Our study showed that lower expression of E-cadherin was associated with the higher clinical staging as well as higher number of metastases. E-cadherin, one of the members of cadherin family, plays a vital role in cell-to-cell adhesion. It is a basic part of the adherence junction. Its role as tumor suppressor has been recognized. Without E-cadherin, cells are able to grow on top of each other, leading to initial formation of cancer . This pathophysiology justified the role of low E-cadherin in cancer progression.
Earlier studies showed that lower E-cadherin expression contributed to higher number of MIBC and high histological cancer grades [14, 15]. Those findings showed the same result as the study conducted by Ziaran et al. All NMIBC cases in our study had high E-cadherin expression, corresponding to other studies [14, 15]. Interestingly, some of the high-grade and MIBC cases retained their E-cadherin expression. This finding suggested the phenomenon of E-cadherin mutation as a factor of cancer progression, other than loss of expression. Mutated E-cadherin is detected in an immunohistochemistry assay, but no longer had its original function in cell adhesion and tumor suppression . Some cancers may also exhibit the ability to downregulate E-cadherin adhesive activity through an unknown mechanism . Both mutated and downregulated E-cadherin retain their expression, which may explain why some cancers with high E-cadherin expression progress to MIBC.
E-cadherin was not statistically associated with multifocality, but data showed high E-cadherin resulted in the existence of multifocality (70.6% vs. 29.4%) than low E-cadherin which the majority found in no multifocality cases (66.7% vs. 33.3%). Current literatures showed that multifocal bladder cancer may arise from two sources: divisions of single cell (clonogenic) and simultaneous multiple transformations (field changes). In theory, clonogenic multifocality may need loss of cell adhesion (represented by E-cadherin), while field changes do not. Both hypotheses were still the subject for extensive studies [16,17,18]. The other explanation is the mutated or downregulated expressed E-cadherin, as discussed above . However, we found no research that specifically studied the impact of the “non-active” expressed E-cadherin to multifocality of bladder cancer.
There was no statistically significant difference between E-cadherin expression with mortality and recurrence (p = 0.29 and p = 0.6, respectively) in our study. Loss to follow-up data was maybe one of the reasons for this result. In contrast, Shi et al. concluded the expression of E-cadherin was very closely associated with the biological behavior of bladder cancer, which may suggest a potential role of E-cadherin in the recurrence and progression of bladder cancer, perhaps with more samples [19,20,21,22,23,24]. Meanwhile, multivariate analysis by Ziaran et al. showed low E-cadherin expression can be a predictor for worse cancer-specific survival. .
Mean of three-year survival was higher in the high E-cadherin expression group. Cumulative survival of low E-cadherin group showed only 40% probability of surviving beyond 36 months, while the high E-cadherin group showed around 70% subjects survived to 36 months. Furthermore, in subgroup analysis, subjects with MIBC had lower probability of survival (64% in high E-cadherin and 40% in low E-cadherin) compared to NMIBC (86%) within three years. The lack of statistical association was perhaps due to loss to follow-up in 17 (42.5%) of subjects. As discussed earlier, E-cadherin holds a significant role in cell-to-cell adhesion . With low E-cadherin, there is the higher risk for cancers to progress and metastasize . This result would be comparable to the differences of expression found in the different staging and grading of bladder cancer which also translate into the tumor’s aggressiveness, and subsequently, the patients’ prognosis. Therefore, E-cadherin expression had the potential to become a prognostic factor in MIBC and NMIBC.
There were several limitations of our study. First, the sample size of our study was limited because our study was a single-center study. Next, our follow-up data were incomplete. Because our hospital was a national referral hospital with patients originated across the country, we encountered difficulties in tracking the subjects after three years. Third, type of treatments received by the subjects were unaccounted in our study, which could lead to outcome bias. Other limitation of this study was unaccounted co-founding factors, such as obesity, diabetes mellitus, chronic lung disease, and congestive heart failure, which may aggravate the recurrence and survival rate. Those co-founding factors were difficult to adjust because of the rarity of the disease and single-centered nature of our study. Nevertheless, we conducted this study because E-cadherin is an important prognostic marker and scarcely studied in our country.