Abstract
It is well established that chronic inflammation underpins the development of a number of human cancers, with pro-inflammatory signaling within the tumor microenvironment contributing to tumor progression and metastasis. CXCL8 is an ELR+ pro-inflammatory CXC-chemokine which mediates its effects via signaling through two G protein-coupled receptors, CXCR1 and CXCR2. Elevated CXCL8-CXCR1/2 signaling within the tumor microenvironment of numerous cancers is known to enhance tumor progression via activation of signaling pathways promoting proliferation, angiogenesis, migration, invasion and cell survival. This review provides an overview of established roles of CXCL8-CXCR1/2 signaling in cancer and subsequently, discusses the possible strategies of targeting CXCL8-CXCR1/2 signaling in cancer, covering indirect strategies (e.g., anti-inflammatories, NFκB inhibitors) and direct CXCL8 or CXCR1/2 inhibition (e.g., neutralizing antibodies, small molecule receptor antagonists, pepducin inhibitors and siRNA strategies). Reports of pre-clinical cancer studies and clinical trials using CXCL8-CXCR1/2-targeting strategies for the treatment of inflammatory diseases will be discussed. The future translational opportunities for use of such agents in oncology will be discussed, with emphasis on exploitation in stratified populations.
Highlights
It is widely accepted that inflammation is a major contributor to the development and progression of many human cancers, with inflammation identified as the seventh hallmark of cancer [1]
We have demonstrated an increase in the expression levels and an altered distribution of CXCL8 and its two receptors, CXCR1 and CXCR2, in prostate biopsy tissue; the altered distribution was consistent with prostate cancer cells being subject to an increased autocrine stimulus, and the intensity of expression was observed to increase from high grade prostatic intra-epithelial neoplasia (PIN) through to castrate-resistant prostate cancer [46]
Other groups had previously characterized that hypoxia induces CXCL8 expression, we showed that hypoxia induced CXCR1 and CXCR2
Summary
It is widely accepted that inflammation is a major contributor to the development and progression of many human cancers, with inflammation identified as the seventh hallmark of cancer [1]. CXCL8 mediates its effects via binding to two heterotrimeric G protein-coupled receptors, CXCR1 and CXCR2 These receptors are normally found on the surface of leukocytes (neutrophils, monocytes, macrophages, basophils, T-lymphocytes) and endothelial cells. A range of signaling pathways may be activated downstream of CXCR1/2, including MAPK, PI3K, PKC, FAK and Src. Reports from various groups have demonstrated that CXCL8 signaling activates multiple transcription factors such as NFκB, AP-1, HIF-1 and STAT3, and in prostate cancer cells, this signaling has been shown to induce activation of the androgen receptor (AR) [35]. Tumor cells harboring oncogenic mutations or loss of tumor suppressor genes that lead to the activation of specific signaling pathways have been shown to regulate CXCL8 or CXCR1/2 expression. CXCL8 synthesis in Ca2+ ionophore-treated neutrophils partially suppressed by cycloheximide, but not actinomycin D [45]
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