Dietary zinc deficiency fuels esophageal cancer development by inducing a distinct inflammatory signature

Abstract

Chronic inflammation is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC). The causes of inflammation in ESCC, however, are undefined. Dietary zinc (Zn)-deficiency (ZD) increases the risk of ESCC. We have previously shown that short-term ZD (6 weeks) in rats induces overexpression of the proinflammatory mediators S100a8 and S100a9 in the esophageal mucosa with accompanying esophageal epithelial hyperplasia. Here we report that prolonged ZD (21 weeks) in rats amplified this inflammation that when combined with non-carcinogenic low doses of the environmental carcinogen, N-nitrosomethylbenzylamine (NMBA) elicited a 66.7% (16/24) incidence of ESCC. With Zn-sufficiency, NMBA produced no cancers (0/21) (Po0.001). At tumor endpoint, the neoplastic ZD esophagus, as compared with Zn-sufficient esophagus, had an inflammatory gene signature with upregulation of numerous cancer-related inflammation genes (CXC and CC chemokines, chemokine receptors, cytokines and Cox-2) in addition to S100a8 and S100a9. This signature was already activated in the earlier dysplastic stage. Additionally, time-course bioinformatics analysis of expression profiles at tumor endpoint and before NMBA exposure revealed that this sustained inflammation was due to ZD rather than carcinogen exposure. Importantly, Zn replenishment reversed this inflammatory signature at both the dysplastic and neoplastic stages of ESCC development, and prevented cancer formation. Thus, the molecular definition of ZD-induced inflammation as a critical factor in ESCC development has important clinical implications with regard to development and prevention of this deadly disease.

Diet-related inflammation and oesophageal cancer by histological type: a nationwide case–control study in Sweden

“…Pro-inflammatory characteristics of food/nutrients have been associated with an increased risk of oesophageal cancer. Zinc deficiency, for example, has been found to activate inflammation with upregulation of numerous cancer-related inflammation genes, thus promoting murine oral oesophageal tumour progression [8,42]. A higher intake of carbohydrates from higher glycaemic index food sources was associated with circulating concentrations of pro-and antiinflammatory immune mediators.…”

“…Inflammation has been implicated in oesophageal carcinogenesis through processes known to be associated with a variety of risk factors, including obesity [4], gastroesophageal reflux [5], smoking [6], the microbiome (e.g. human papillomavirus) [7], and diet [8]. Consistently, diet has been shown to modulate inflammation [9].…”

“…Although the anti-or pro-inflammatory properties of food or nutrients are established, it is unclear how they function in the development of oesophageal cancer. Until now, due to the difficulty in measuring the inflammatory effects of food or nutrients, few studies have examined single food or nutrient-related inflammation and oesophageal cancer risk [8,13]. More importantly, no study has employed a measure of diet-related inflammation based on the whole diet.…”

Zinc transporters and dysregulated channels in cancers

“…Among them, Zn deficiency is well-known to enhance esophageal tumor induction (88–90). Fong et al , have conducted serial studies using N-nitrosomethylbenzylamine (NMBA)-induced esophageal cancer rat or mouse models to understand the impact of dietary Zn deficiency on carcinogenesis and tumor development (88, 91–101). In these studies, the animals were fed with either Zn-deficient or Zn-sufficient diet.…”

Dietary Consumption of Black Raspberries or Their Anthocyanin Constituents Alters Innate Immune Cell Trafficking in Esophageal Cancer

“…Inflammatory cytokine expression changes in human esophageal SCC (14,15). The cytokine PTX3 is downregulated in human esophageal SCC tissue and cell lines (16).…”