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.

The role of Cdc42 Rho GTPase in the cystic fibrosis intestinal epithelial barrier

“…An association between tight junction function and hyperproliferation has been noted in colorectal tumors, with increased proliferation accompanying leakier tight junctions and greater metastatic potential 113,114 . In the case of CF, hyperproliferation and tight junction structural and functional abnormalities could be contributing factors to the increased incidence of GI cancer that pwCF experience compared to the general population 18 .…”

“…Aberrantly increased Cdc42 activity is associated with increased GI cancer invasion and metastasis, and Cdc42 has gained interest as a target in cancer treatment 73,197 . This highlights the importance of determining the mechanisms of increased Cdc42 activity in CF, especially as pwCF are at an increased risk of developing GI cancer 18 .…”

“…Interestingly, increased intestinal permeability is characteristic of other diseases, including gastrointestinal cancer, inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis), and celiac disease, which are experienced at a higher frequency by pwCF compared to the general population 18,19,[38][39][40][41] . The clinical significance of increased intestinal permeability in pwCF is not fully understood, but it is believed that the gut microbiota influence disease severity and progression in the hepatobiliary and respiratory systems via the translocation of microbial factors into the portal circulation 42 .…”

“…The dysregulation of tight junction structure and function is associated with chronic GI inflammation 39 , carcinogenesis 174 , and tumor metastasis 113 . Both chronic GI inflammation 175 and an increased risk of GI cancer are experienced by pwCF 18 , with the latter occurring at a younger age than that of the general population 18,176 . The tight junction structure is made up of several transmembrane proteins that are connected to cytoplasmic scaffolding proteins and the actin cytoskeleton 177 .…”

“…Intestinal inflammation is present in the majority of pwCF, characterized by an increase in immune cells in the lamina propria, increased fecal calprotectin (a neutrophil marker), and the presence of structural changes to the mucosa, including mucosal ulceration, edema, and erythema 16,17 . This chronic, low-grade intestinal inflammation may be a contributing factor to the increase in the risk of developing GI cancer experienced by pwCF 18,19 . The origins of intestinal inflammation in pwCF are still not entirely understood, and dysbiosis is thought to be a contributing factor to the inflammatory phenotype 17,[20][21][22] .…”