Encyclopedia
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects:
Oncology
Cystic fibrosis (CF) is a genetic condition that affects the lungs, digestion, and other body systems. People with CF have a higher chance of developing certain types of cancer. Gastrointestinal cancers encompass a range of malignancies affecting the digestive tract, including the esophagus, stomach, small intestine, colon, rectum, pancreas, and liver. Understanding the link between CF and gastrointestinal cancers is important for improving patient care, implementing appropriate surveillance and screening measures, and identifying potential therapeutic interventions.
- cystic fibrosis
- CFTR gene
- cancer risk
1. Introduction
Cystic fibrosis (CF) is a complex genetic disorder that primarily affects the respiratory and digestive systems. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in dysfunctional CFTR protein [1,2]. CF’s hallmark is its impact on the production of thick, sticky mucus, which obstructs airways, leading to recurrent respiratory infections and impaired lung function. Additionally, the digestive tract’s secretions are affected, causing challenges in nutrient absorption and digestive processes [3].
2. Esophageal Cancer
Esophageal cancer is a relatively rare but aggressive malignancy that poses significant challenges to patients and healthcare providers. While the exact molecular mechanisms linking CF and esophageal cancers are not yet fully understood, several factors have been proposed to contribute to this association [7].
One potential mechanism is chronic inflammation resulting from CFTR dysfunction. The thickened mucus and impaired clearance in the respiratory and digestive systems of CF patients create an environment conducive to chronic inflammation. Chronic inflammation is known to play a key role in carcinogenesis, and it has been suggested that long-term inflammation in the esophagus may increase the risk of developing esophageal cancer in individuals with CF [29].
Additionally, CFTR mutations may impact the composition of the esophageal microbiota. Dysbiosis, an imbalance of bacterial species in the esophagus, has been associated with an increased risk of esophageal diseases, including esophageal cancer. CF patients may have altered esophageal microbiota due to the effects of CFTR dysfunction, and this dysbiosis could potentially contribute to the development of esophageal malignancies [30].
Moreover, CF patients often face nutritional challenges due to malabsorption and malnutrition. These nutritional issues may lead to deficiencies in key vitamins and minerals, which are essential for maintaining cellular health and DNA repair mechanisms. Such deficiencies could increase the susceptibility to cellular damage and the risk of developing esophageal cancers [31].
Furthermore, recent studies have implicated specific molecular pathways in the association between CFTR dysfunction and esophageal cancer development. For example, it has been suggested that CFTR mutations may lead to alterations in calcium signaling pathways, which play a critical role in cell proliferation, differentiation, and apoptosis. Dysregulation of calcium signaling can contribute to uncontrolled cell growth and the development of cancer [32].
Another potential molecular mechanism involves the disruption of epithelial cell homeostasis in the esophagus. CFTR dysfunction may impair the transport of bicarbonate ions, which are important for maintaining the proper pH balance in the esophageal epithelium. This disruption can lead to cellular stress, DNA damage, and increased susceptibility to carcinogenesis [33,34].
Finally, adults with CF have a higher risk of developing Barret’s esophagus, which is a precursor for esophageal cancer [35].
Despite these potential associations and molecular mechanisms, the exact link between CF and esophageal cancers remains an active area of research. The relative risk of esophageal cancer in patients with CF is not well-established due to limited available data. As of now, there is a lack of consensus on the specific relative risk values for esophageal cancer in CF patients. The rarity of esophageal cancer in CF patients and the complexity of its underlying mechanisms make it challenging to draw definitive conclusions. Further studies are needed to elucidate the precise molecular pathways connecting CFTR dysfunction and the development of esophageal malignancies.
3. Gastric Cancer
Gastric cancer, also known as stomach cancer, is a malignant tumor that develops in the stomach lining. CFTR dysfunction in the stomach can lead to the accumulation of thick mucus, impairing mucociliary clearance. The retained mucus creates a favorable environment for bacterial colonization, resulting in chronic gastritis and inflammation. Chronic inflammation, characterized by the release of pro-inflammatory cytokines, chemokines, and growth factors, can promote genetic mutations, stimulate cellular proliferation, and enhance angiogenesis, ultimately contributing to the development and progression of gastric cancer [36,37].
CFTR plays a role in regulating chloride and bicarbonate ion transport, which impacts gastric acid secretion. CFTR dysfunction can lead to altered gastric acid production and pH levels. Reduced gastric acid secretion may increase the risk of gastric cancer by impairing microbial defense mechanisms and promoting the growth of Helicobacter pylori, a bacterium implicated in gastric cancer development. Moreover, altered gastric pH can affect the digestion and absorption of dietary factors that may modulate gastric carcinogenesis [38,39].
In addition to CFTR mutations, CF-related genetic variations may contribute to the increased risk of gastric cancer. Genome-wide association studies have identified certain genetic variants associated with both CF and gastric cancer susceptibility. These genetic variations may affect immune response, DNA repair mechanisms, or other processes involved in gastric carcinogenesis, highlighting potential shared genetic pathways between CF and gastric cancer [40,41].
