What Role Does CFTR Play in Development, Differentiation, Regeneration and Cancer?

Abstract

One of the key features associated with the substantial increase in life expectancy for individuals with CF is an elevated predisposition to cancer, firmly established by recent studies involving large cohorts. With the recent advances in cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and the increased long-term survival rate of individuals with cystic fibrosis (CF), this is a novel challenge emerging at the forefront of this disease. However, the mechanisms linking dysfunctional CFTR to carcinogenesis have yet to be unravelled. Clues to this challenging open question emerge from key findings in an increasing number of studies showing that CFTR plays a role in fundamental cellular processes such as foetal development, epithelial differentiation/polarization, and regeneration, as well as in epithelial-mesenchymal transition (EMT). Here, we provide state-of-the-art descriptions on the moonlight roles of CFTR in these processes, highlighting how they can contribute to novel therapeutic strategies. However, such roles are still largely unknown, so we need rapid progress in the elucidation of the underlying mechanisms to find the answers and thus tailor the most appropriate therapeutic approaches.

Keywords: carcinogenesis; cystic fibrosis; epithelial differentiation; epithelial regeneration; epithelial–mesenchymal transition EMT; wound healing.

Figure 1

Cystic fibrosis transmembrane conductance regulator (CFTR) impacts several fundamental cellular processes.

Figure 2

Interplay of CFTR, epithelial differentiation and secretory traffic.

Figure 3

Steps of epithelial regeneration in normal (A) and CF (B) epithelia (see text for details). [Adapted from: [15,130]].

Figure 4

Proposed roles of CFTR in the three different epithelial–mesenchymal transition (EMT) settings.