Targeting chemokine pathways in esophageal adenocarcinoma

Abstract

y These authors Contributed equally to this work. E sophageal 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.

Chemokines and their receptors in esophageal cancer—the systematic review and future perspectives

“…The overall and disease-free Fig. 1 The structure of chemokines and their receptors [21][22][23][24][25] survival rates were significantly lower in patients with positive CXCL12 expression compared to those with negative CXCL12 immunoreactivity, what was confirmed using univariate analysis. The authors concluded that CXCL12 expression is an important predictor of lymph node metastasis and poor prognosis of ESCC patients' survival [44].…”

“…On the other hand, a developing neoplasm might induce both local and systemic inflammatory responses [28]. It has been shown that various proinflammatory mediators, including cytokines, reactive oxygen mediates, increased expression of oncogenes, matrix Table 1 The classification of chemokines and their receptors [21][22][23][24] Subfamily of chemokines Name of chemokines Other names of chemokines Receptors…”

“…Chemokines are a large family of soluble chemotactic cytokines that bind to their cognate G protein-coupled receptors (GPCRs) to cause a cellular response, such as migration, adhesion, or chemotaxis [21][22][23][24]. They are produced by tissue cells and leukocytes; thus, these small-weight proteins regulate leukocytes' migration in inflammation and immunity processes.…”

“…Over 50 chemokines have been identified, and they were grouped into four classes based on the positions of key cysteine residues (CXC, CX3C, CC, and C). The classification of chemokines and their receptors was presented in Table 1 [22][23][24][25]. About 20 chemokine receptors have been discovered.…”

“…1. Chemokines and their receptors are known to play important roles in inflammation, infection, and tissue injury as well as in the development of cardiovascular and malignant diseases [22][23][24].…”