Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment

TLDR

Invasion and dissemination of well‑differentiated colorectal carcinomas are often linked to loss of epithelial differentiation and gain of mesenchyme‑like traits at the invasive front. The authors propose that the tumor microenvironment drives progression of well‑differentiated colorectal carcinomas by inducing transient phenotypic transitions through modulation of intracellular β‑catenin distribution. Differentiated epithelial growth patterns were preserved in central primary tumors and metastases, whereas β‑catenin localization shifted from nuclear in dedifferentiated invasive‑front cells to membrane/cytoplasmic in polarized epithelial metastatic cells, accompanied by altered E‑cadherin expression and proliferation.

Abstract

Invasion and dissemination of well-differentiated carcinomas are often associated with loss of epithelial differentiation and gain of mesenchyme-like capabilities of the tumor cells at the invasive front. However, when comparing central areas of primary colorectal carcinomas and corresponding metastases, we again found the same differentiated epithelial growth patterns. These characteristic phenotypic changes were associated with distinct expression patterns of β-catenin, the main oncogenic protein in colorectal carcinomas, and E-cadherin. Nuclear β-catenin was found in dedifferentiated mesenchyme-like tumor cells at the invasive front, but strikingly, as in central areas of the primary tumors, was localized to the membrane and cytoplasm in polarized epithelial tumor cells in the metastases. This expression pattern was accompanied by changes in E-cadherin expression and proliferative activity. On the basis of these data, we postulate that an important driving force for progression of well-differentiated colorectal carcinomas is the specific environment, initiating two transient phenotypic transition processes by modulating intracellular β-catenin distribution in tumor cells.