The Interleukin-8 Pathway in Cancer
The Interleukin-8 Pathway in Cancer
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DOI：
10.1158/1078-0432.ccr-07-4843
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发表时间：
2008-11-01
影响因子：
11.5
通讯作者：
Wilson, Catherine
中科院分区：
文献类型：
--
作者：
Waugh, David J. J.;Wilson, Catherine
白细胞介素-8 （IL-8）是一种促炎的CXC趋化因子，与促进中性粒细胞趋化和脱颗粒有关。该趋化因子激活两个细胞表面G蛋白偶联受体（CXCR1和CXCR2）下游的多种细胞内信号通路。在癌细胞、内皮细胞、浸润性中性粒细胞和肿瘤相关巨噬细胞中，IL-8和/或其受体的表达增加，表明IL-8可能是肿瘤微环境中一个重要的调节因子。IL-8信号的诱导激活了多个上游信号通路，这些信号通路(a)通过调节众多转录因子活性影响基因表达，(b)在翻译水平上调节细胞蛋白质组，和/或(c)通过翻译后调节调节蛋白影响细胞骨架的组织。由于效应物和下游靶点的多样性，IL-8信号传导促进内皮细胞的血管生成反应，增加内皮细胞和癌细胞的增殖和存活，并增强癌细胞、内皮细胞和浸润性中性粒细胞在肿瘤部位的迁移。因此，在许多异种移植和原位体内模型中，IL-8的表达与肿瘤的血管生成、致瘤性和转移有关。最近，IL-8信号被认为与雄激素受体的转录活性调控有关，支持前列腺癌细胞向雄激素不依赖型增殖的转变。此外，应激和药物诱导的IL-8信号已被证明可赋予癌细胞化疗耐药。因此，抑制IL-8信号的作用可能是针对肿瘤微环境的重要治疗干预措施。
Interleukin-8 (IL-8) is a proinflammatory CXC chemokine associated with the promotion of neutrophil chemotaxis and degranulation. This chemokine activates multiple intracellular signaling pathways downstream of two cell-surface, G protein-coupled receptors (CXCR1 and CXCR2). Increased expression of IL-8 and/or its receptors has been characterized in cancer cells, endothelial cells, infiltrating neutrophils, and tumor-associated macrophages, suggesting that IL-8 may function as a significant regulatory factor within the tumor microenvironment. The induction of IL-8 signaling activates multiple upstream signaling pathways that (a) impinge on gene expression via regulation of numerous transcription factor activities, (b) modulate the cellular proteome at the level of translation, and/or (c) effect the organization of the cell cytoskeleton through post-translational regulation of regulatory proteins. As a consequence of the diversity of effectors and downstream targets, IL-8 signaling promotes angiogenic responses in endothelial cells, increases proliferation and survival of endothelial and cancer cells, and potentiates the migration of cancer cells, endothelial cells, and infiltrating neutrophils at the tumor site. Accordingly, IL-8 expression correlates with the angiogenesis, tumorigenicity, and metastasis of tumors in numerous xenograft and orthotopic in vivo models. Recently, IL-8 signaling has been implicated in regulating the transcriptional activity of the androgen receptor, underpinning the transition to an androgen-independent proliferation of prostate cancer cells, In addition, stress and drug-induced IL-8 signaling has been shown to confer chemotherapeutic resistance in cancer cells. Therefore, inhibiting the effects of IL-8 signaling may be a significant therapeutic intervention in targeting the tumor microenvironment.