Lipid droplet biogenesis and COX-2 pathway activation are triggered by Barrett’s esophagus and adenocarcinoma, but not esophageal squamous cell carcinoma risk factors

Abstract

Esophageal cancer (EC) is an aggressive disease, presenting two main histological subtypes: adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). The two EC subtypes widely differ concerning virtually all factors. ESCC development is mainly associated with tobacco and alcohol abuse, whereas obesity and chronic gastroesophageal reflux disease (GERD) are important risk factors not only for EAC, but also for for Barrett’s esophagus (BE), an intestinal metaplasia that precedes EAC. Obesity triggers ectopic lipid droplets (LD) accumulation in non-adipose tissues. LD are organelles involved in cell metabolism, signaling, proliferation and production of inflammatory mediators. Therefore, the aim of this work was to investigate LD occurrence and role in EC. This study shows progressive LD levels increase along EAC development, in esophageal samples from non-obese through obese individuals, as well as BE, and EAC patients, whereas no significant changes were observed in ESCC samples, when compared to non-tumor samples. Additionally, in order to mimic BE and EAC risk factors exposure, a non-tumor esophageal cell line was incubated with oleic acid (OA) and acidified medium and/or deoxycholic acid (DCA), revealing a significant increment in LD amount as well as in COX-2 and CXCL-8 expression, and in IL-8 secretion. Further, COX-2 expression and LD amount presented a significant positive correlation and were detected co-localized in EAC, but not in ESCC, suggesting that LD may be the site for eicosanoid production in EAC. In conclusion, this study shows that obesity, and BE- and EAC-associated inflammatory stimuli result in a gradual increase of LD, that may be responsible for orchestrating inflammatory mediators’ production and/or action, thus contributing to BE and EAC genesis and progression.

GWAS meta-analysis of 16 790 patients with Barrett’s oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level

“…In the following, the most promising candidate gene per locus is highlighted: LDAH at 2p24 plays a role in tumour suppression and proliferation 49. The corresponding protein localises to lipid droplets and increased levels of lipid droplets have been found in EA versus BE and BE versus normal tissue 50 . RSRC1 at 3p25 is involved in mRNA splicing and may suppress gastric cancer cell proliferation 51 .…”

Interplay between Lipid Metabolism, Lipid Droplets, and DNA Virus Infections

“…Studies in different cell types, such as epithelial cells (IEC-6, CACO-2, and EAC cells) and macrophages infected with Mycobacterium bovis bacillus Calmette-Guerin (BCG), showed that LDs co-localize with COX-2 [ 69 ]. Importantly, this colocalization has been associated with increased prostaglandin E 2 levels at the sites where LDs were localized [ 70 , 71 , 72 , 73 , 74 ].…”

Targeting Strategies for Aberrant Lipid Metabolism Reprogramming and the Immune Microenvironment in Esophageal Cancer: A Review

“…According to the experimental studies of Carrossini et al, in BE and EAC, associated inflammatory stimulation would lead to a gradual increase in LD and a significant increase in IL-8 secretion. is phenomenon reveals an interaction between lipid droplets and inflammatory mediators, thus facilitating BE and EAC's occurrence and development [49]. Moreover, exogenous lipids could disrupt this metabolic program and have a negative effect on their effector function and ability to respond to stimuli, especially in the case of obesity [192][193][194].…”

“…As demonstrated by recent investigations, the interaction of DGAT2 and MGAT2 can lead to the biosynthesis of lipid substrates for TGs [ 130 ]. According to Carrossini et al, LD increased with EAC evolution, which arose from the exposure of the esophageal epithelium to the hazard factors correlated with BE and EAC [ 49 ].…”