The role of haem transport and iron chelation in oesophageal cancer

Abstract

The incidence of oesophageal adenocarcinoma (OAC) is increasing at an alarming rate in the Western World. Despite advances in surgical technique and patient selection, overall survival remains abysmal. Understanding the molecular and genetic events in the evolution of OAC is crucial to improving outcome. The role of iron in the carcinogenesis of OAC is supported by epidemiological and experimental evidence. Oesophageal cancers are iron loaded and aggressively capture systemic iron to potentiate a malignant phenotype. This project aimed to establish that OAC cells are also capable of acquiring haem and to explore the potential of iron chelation therapy in the treatment of oesophageal cancer. Haem import proteins are sequentially over expressed in the evolution of OAC. Culturing OAC cells with supplementary haem significantly enhances viability, proliferation, migration and anchorage independent growth. Abrogation of haem import protein expression reverses the stimulatory effect of supplementary haem and significantly reduces tumour burden in-vivo. Different classes of iron chelators exhibit potent in-vitro and in-vivo anti-neoplastic action in oesophageal malignancy. Iron chelators demonstrate chemo-sensitising properties and are able to overcome chemo-resistance. Haem import proteins are potential therapeutic targets in the treatment of oesophageal malignancy. Iron chelation therapy represents an effective, predictable and well tolerated adjunct to standard chemotherapy and should be considered for clinical trial