Various other molecular pathways have been implicated in the association between CFTR dysfunction and gastric cancer development. For instance, CFTR dysfunction may lead to altered calcium signaling, affecting cell proliferation, differentiation, and apoptosis, which are critical processes in gastric carcinogenesis. Disruption of epithelial cell homeostasis, impaired bicarbonate ion transport, and subsequent cellular stress and DNA damage may also contribute to the development of gastric cancer in CF [42,43].
Therefore, the association between CF, CFTR, and gastric cancer involves complex molecular mechanisms. Chronic inflammation, altered gastric acid secretion, CF-related malnutrition, genetic variations, and disrupted cellular pathways collectively contribute to the increased risk of gastric cancer in individuals with CF.
Similar to esophageal cancer, the relative risk of gastric cancer in patients with CF is not well-defined. The available data on the association between CF and gastric cancer are limited, making it challenging to estimate precise relative risk values for this specific cancer type.
Further research is needed to fully elucidate these mechanisms and their interplay in the development and progression of gastric cancer in CF patients.
4. Pancreatic Cancer
Pancreatic cancer is a devastating disease characterized by its aggressiveness and poor prognosis. CF patients have an increased relative risk of developing pancreatic cancer. Studies have reported relative risk values ranging from 5 to 10 times higher in CF patients compared to the general population [17,19,44,45]. CFTR dysfunction caused by mutations in the CFTR gene leads to abnormal ion transport across epithelial cells, including those lining the pancreatic ducts. The resulting impaired CFTR function leads to altered fluid secretion and increased viscosity of pancreatic secretions, ultimately leading to ductal obstruction. The accumulation of thickened secretions creates a microenvironment conducive to inflammation, fibrosis, and cellular damage, potentially predisposing individuals with CF to pancreatic cancer [44,45].
CFTR dysfunction and pancreatic duct obstruction trigger chronic inflammation in the pancreas. Inflammatory processes involve the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species, leading to cellular damage and genetic mutations. Prolonged inflammation can induce DNA damage, dysregulate cellular signaling pathways, and disturb cell growth and survival mechanisms, all of which are implicated in pancreatic cancer development [46].
CF-related pancreatic insufficiency often coexists with bile duct abnormalities and impaired bile flow. These conditions can result in increased exposure of pancreatic tissue to bile acids, digestive enzymes, and duodenal reflux. The duodenal refluxate, consisting of bile acids and other duodenal contents, can cause cellular injury, inflammation, and oxidative stress in the pancreas. Sustained exposure to these damaging factors may contribute to the initiation and progression of pancreatic cancer [47,48].
In addition to CFTR mutations, CF-related genetic factors have been implicated in pancreatic cancer development. Genome-wide association studies have identified specific genetic variants associated with both CF and pancreatic cancer susceptibility. These variants may affect immune response, cellular metabolism, or other pathways involved in pancreatic carcinogenesis. Investigating these shared genetic factors can provide valuable insights into the molecular mechanisms connecting CF and pancreatic cancer [49,50].
Growing evidence suggests that alterations in the gut microbiota, known as dysbiosis, may play a role in pancreatic cancer development. CF-related pancreatic insufficiency, altered bile flow, and impaired digestive processes can disrupt the gut microbial ecosystem. Dysbiosis in CF patients may result in the production of harmful metabolites, chronic inflammation, and perturbation of the host–microbiota interaction, which may contribute to pancreatic carcinogenesis [51,52].
In conclusion, the association between CF, CFTR, and pancreatic cancer involves intricate molecular mechanisms. CFTR dysfunction, pancreatic duct obstruction, chronic inflammation, altered bile flow, CFTR-related genetic factors, impaired nutrient absorption, and microbiota dysbiosis collectively contribute to the increased risk of pancreatic cancer in individuals with CF. Further research is necessary to fully elucidate these molecular mechanisms and their interplay in the development and progression of pancreatic cancer in CF patients.
5. Liver Cancer
CFTR dysfunction resulting from CF-associated mutations disrupts chloride and bicarbonate transport, leading to impaired bile secretion and altered bile composition. This disturbance in bile flow can cause cholestasis and subsequent hepatic fibrosis [53]. Prolonged fibrotic changes in the liver microenvironment create a pro-inflammatory milieu and promote cellular proliferation, thereby increasing the risk of hepatocellular carcinoma (HCC). Studies have shown that CF patients with liver cirrhosis have an increased risk of developing HCC [54,55].
CFTR dysfunction contributes to chronic inflammation and oxidative stress in the liver. Impaired CFTR function leads to the accumulation of bile acids, which can induce oxidative damage and activate inflammatory pathways. Chronic inflammation and oxidative stress create a favorable environment for the development of hepatic cancer by promoting DNA damage, genomic instability, and cellular proliferation. Studies have demonstrated increased levels of pro-inflammatory markers and oxidative stress in CF-related liver disease [56,57].
