Abstract
Esophageal adenocarcinoma is now the most common form of esophageal cancer, and the prognosis for patients with this disease is poor. Understanding the mechanisms of disease development through premalignant Barrett’s esophagus, a consequence of GERD, and factors predicting a positive response to treatment is necessary to improve outcomes. Vitamin D is a hormone that acts as an immunomodulator and regulator of cellular proliferation with anticancer properties, and has been implicated in the prevention of some cancers. Its main source in light skinned individuals is the sun, and there is an epidemiological association between increased exposure to ultraviolet irradiation and decreased incidence of esophageal adenocarcinoma. Refluxed acid and bile create an inflammatory milieu that in part may be mediated by 1,25(OH)2D by interacting with cyclooxygenase pathways, mitigating DNA damage, playing a role in bile acid metabolism, and influencing the immune cell population. 1,25-dihydroxyvitamin D may inhibit the Th1 response associated with reflux esophagitis while fostering the Th2 response associated with Barrett’s esophagus. Other immune cells including macrophages, dendritic cells, Th17 cells, and Tregs may be influential to the development or prevention of EAC, but their specific roles and interaction with 1,25(OH)2D is undefined. Hedgehog and NF-κB signaling are increased in BE and EAC, and although some interaction with 1,25(OH)2D may be present, it is difficult to credit this with a significant implication. The effects of 1,25(OH)2D are mediated by VDR. Vitamin D receptor is expressed in normal gastric cardia, Barrett’s esophagus, and esophageal adenocarcinoma, but absent in normal esophageal squamous mucosa. Staining intensity of VDR assessed by immunofluorescence correlates inversely with histologic grade, and staining is more intense in tissue that did not respond to neoadjuvant treatment, although no statistically significant correlations were found. Considering this, it is plausible that the extent of VDR expression is related to tumor progression and response to therapy, but it is equally as plausible that these data are merely random.