CFTR and Gastrointestinal Cancers: An Update

Abstract

Cystic Fibrosis (CF) is a disease caused by mutations in the CFTR gene that severely affects the lungs as well as extra-pulmonary tissues, including the gastrointestinal (GI) tract. CFTR dysfunction resulting from either mutations or the downregulation of its expression has been shown to promote carcinogenesis. An example is the enhanced risk for several types of cancer in patients with CF, especially cancers of the GI tract. CFTR also acts as a tumor suppressor in diverse sporadic epithelial cancers in many tissues, primarily due to the silencing of CFTR expression via multiple mechanisms, but especially due to epigenetic regulation. This review provides an update on the latest research linking CFTR-deficiency to GI cancers, in both CF patients and in sporadic GI cancers, with a particular focus on cancer of the intestinal tract. It will discuss changes in the tissue landscape linked to CFTR-deficiency that may promote cancer development such as breakdowns in physical barriers, microbial dysbiosis and inflammation. It will also discuss molecular pathways and mechanisms that act upstream to modulate CFTR expression, such as by epigenetic silencing, as well as molecular pathways that act downstream of CFTR-deficiency, such as the dysregulation of the Wnt/β-catenin and NF-κB signaling pathways. Finally, it will discuss the emerging CFTR modulator drugs that have shown promising results in improving CFTR function in CF patients. The potential impact of these modulator drugs on the treatment and prevention of GI cancers can provide a new example of personalized cancer medicine.

Keywords: CFTR; cystic fibrosis; gastrointestinal cancers; modulators; tumor suppressor gene.

Figure 1

CFTR dysfunction in the GI tract and its association with carcinogenesis. (A) CFTR deficiency disrupts protective physical barriers resulting in microbial dysbiosis, inflammation as well as immune cell infiltration. Deficiency of CFTR results in the failure of intestinal chloride as well as bicarbonate ion transport and the accompanying efflux of water molecules. Loss of CFTR accounts for the dehydration of the mucus layer, making it permissive for bacterial infiltration and also results in intestinal obstruction. The disruption of epithelial barrier causes infiltration of pathogenic and commensal bacteria, inflammation, infiltration of immune cells and epithelial tissue damage. These alterations result in the generation of a favorable niche which promotes the initiation and progression of GI cancers [11]. (B) CFTR downregulation enhances Wnt/β-catenin signaling. Expression levels of CFTR is highest in the intestinal crypts, in particular at the base of the crypt in the stem cell compartment, with expression levels lower in the intestinal lumen. Wnt expression levels follow a similar gradient under normal conditions. Loss of CFTR activity in the crypts increases intracellular pH (pHi) and results in stabilization of the plasma membrane association of Disheveled (Dvl). This ultimately enhances Wnt/β-catenin signaling via the nuclear translocation of cytoplasmic β-catenin. Nuclear β-catenin promotes the expression of genes involved in survival as well as proliferation of intestinal stem cells, which increases the risk of intestinal tumor development. (C) CFTR dysfunction promotes carcinogenesis. Loss of CFTR function in a cell can occur due to genetic mutations or different epigenetic mechanisms including promoter hypermethylation, activity of certain transcription factors, changes in chromatin architecture as well as miRNAs, resulting in the downregulation of CFTR expression. Downregulation of CFTR results in increased cellular proliferation along with decreased apoptosis, increased invasive behavior, mitochondrial dysfunction resulting in ROS generation and increased proinflammatory signaling. These properties are mediated by specific signaling pathways, including the p-38 MAPK and NF-κB pathways. These alterations in cellular behavior promote cancer progression. As CFTR modulator drugs have shown efficacy in CF patients, they may also show promising results when used in cancer cells where the function of CFTR is lost. This figure was created using BioRender software.

Figure 1

CFTR dysfunction in the GI tract and its association with carcinogenesis. (A) CFTR deficiency disrupts protective physical barriers resulting in microbial dysbiosis, inflammation as well as immune cell infiltration. Deficiency of CFTR results in the failure of intestinal chloride as well as bicarbonate ion transport and the accompanying efflux of water molecules. Loss of CFTR accounts for the dehydration of the mucus layer, making it permissive for bacterial infiltration and also results in intestinal obstruction. The disruption of epithelial barrier causes infiltration of pathogenic and commensal bacteria, inflammation, infiltration of immune cells and epithelial tissue damage. These alterations result in the generation of a favorable niche which promotes the initiation and progression of GI cancers [11]. (B) CFTR downregulation enhances Wnt/β-catenin signaling. Expression levels of CFTR is highest in the intestinal crypts, in particular at the base of the crypt in the stem cell compartment, with expression levels lower in the intestinal lumen. Wnt expression levels follow a similar gradient under normal conditions. Loss of CFTR activity in the crypts increases intracellular pH (pHi) and results in stabilization of the plasma membrane association of Disheveled (Dvl). This ultimately enhances Wnt/β-catenin signaling via the nuclear translocation of cytoplasmic β-catenin. Nuclear β-catenin promotes the expression of genes involved in survival as well as proliferation of intestinal stem cells, which increases the risk of intestinal tumor development. (C) CFTR dysfunction promotes carcinogenesis. Loss of CFTR function in a cell can occur due to genetic mutations or different epigenetic mechanisms including promoter hypermethylation, activity of certain transcription factors, changes in chromatin architecture as well as miRNAs, resulting in the downregulation of CFTR expression. Downregulation of CFTR results in increased cellular proliferation along with decreased apoptosis, increased invasive behavior, mitochondrial dysfunction resulting in ROS generation and increased proinflammatory signaling. These properties are mediated by specific signaling pathways, including the p-38 MAPK and NF-κB pathways. These alterations in cellular behavior promote cancer progression. As CFTR modulator drugs have shown efficacy in CF patients, they may also show promising results when used in cancer cells where the function of CFTR is lost. This figure was created using BioRender software.