Rationale and Means to Target Pro-Inflammatory Interleukin-8 (CXCL8) Signaling in Cancer.
Rationale and Means to Target Pro-Inflammatory Interleukin-8 (CXCL8) Signaling in Cancer.
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DOI：
10.3390/ph6080929
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发表时间：
2013-08-06
期刊：
影响因子：
--
通讯作者：
Waugh DJ
中科院分区：
文献类型：
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作者：
Campbell LM;Maxwell PJ;Waugh DJ
众所周知，慢性炎症是许多人类癌症发展的基础，肿瘤微环境中的促炎信号传导有助于肿瘤进展和转移。CXCL 8是ELR+促炎CXC趋化因子，其通过两种G蛋白偶联受体CXCR 1和CXCR 2的信号传导介导其作用。已知许多癌症的肿瘤微环境中升高的CXCL 8-CXCR 1/2信号传导通过激活促进增殖、血管生成、迁移、侵袭和细胞存活的信号传导途径来增强肿瘤进展。本文综述了CXCL 8-CXCR 1/2信号转导在癌症中的作用，随后讨论了靶向CXCL 8-CXCR 1/2信号转导的可能策略，包括间接策略（例如，抗炎药、NFκB抑制剂）和直接的CXCL 8或CXCR 1/2抑制（例如，中和抗体、小分子受体拮抗剂、肽蛋白抑制剂和siRNA策略）。将讨论使用CXCL 8-CXCR 1/2靶向策略治疗炎症性疾病的临床前癌症研究和临床试验报告。将讨论在肿瘤学中使用这些药物的未来翻译机会，重点是分层人群的开发。
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.