Risk of malignant melanoma in patients with celiac disease: what is the truth?

Abstract

Dear Editor: Celiac disease (CD) is an increasingly common disease. It is a chronic inflammatory disorder of the small intestine that is triggered by a harmful immune response to the ingestion of cereal gluten proteins in genetically predisposed subjects. The age of CD onset ranges from early childhood to old age. More than 40 % of patients with CD present to clinicians other than gastroenterologists or internists with atypical manifestations. Patients affected by CD carry an increased risk of developing certain malignancies. However, there is uncertainty regarding the risk of malignant melanoma in patients with CD given the conflicting epidemiological results on the association between these two disorders. Autoantibodies specific for the enzyme transglutaminase 2 (TG2) are considered a hallmark of the gluten-sensitive enteropathy. Chronic dietary exposure to dietary gluten is invariably connected with the production of autoantibodies against TG2 in celiac patients. TG2 is a calcium dependent enzyme in mammals that is abundantly detected in various cells and tissues. TG2 is implicated in the orchestration of a number of cell survival signaling pathways. It is found in both intracellular and extracellular locations. In the intracellular environment, TG2 is reported to play a pro-apoptotic as well as an anti-apoptotic role, depending on the cellular context and biological cues. The pathogenesis of CD is supposed to be determined by the activity of both extracellular and intracellular TG2. It has been shown that TG2 in the small intestinal mucosa is predominantly inactive under normal physiological conditions implying that it must therefore be activated. The TG2targeted autoantibodies are bound to their antigen in the basement membrane underlining the small-bowel mucosal epithelium. The disease-specific TG2-targeted autoantibodies have been experimentally shown to exert various biological effects on different cell types denoting that the activation of intracellular and/or extracellular TG2 can have an impact on the wide range of intestinal and extra-intestinal symptoms observed in CD. Short splice variants of TG2 have been observed in different organs and tissues. These variants have been found to have a lower calcium requirement in comparison to full-length TG2. Polymorphism of TG2 is characterized by an unusually low frequency of genomic variants suggesting the possibility that they may be involved in the development of pathologic conditions that will be very hard to find considering their very low frequency of occurrence. Melanoma is considered the deadliest form of skin cancer whose incidence is rapidly growing. In the stage I and II disease, complete surgical excision of the primary tumor is connected with a more like 95 % success rate. Conversely, in the stage III and stage IV disease, when melanoma patients present with distant metastasis, surgical interventions are of limited use. Furthermore, almost always systemic medication has minimal success because of the high intrinsic resistance exhibited by melanoma cells against anti-cancer drugs. A large body of evidence supports the hypothesis that melanoma cells become resistant to chemotherapy by exploiting their intrinsic resistance to apoptosis. It has been reported that TG2 expression is selectively upregulated during advanced developmental stages of melanoma accounting for the development of chemoresistance in melanoma cells. Importantly, it has been indicated that TG2 absence in the host is a favoring condition for the formation and development of themetastasis, while the presence of TG2 in themelanoma cells may be a strategy for inducing metastasis and chemoresistance. Hypercalcemia is a rare, but potentially life-threatening effect of metastatic melanoma. However, the incidence of * Raffaella Mormile raffaellamormile@alice.it