. There could be two reasons for this. The first may be the ethnic differences between the two groups studied and the other may be the different antigen retrieval systems used in the two studies. Indeed, we tested out the antigen retrieval protocol used by Kobayashi et al
and found that the signals were much weaker than those obtained after pressure cooking. In addition, we found that nuclear β catenin was expressed in a small number of Peutz-Jeghers and hyperplastic polyps, not only suggesting that these polyps have a higher malignant potential, which correlates well with the findings of Back et al
and Leggett et al
but also indicating that deregulation of the β catenin pathway occurs early in colorectal carcinogenesis. An in depth investigation of β catenin immunostaining in endoscopic colorectal adenoma and polyp biopsies is necessary to assess the risk for those patients of developing colorectal carcinoma in the future. We only identified 19 patients with adenoma who subsequently developed carcinoma, and that sample size was too small to make any conclusions about the size of the cancer risk of nuclear β catenin expression in patients with adenoma.
“For the first time we have shown that the expression of nuclear β catenin is significantly higher in adenomas with synchronous carcinomas than in pure adenomas alone, providing evidence that high expression of nuclear β catenin is associated with a higher cancer risk”
Nuclear β catenin expression was highly correlated with both lymph node metastasis and patient survival, supporting the suggestion by previous authors15,16
that nuclear β catenin expression could be used as a powerful prognostic indicator. However, these results differ from those of Gunther et al
perhaps because different ethnic groups may have different clinical outcomes or because the antigen retrieval and immunohistochemical techniques used in 1998 were less sensitive than those used in recent years.
Finally, because nuclear β catenin was expressed in colorectal adenocarcinomas, but not in other CK20 positive adenocarcinomas, staining for nuclear β catenin and CK20 could be used to identify colorectal carcinoma. The low nuclear β catenin IHC scores found in colorectal mucinous adenocarcinoma implies that this tumour does not exploit the β catenin related pathway in carcinogenesis. A larger study is needed to elucidate whether staining for nuclear β catenin and CK20 could be used as a novel colorectal cancer marker, but we have already detected 20 nuclear β catenin positive metastatic colorectal cancers from various sites (data not shown).
In line with earlier reports,21,22
heterogeneous expression of β catenin was also found in our cohort, perhaps as a result of variations in tumour differentiation. Our results are reliable, not only because normal colorectal tissue was used as an internal positive control in each section, and external negative controls were also included in each batch of staining, but also because our evaluation method has been used previously by us,13,23
and should be reliable for scoring purposes.
Take home messages
- Nuclear β catenin expression increased significantly with the progression of colorectal tissue from normal epithelial tissue, polyps, adenomas, to carcinomas
- Nuclear β catenin expression was higher in patients who subsequently developed colorectal carcinoma than in those with colorectal adenoma alone
- Patients with colorectal cancer and high nuclear β catenin expression had a higher incidence of lymph node metastasis and shorter overall survival
- Nuclear β catenin expression in colorectal adenocarcinomas was significantly higher than in other cytokeratin 20 positive adenocarcinomas
- Thus, nuclear β catenin expression is a potential prognostic factor in patients with colorectal cancer, and together with cytokeratin 20, it could be used to identify colorectal carcinoma in the Hong Kong population
Taken together, the findings of our study will undoubtedly advance our understanding of the role of nuclear β catenin in colorectal carcinogenesis and, in addition, suggest that nuclear β catenin, despite different outcomes in different ethnic groups, is a potential prognostic and diagnostic marker in patients with colorectal cancer from Hong Kong.