Targeting chemokine pathways in esophageal adenocarcinoma

Abstract

Esophageal adenocarcinoma (EAC) is one of the fastest growing malignancies in the US and needs newer therapeutic and diagnostic strategies. Chronic inflammation plays a role in the pathogenesis of EAC and contributes to the dysplastic conversion of normal esophageal epithelium to Barrett's esophagus and frank adenocarcinoma. Chemokines play important roles in mediating inflammation and recent evidence implicates these ligands and their receptors in the development and spread of various tumors. We demonstrated that the chemokines IL8, CXCL1 and CXCL3 are significantly overexpressed during esophageal carcinogenesis and accompanied by amplification and demethylation of the chr4q21 gene locus. We also demonstrated that IL8 levels can be detected in serum of patients with EAC and can serve as potential biomarkers. We now demonstrate that inhibition of IL8 receptor, CXCR2, leads to decreased invasiveness of esophageal adenocarcinoma derived cells without affecting cellular proliferation. Taken together, these studies reveal the important roles that chemokines play in development of esophageal cancer and demonstrate that these pathways can serve as potential therapeutic targets.

Keywords: CXCR2; IL8; barrett's esophagus; chemokines; esophageal adenocarcinoma.

Figure 1.

CXCR2 inhibition leads to reduced invasiveness of esophageal adenocarcinoma cells. Treatment with CXCR2 inhibitor, SB332235, did not lead to inhibition of proliferation of OE33 cell lines at 48 hrs by MTT assay (Mean +/− s.e.m of 3 independent experiments is shown) (A). Treatment with CXCR2 inhibitor, SB332235, led to inhibition of matrigel invasion of OE33 cell lines at 48 hrs at different dose levels (Mean +/− s.e.m of 3 independent experiments is shown; TTest with P value < 0.05 (*) (B). Representative pictographs shows decreased invasion after CXCR2 inhibition (C).