With increased life expectancy, the majority of the CF patients now survive at least to adolescence and almost one-third attain adulthood. This increased life span for CF patients, although good, has brought to our attention that people carrying the CFTR gene mutation may have an increased risk of developing cancer, particularly in the digestive tract.55 The development of cancer is a multistep process that includes initiation due to gene mutation, promotion by accumulating the oncogenic mutation, and progression toward a malignant phenotype via further genetic and epigenetic changes. Although all people are equally prone to gene mutation, only a few get it in their lifetime. In fact, the development of cancer is a variable function of a person's genetic background, environmental exposure, diet, and lifestyle.
Pancreatic cancer, the fourth leading cause of cancer-related deaths in the United States,56 has been discussed in Chapter 19, Chapter 21, and
Chapter 25. The association of pancreatic cancer with CF has long been suspected, however, there is no clear or direct evidence to prove such a linkage. In a cohort study conducted to evaluate the risk of cancer in CF, involving 412 patients, a significant excess of pancreatic and small-intestine cancers has been reported.57 Later on, another investigation also reported similar findings (i.e., an increased risk of digestive tract cancers in CF patients); however, the overall risk of cancer among them was similar to that of the general population.55
Although we may consider that CF has a link with cancer development, the question arises whether it is directly related to some not yet recognized functions of CFTR or is due to chronic disease conditions. To date, we do not have direct evidence that can relate the CFTR defect with cancer development. Moreover, almost all the cases have been recognized later in life, denying a direct involvement of CFTR with carcinogenesis.55,58,59 Therefore, it seems likely that cancer progression is secondary to the long-term disability of CFTR. The enhanced risks of organ-specific cancer (e.g., digestive tract cancer) in CF patients may be related to the differential expression patterns of CFTR gene in different body organs and to the susceptibility of that organ to damage by CFTR dysfunction. Pancreatic ducts and other digestive tissue (bile ducts, intestinal crypts, etc.) express high levels of the CFTR protein in comparison to several other body organ tissues. Furthermore, persistent pathologic alterations (e.g., tissue damage, cyst formation, etc.), leading to increased cell turnover, might also predispose these organ's cells toward oncogenic transformation. An observed deficiency of selenium, an antioxidant that offers protection against several diseases including cancer, may also increase the risk of carcinoma in CF patients.60
In a study on the expression of pancreatic tumor-associated mucin genes (MUC1 and MUC4) in the pancreatic tumor cell line derived from a CF patient (CFPAC1) and its CFTR corrected subline, CFPAC-PLJ-CFTR, we have reported that the overexpression of MUC4 is associated with CF phenotype.61 Also, no CFTR expression was detected in 12 (75%) of the 16 pancreatic tumor cell lines tested, although pancreas is considered as a site of high CFTR expression. We have further confirmed the linkage between the CFTR defect and MUC4 overexpression, using short-interfering RNA (siRNA) mediated gene silencing of CFTR (Singh et al., unpublished data). MUC4 is a membrane bound mucin, which is aberrantly expressed in pancreatic tumor tissue and cancer cell lines, that has no detectable expression in the normal pancreas.62 Recently, we have also shown that the knockdown of MUC4 in a metastatic pancreatic tumor cell line, CD18/HPAF, results in reduced tumor growth both in vitro and in vivo and decreases the tumor cell potential to metastasize.63 Therefore, an association between the CFTR defect and MUC4 up-regulation, along with the observed CFTR down-regulation in pancreatic cancer cell lines may be of significance in understanding CF-linked risks of pancreatic tumor development and progression.
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