The role of inflammation in cancer of the esophagus

Abstract

Esophageal adenocarcinoma is the eighth most common malignancy worldwide. The overall prognosis is poor, with 5-year survival ranges of approximately 15–25%, and 30–50% for patients who can be treated with curative intent. There has been a marked increase in incidence of esophageal adenocarcinoma over the last 30 years, with chronic and severe reflux, diet and obesity identified as principal factors fuelling this rise in the West. Esophageal adenocarcinoma is an exemplar model of an inflammation-associated cancer. The key molecular pathways driving tumor development and influencing tumor biology are the subject of considerable research efforts, and is the principal focus of this review. In addition, the diverse range of changes occurring in the local immune response, tissue microenvironment, metabolic profile, intracellular signaling mechanisms and microRNA signatures are discussed, as well as novel targeted therapies.

Keywords::

• adenocarcinoma
• Barrett’s esophagus
• esophagus
• gastroesophageal reflux disease
• inflammation

Financial & competing interests disclosure

K O’Sullivan is funded by a scholarship grant from the Irish Cancer Society [grant code CRS120SU]. J Phelan is funded by a scholarship grant from Science Foundation Ireland [grand code SFI/RFP-CA-3137] The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The incidence of esophageal adenocarcinoma is rising at an unprecedented rate, and recent years have witnessed many advances in the understanding of the pathogenesis of the neoplastic-associated inflammatory processes.

• As an exemplar model of inflammatory driven cancer, the study of the molecular progression of Barrett’s to adenocarcinoma transition has deepened our understanding.

• A number of proinflammatory states are now known to be involved including obesity and gastro-esophageal reflux disease.

• The site of inflammation attracts immune cells whose infiltration is facilitated by generation of an extracellular matrix.

• Release of proinflammatory mediators such as IL-6, IL8 and TGF-β promotes cell growth and invasion via activation of intracellular signaling pathways such as NF-κB and STAT3. This results in the up-regulation of targeted anti-apoptotic and pro-tumorigenic genes.

• Additional processes involved include alteration in energy metabolism as a result of hypoxia within tumor cells.

• Inflammation induces genomic instability, which is believed to facilitate the neoplastic progression of Barrett’s via loss of cell cycle checkpoint machinery and tumor-suppressor loci.

• Current therapeutic foci include NSAIDs, statins and dietary chemoprevention, and there is some evidence to suggest that anti-reflux therapy and weight loss may also be of interest. Further studies are required, however, to validate their usefulness.

Notes