Esophageal squamous cell cancer susceptibility: Environmental and nutritional associations reveal a universally applicable pathogenesis scenario (Review)

Abstract

Some epidemiological features, such as marked variations of incidence between geographical regions, are unique to esophageal squamous cell carcinoma (ESCC). The objective of this evaluation of only ESCC was to collate those factors that have quantitative and biological credibility, enabling the deduction of an etiological hypothesis to explain this, based on facts. Worldwide, 80% of new cases arise in less developed regions and are generally not associated with alcohol or tobacco use. Abstinence was also usual in some European localities where a high incidence occurred in certain remote regions, as well as in patients with malabsorption syndromes. All had multiple micronutrient deficiencies, resulting in atrophy and chronic esophagitis that preceded clinical carcinomas. The esophagus has an extraordinarily high cell replication rate requiring higher micronutrient nutrition than other epithelia. Stable communities worldwide, whose staple diet was maize (corn) or wheat were invariably at high risk, whereas the use of nutritious food sources resulted in an unusually low risk. The susceptibility of animals fed such diets mirrored the human situation exactly. Pertinent deficiencies identified thus far are riboflavin, nicotinamide, molybdenum (Mo), magnesium (Mg), manganese (Mn), selenium (Se) and zinc (Zn). Subclinical deficiencies of these have been shown to enhance the susceptibility of rats to ESCC. Extraordinary carcinogen exposure has only been shown in rural epidemic regions. Geologically determined poor soils yield plants vulnerable to fungal pathogens, some of which are carcinogenic to the rat esophagus. Tobacco exerts its synergistic effects on the nutritionally impaired esophagus. Nitrosamine exposure is not unusual; however, regenerative stress such as that caused by constrictions and hot drinks increase the risk. The common underlying determinant of susceptibility worldwide is chronic deficiencies of multiple micronutrients that normally maintain the integrity of the esophagus and are necessary for a number of anti-carcinogenic mechanisms. Micronutrient fortification of staple foods appears to markedly reduce the risk.