The antioxidant response in Barrett's tumorigenesis: A double-edged sword

Abstract

Esophageal adenocarcinoma (EAC) is the dominant form of esophageal malignancies in the United States and other industrialized countries. The incidence of EAC has been rising rapidly during the past four decades. Barrett's esophagus (BE) is the main precancerous condition for EAC, where a metaplastic columnar epithelium replaces normal squamous mucosa of the lower esophagus. The primary risk factor for BE and EAC are chronic gastroesophageal reflux disease (GERD), obesity and smoking. During the BE-dysplasia-EAC sequence, esophageal cells are under a tremendous burden of accumulating reactive oxygen species (ROS) and oxidative stress. While normal cells have intact antioxidant machinery to maintain a balanced anti-tumorigenic physiological response, the antioxidant capacity is compromised in neoplastic cells with a pro-tumorigenic development antioxidant response. The accumulation of ROS, during the neoplastic progression of the GERD-BE-EAC sequence, induces DNA damage, lipid peroxidation and protein oxidation. Neoplastic cells adapt to oxidative stress by developing a pro-tumorigenic antioxidant response that keeps oxidative damage below lethal levels while promoting tumorigenesis, progression, and resistance to therapy. In this review, we will summarize the recent findings on oxidative stress in tumorigenesis in the context of the GERD-BE-EAC process. We will discuss how EAC cells adapt to increased ROS. We will review APE1 and NRF2 signaling mechanisms in the context of EAC. Finally, we will discuss the potential clinical significance of applying antioxidants or NRF2 activators as chemoprevention and NRF2 inhibitors in treating EAC patients.

Cranberry Polyphenols in Esophageal Cancer Inhibition: New Insights

“…The ability of C-PAC and AFG to decrease NRF2 in BE and EAC cell lines is intriguing as the NRF2/KEAP1 pathway is upregulated in BE and EAC based on recent COSMIC database analysis [ 91 ]. Polyphenols including luteolin, apigenin and chrysin inhibit NRF2 in multiple cancer cell lines resulting in inhibition of multidrug-resistant drug transporters, increased sensitivity to chemotherapeutic drugs and ROS-induced cell death [ 92 ].…”

Nrf2/Keap1-Pathway Activation and Reduced Susceptibility to Chemotherapy Treatment by Acidification in Esophageal Adenocarcinoma Cells

“…While Nrf2 mutations are not frequent in EAC, Nrf2 represents a potential durable intracellular molecule [ 29 ]. While there is a NRF2-activation in Barrett’s esophagus and EAC, so far, no clinical relevant NRF2-inhibitor is available [ 30 ].…”

The Oxidative Damage and Inflammation Mechanisms in GERD-Induced Barrett’s Esophagus

“…In addition, genetic variations are involved in BE. Variants of GSTP1 (such as rs1695A > G missense variant) are frequently linked to risks of infiltration and esophageal adenocarcinoma (EAC) due to the reduction of antioxidant enzymatic activity ( Peng et al, 2021 ). Therefore, the detailed molecular mechanism of oxidative damage and inflammation involved in GERD-induced BE should be further explored.…”