CFTR has been shown to play a role in liver regeneration. During liver injury, CFTR expression is upregulated, suggesting its involvement in the regenerative process. CFTR-deficient mice exhibit impaired liver regeneration, suggesting that altered CFTR expression and function may disrupt the regenerative capacity of liver cells. Impaired liver regeneration can contribute to the development of hepatic cancer [58,59].
In addition to CFTR mutations, other CF-related genetic factors have been associated with an increased risk of hepatic cancer. Genetic variations in CFTR modifier genes, such as the Solute Carrier Organic Anion Transporter (SLCO) family, have been implicated in hepatocarcinogenesis. These variations may affect drug metabolism, transport, and cellular pathways involved in liver cancer development. Studies have identified associations between CFTR-related genetic variations and increased susceptibility to liver cancer in CF patients [60,61].
CF patients may have a slightly elevated risk of developing liver cancer, although the relative risk values vary across studies. Relative risk values around 1.5 to 2.0 have been suggested [17,19].
In summary, there has been growing evidence supporting a link between CF, CFTR dysfunction, and the development of hepatic cancer. The molecular mechanisms underlying this association involve CFTR dysfunction-related hepatic fibrosis, chronic inflammation, oxidative stress, impaired liver regeneration, CFTR-related genetic factors, and nutritional deficiencies.
6. Intestinal Cancers
6.1. Colorectal Cancer
Colorectal cancer (CRC) is a malignant neoplasm that arises from the epithelial cells lining the colon or rectum. Patients with CF are at a 6-fold higher risk for CRC [19,37,62]. The mechanisms underlying this association are not yet fully understood, but several factors have been implicated.
CFTR dysfunction in the intestinal epithelium leads to persistent inflammation and oxidative stress. The impaired CFTR function affects ion transport, mucus clearance, and the integrity of the intestinal barrier [63,64]. These disruptions create an environment conducive to chronic inflammation and oxidative stress, which can promote the development of CRC. Inflammation and oxidative stress induce DNA damage, genomic instability, and cellular proliferation, key factors in carcinogenesis.
Recent studies have highlighted the role of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in CRC development. Increased expression of these cytokines has been observed in CF patients, indicating a potential link between CF-associated inflammation and CRC [65,66]. Additionally, oxidative stress resulting from impaired CFTR function can lead to the accumulation of reactive oxygen species (ROS), causing DNA damage and favoring the initiation and progression of CRC [67,68].
CF patients often exhibit dysbiosis, an imbalance in the composition and function of the gut microbiota. Dysbiosis in CF is characterized by a reduction in beneficial bacteria, such as Bifidobacterium and Lactobacillus species, and an increase in potentially harmful bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. Dysbiosis can contribute to inflammation, impaired intestinal barrier function, and increased susceptibility to CRC. The specific dysbiosis patterns associated with CRC in CF patients warrant further investigation [69,70].
Recent studies have highlighted the potential role of specific bacterial species in CRC development. For example, Fusobacterium nucleatum, a common member of the gut microbiota, has been associated with CRC progression by promoting inflammation and impairing immune surveillance [71,72]. In CF patients, dysbiosis and altered microbial composition may create a microenvironment conducive to the growth of pathogenic bacteria, further contributing to the development of CRC.
In addition to CFTR mutations, CF-related genetic factors may influence the risk of CRC development in CF patients. Modifier genes that interact with CFTR, such as those involved in inflammation, immune response, and cellular proliferation, may play a role in CRC susceptibility. Variations in these genes can modify the disease phenotype and influence the development of CRC in CF patients [73,74].
Recent studies have identified genetic polymorphisms associated with both CF and CRC, suggesting a potential genetic link between the two conditions. For example, the TNF-α gene polymorphism has been implicated in both CF and CRC susceptibility [75]. These genetic factors may modulate the inflammatory response, alter immune cell function, and contribute to the development of CRC in CF patients.
Current guidelines recommend CRC surveillance for CF patients starting at the age of 40 or 10 years before the youngest affected relative’s diagnosis (whichever comes first). The surveillance typically involves periodic colonoscopies with the aim of detecting precancerous polyps or early-stage CRC. Additionally, individuals with CF who present with concerning symptoms such as unexplained gastrointestinal bleeding or persistent change in bowel habits should undergo timely evaluation [76,77].
6.2. Small Bowel Adenocarcinoma
Small bowel adenocarcinoma (SBA) is a rare but aggressive form of intestinal cancer that can occur in CF patients. The underlying mechanisms linking CF and SBA are not yet fully elucidated, but several factors may contribute to its development.
Several tumor suppressor genes have been implicated in SBA development, including TP53, APC, and SMAD4. TP53, commonly known as the “guardian of the genome”, plays a crucial role in DNA repair and cell cycle regulation. CFTR dysfunction could potentially affect TP53 function, compromising its ability to suppress tumor formation and progression in the small intestine [78,79]. Further studies are needed to elucidate the specific molecular interactions between CFTR and tumor suppressor genes in the context of SBA development.
This entry is adapted from the peer-reviewed paper 10.3390/cancers15174244
This entry is offline, you can click here to edit this entry!
