From genetics to signaling pathways: molecular pathogenesis of esophageal adenocarcinoma

Abstract

Esophageal adenocarcinoma (EAC) has one of the fastest rising incidence rates in the U.S. and many other Western countries. One of the unique risk factors for EAC is gastroesophageal reflux disease (GERD), a chronic digestive condition in which acidic contents from the stomach, frequently mixed with duodenal bile, enter the esophagus resulting in esophageal tissue injury. At the cellular level, progression to EAC is underlined by continuous DNA damage caused by reflux and chronic inflammatory factors that increase the mutation rate and promote genomic instability. Despite recent successes in cancer diagnostics and treatment, EAC remains a poorly treatable disease. Recent research has shed new light on molecular alterations underlying progression to EAC and revealed novel treatment options. This review focuses on the genetic and molecular studies of EAC. The molecular changes that occur during the transformation of normal Barrett's esophagus to esophageal adenocarcinoma are also discussed.

Keywords: Barrett’s esophagus; Esophageal adenocarcinoma; Esophageal cancer; GERD; p53.

Figure 1.. Key molecular alterations associated with progression of Barrett’s metaplasia to esophageal adenocarcinoma.

Gastroesophageal reflux and other carcinogenic stimuli cause genetic and epigenetic alterations. Multiple pathways regulating cell growth, proliferation, apoptosis, differentiation, inflammation and angiogenesis are commonly affected. The molecular changes occur at early stages of tumorigenic process and increase with tumor progression. COX-2 – Cyclooxygenase-2; VEGF – Vascular endothelial growth factor; TGF-α – Transforming growth factor α; NFκB – Nuclear factor kappa-light-chain-enhancer of activated B cells.

Figure 2.. Gastroesophageal reflux induces genotoxic stress and promotes esophageal tumorigenesis.

Gastroesophageal reflux causes aberrant production of reactive oxygen species (ROS), which cause DNA damage and multiple genetic and epigenetic alterations. Mitochondria and NADPH oxidases are strong inducers of ROS in the esophagus. Reflux-induced ROS mediate the isoLG adduction of p53 protein and its inhibition. SSBs – Single strand breaks; DDBs – Double strand breaks.

Figure 3.. Schematic representation of major signalling pathways involved in the development and progression of esophageal adenocarcinoma.

Exposure of esophageal cells to gastroesophageal reflux causes the dysregulation of multiple signalling pathways that promote Barrett’s esophagus and esophageal adenocarcinoma. Activation of RTKs, Notch, Wnt, Hedgehog and other signalling cascades were found in esophageal adenocarcinoma. RTK – receptor tyrosine kinase; NICD- Notch intracellular domain; Hh – Hedgehog; TGF-β – transforming growth factor β; COX-2 – Cyclooxygenase-2; PKC – protein kinase C.