Mechanisms of Disease: Carcinogenesis in Barrett's Esophagus

Navtej S Buttar; Kenneth K Wang


Nat Clin Pract Gastroenterol Hepatol. 2004;1(2) 

In This Article

Molecular Aberrations

The pathophysiologic changes outlined above are often associated with prosurvival signaling pathways and mutations that result directly or indirectly in carcinogenesis-promoting molecular and cellular aberrations (Figure 3).

Molecular aberrations during carcinogenesis in Barrett's esophagus. Molecular aberrations during carcinogenesis in Barrett's esophagus can be divided into prosurvival signals, antideath signals and the signaling promoting immortilization, invasion and metastasis. The loss of p16 function and p53 function are the most extensively studied molecular aberrations. Loss of p16 function is an early event, while the loss of p53 function starts appearing once dysplasia develops in Barrett's mucosa. APC, adenomatous polyposis coli; COX-2, cyclooxygenase-2; EGFR, epidermal growth factor receptor; LOH, loss of heterozygosity; MMP, matrix metalloproteinases; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. This figure is modified with permission from Jennifer Parsons Brumbaugh © (2000-2004) Johns Hopkins University.

There is increased pro-growth signaling related to increased expression of transforming growth factor- (TGF-) and epidermal growth factor receptor (EGFR) during the progression of neoplasia in Barrett's esophagus.[43,44] Early in the progression of neoplasia, epigenetic changes also result in the silencing of the growth-inhibitory p16 gene by promoter methylation.[45] These changes are associated with increased cyclin D and E expression.[46,47] Along with loss of heterozygocity (LOH) at chromosome 13q,[48] which is the locus for the retinoblastoma gene, increased cyclin D and E expression result in the entry of epithelial cells from the G1 into the S phase of the cell cycle. These changes lead to growth self sufficiency in Barrett's epithelial cells, which is one of the common requisites of carcinogenesis. Loss of the TGF-ß1 receptor and LOH of the SMAD4 locus (18q21.1), which normally provide antigrowth signals via p15, p16, p21 and p27, are further stimuli for unchecked growth.[49]

The prosurvival signals outlined above promote rapid cell cycling in Barrett's mucosa. These cells reside in a pathologic environment of reflux-related low-grade inflammation, increased reactive oxygen species, compromised antioxidant defenses and exposure to activated nitroso compounds. This combination puts a mutagenic pressure on epithelial cells. If the cells had an intact damage control system, such as a functional p53 gene and protein, they would be forced into cell cycle arrest via p21waf1 signals to allow the repair of the DNA damage;[50] if the damage could not be repaired, p53 would activate apoptotic signaling and remove such abnormal cells from the epithelium.[50] Exactly how pathologic host and environment changes in Barrett's esophagus result in p53 dysfunction have not been clearly defined, but most patients with progressive neoplasia do develop abnormal p53 function.[50]

Increasing rates of LOH at chromosome 17p (the p53 gene locus), mutations in the p53 gene[19,50] and, therefore, a clonal expansion of cells with abnormal DNA, are thought to be important events during the progression of neoplasia in Barrett's esophagus.[19] The clones may then prolong their survival by evading apoptosis. Cells with advanced neoplastic changes show decreased FAS expression and increased Fas ligand (FasL) expression.[51] The lack of Fas expression allows these cells to protect themselves from apoptosis, which can normally be induced by FasL-expressing lymphocytes during tumor surveillance.[51] Moreover, increased FasL expression by dysplastic Barrett's epithelial cells can induce apoptosis in Fas-expressing lymphocytes that are performing tumor surveillance.[51]

After a predetermined number of cell divisions epithelial cells normally undergo senescence or growth arrest owing to critical shortening of telomeric DNA, which is lost with every cell division. Barrett's epithelial cells, however, develop limitless replicative potential by maintaining TELOMERE length.[52] During the process of carcinogenesis, there is an increased level of the RNA component of telomerase complex and an increased expression of telomerase reverse catalytic subunit in Barrett's mucosa.[52] These changes help maintain the length of the telomeric DNA. Cumulative molecular and cellular changes in many of the pathways mentioned above result in Barrett's epithelial cells that have a survival benefit and a limitless ability to divide. These cells develop abnormal localization of ß-CATENIN into the nucleus because of promoter hypermethylation of the adenomatous polyposis coli (APC) gene and acquire an invasive phenotype.[53] With abnormal VEGF signaling and MMP secretion,[54,55] dysplastic Barrett's epithelial cells further promote angiogenesis and matrix remodeling conducive to invasion and eventual metastasis.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: