| dc.description.abstract | Cystic Fibrosis (CF) is a severe genetic disease where mutations in the CFTR gene lead to thick mucus in the lungs which makes it difficult to breath. The development of new drugs has tremendously increased the life expectancy of many CF patients up to 82.5 years. Even though these new drugs are a huge breakthrough, the aging CF patients face new difficulties as they have a large risk to develop colorectal cancer (CRC). There is no clear explanation for the increased CRC risk yet, several studies describe different potential underlying reasons. Here, we summarize the current literature on the risk of CRC in CF patients and suggest directions for future research.
In the first part of this report we summarize relevant research papers about CRC in CF patients. The risk of CRC is significantly increased in CF patients compared to the normal population, especially after organ transplantation. Additionally, CF patients are generally younger when they develop CRC. Furthermore, studies on the risk of CRC in CF carriers reported conflicting results. Therefore, it remains uncertain if CF carriers have an increased risk of CRC as well. We also looked into studies investigating CRC in patients without CF which reported CFTR mutations and defective CFTR protein. This suggest a relationship between CRC and defective CFTR even in non-CF patients.
In the second part of this report we focus on understanding the molecular mechanism behind the increased CRC risk in CF. CRC usually develops due to mutations that activate a cell signaling cascade called the Wnt/b-catenin pathway which effects cell division/proliferation. Multiple studies indicated that the mutated CFTR protein in CF patients can also activate the Wnt/β-catenin pathway and thereby contributes to the development of CRC. Several theories on how mutated CFTR leads to CRC development exist, this report has summarized two of them. First, as CFTR plays an important role in fluid homeostasis, mutated CFTR leads to an unbalanced fluid homeostasis which increases the pH in colon cells. This increased pH stabilizes certain protein interactions that eventually activate the Wnt/β-catenin pathway. Additionally, the raised pH prevents cell death and stimulates cell division. Second, the CFTR protein normally interacts with proteins that decrease the Wnt/β-catenin pathway. Mutated CFTR limits the function of these proteins thereby increasing the Wnt/β-catenin pathway.
To conclude, we describe that CF patients indeed have an increased risk of CRC at a younger age, and especially after transplantation. CFTR regulation of the Wnt/β-catenin pathway could be one of the major contributing factors although the exact molecular mechanisms remain unknown. Therefore, we propose further research in human organoids and CF patients, including carriers and non-CF CRC patients, to fully elucidate how mutated CFTR leads to CRC development. Future research may eventually contribute to an earlier diagnosis and better treatment of CRC in CF patients. | |
