Our current management of cancer risk in Barrett’s esophagus is to perform endoscopic surveillance for the detection of dysplasia. However, dysplasia is an imperfect predictor of cancer risk for a variety of reasons including biopsy sampling error, poor intra- and inter-observer reproducibility of dysplasia interpretations and the poor predictive value for negative, indefinite, low-grade, and even high-grade dysplasia.1–3 Dysplasia is a conglomerate of histologic abnormalities that suggest that clones of cells have acquired neoplastic properties that predispose them to cancer formation. Therefore, dysplasia is a surrogate marker for cells that have accumulated enough genetic damage that they now possess some of the physiologic properties of cancer cells. Therefore, a better indicator of cancer risk would be detection of the genetic damage itself before the histologic manifestations of dysplasia are even apparent. In addition, the identification of molecular biomarkers may offer easy reproducibility and standardization in addition to the truly early detection of neoplastic progression.
In the traditional phenotypic model, carcinogenesis in Barrett’s esophagus is viewed as occurring in discrete steps from metaplasia to dysplasia and finally to carcinoma. In the genetic model, neoplastic progression is envisioned as a continuum over which cells progressively accumulate genetic abnormalities until they acquire the six essential physiologic hallmarks of cancer.4 These cancer hallmarks include the ability of cells (1) to provide their own growth signals, (2) to avoid growth inhibitory signals, (3) to avoid apoptosis, (4) to replicate without limit, (5) to sustain angiogenesis (the formation of new blood vessels), and (6) to invade and metastasize. These hallmarks represent the physiologic traits that must be acquired by cells during the genesis of all human tumors and, therefore, are not specific for neoplastic progression of Barrett’s esophagus. However, there are differences among human tumors regarding the specific genetic alterations acquired that endow the cell with each of these physiologic hallmarks and we will highlight some of the genetic alterations that occur in Barrett’s esophagus which allow the cell to acquire each of the hallmarks.
Hallmark 1: The Ability to Provide Growth Signals
In general, this occurs by the activation of oncogenes. Genes that stimulate cell growth in normal cells are termed protooncogenes. When these same genes become overactive as a result of certain types of mutations, they are called oncogenes. Thus, oncogene activation leads to uncontrolled cell growth. Examples of oncogenes implicated in Barrett’s carcinogenesis include cyclins D1 and E, transforming growth factor-α, epidermal growth factor, and the epidermal growth factor receptor.5
Hallmark 2: The Ability to Avoid Growth Inhibitory Signals
In general, growth inhibitory signals are transmitted by tumor suppressor genes. Tumor suppressor genes are normal genes that restrain cell proliferation. When tumor suppressor genes are inactivated, the cells are able to avoid growth inhibitory signals allowing for uncontrolled proliferation. Mutation, deletion of the chromosomal region containing the gene (called loss of heterozygosity (LOH)), and attachment of methyl groups to the promoter region of genes (called promoter hypermethylation) are ways in which tumor cells can inactivate tumor suppressor genes. Examples of tumor suppressor genes inactivated during neoplastic progression of Barrett’s esophagus include p53, p16, and the adenomatous polyposis coli (APC) gene.5
Hallmark 3: The Ability to Avoid Apoptosis
Apoptosis is a pre-programmed mechanism for normal cells to self-destruct. This is beneficial to normal cells, in that it prevents cells with damaged, mutated DNA from undergoing replication. However, to cancer cells, apoptosis is detrimental, and cancer cells must find ways to avoid self-destruction. Barrett’s cells have found a variety of ways to overcome triggering apoptosis. For example, as already discussed, inactivation of p53 is one way in which Barrett’s cells avoid inducing apoptosis in response to DNA damage or mutation. Another way Barrett’s cells avoid apoptosis is by the upregulation of cycloxygenase-2, a gene whose protein product exerts antiapoptotic effects. Finally, Barrett’s cancer cells have been found to express Fas-ligand, a death-promoting ligand that can activate the apoptotic cascade within the tumor killing immune cells resulting in their destruction.6,7
Hallmark 4: The Ability to Replicate without Limit
Normally, as cells undergo successive cell divisions, they reach senescence. Senescence is an intrinsic mechanism of cells that limits their normal proliferative capacity. The triggering of senescence involves the loss of telomeres which are repetitive pieces of DNA located at the ends of chromosomes. When telomeres become too short, senescence ensues. Telomerase is the enzyme that allows for the synthesis and stabilization of telomeres.8 Stable telomeres confer immortality to the cell. In contrast to normal esophageal tissues, benign Barrett’s esophagus expresses low levels of telomerase, which appears to increase as the metaplastic cells progress to high-grade dysplasia and cancer.9
Hallmark 5: The Ability to Sustain Angiogenesis
In order for a tumor to increase in size, it must maintain an adequate blood supply. The synthesis of new blood vessels is termed angiogenesis. One way in which tumor cells synthesize new blood vessels is by secreting vascular endothelial growth factors (VEGFs) which promote the proliferation and migration of endothelial cells upon binding to their receptors, the vascular endothelial growth factor receptors (VEGFRs). The expression of VEGFs and VEGFRs has been found in metaplastic Barrett’s esophagus as well as in neoplastic Barrett’s tissues.10,11
Hallmark 6: The Ability to Invade and Metastasize
Although the mechanisms of cancer cell invasion and metastasis are poorly understood, abnormalities in cell–cell interaction mediated by cadherins and catenins are thought to play a role.12 In the neoplastic progression of Barrett’s esophagus, the normal membraneous location of E-cadherin and β-catenin decreases, and the cytoplasmic and nuclear staining for these proteins increases as the degree of dysplasia increases.13 In addition, Barrett’s cancers have been found to express matrix metalloproteases which degrade the extracellular matrix and facilitate invasion.14