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Theranostics 2017; 7(6):1543-1588. doi:10.7150/thno.15625 This issue Cite

Review

Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases

Helen Ha¹, Bikash Debnath^{1, 2}, Nouri Neamati^{1, 2✉}

1. Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, California 90033, United States;
2. Department of Medicinal Chemistry, College of Pharmacy, and Translational Oncology Program, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, Michigan 48109, United States.
* First two authors contributed equally

✉ Corresponding author: Email: neamatiedu. Phone: 734-647-2732

Abstract

The chemokine receptors CXCR1/2 and their ligand CXCL8 are essential for the activation and trafficking of inflammatory mediators as well as tumor progression and metastasis. The CXCL8-CXCR1/2 signaling axis is involved in the pathogenesis of several diseases including chronic obstructive pulmonary diseases (COPD), asthma, cystic fibrosis and cancer. Interaction between CXCL8 secreted by select cancer cells and CXCR1/2 in the tumor microenvironment is critical for cancer progression and metastasis. The CXCL8-CXCR1/2 axis may play an important role in tumor progression and metastasis by regulating cancer stem cell (CSC) proliferation and self-renewal. During the past two decades, several small-molecule CXCR1/2 inhibitors, CXCL8 releasing inhibitors, and neutralizing antibodies against CXCL8 and CXCR1/2 have been reported. As single agents, such inhibitors are expected to be efficacious in various inflammatory diseases. Several preclinical studies suggest that combination of CXCR1/2 inhibitors along with other targeted therapies, chemotherapies, and immunotherapy may be effective in treating select cancers. Currently, several of these inhibitors are in advanced clinical trials for COPD, asthma, and metastatic breast cancer. In this review, we provide a comprehensive analysis of the role of the CXCL8-CXCR1/2 axis and select genes co-expressed in this pathway in disease progression. We also discuss the latest progress in developing small-molecule drugs targeting this pathway.

Keywords: CXCL8, CXCR1, CXCR2, chronic obstructive pulmonary diseases, cancer, cancer stem cells, tumor microenvironment, inhibitor, antibody.

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