文章：

G蛋白偶联受体与癌症

G-protein-coupled receptors and cancer

原文发布日期：2007-02-01

DOI: 10.1038/nrc2069

类型: Review Article

开放获取: 否

要点：

1. G-protein-coupled receptors (GPCRs) comprise a large family of cell-surface receptors that regulate many cell functions, including cell proliferation, survival and motility, and have recently emerged as key players in tumour growth, angiogenesis and metastasis.
2. Although some endocrine tumours arise from constitutively-active mutant forms of GPCRs and G proteins, the aberrant overexpression of GPCRs and their autocrine and paracrine activation by agonists released by tumour or stromal cells represents the most frequent tactic used by cancer cells to stimulate GPCRs and their signalling networks.
3. Prostaglandin E2 (PGE2) resulting from cyclooxygenase 2 (COX2) activity, the release of chemokines such as stromal cell-derived factor 1 (SDF1; also known as CXCL12) and interleukin 8 (IL8; also known as CXCL8), lipids such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), and neuropeptides such as gastrin-releasing peptide (GRP) and endothelin are all implicated in stromal–cancer-cell interactions that promote tumour growth, neovascularization and metastatic spread.
4. Tumour cell proliferation is regulated by many neuropeptides, PGE2, thrombin, S1P, LPA and IL8, which signal through their cognate receptors to stimulate Gα_s, Gα_i, Gα_q and Gα₁₂ thereby initiating the activity of a signalling network that includes second-messenger-generating systems, small GTPases of the Ras and Rho families, and mitogen-activated protein kinase (MAPK) cascades that regulate the nuclear expression of growth-promoting genes.
5. Tumour cells that express CXCR4 receptors are guided towards gradients of the chemoattractant SDF1, which is released by organs that serve as secondary sites for cancer cell colonization.
6. IL8 that is released from cancer cells and endothelial cells promotes angiogenesis by acting on CXCR2 receptors to supply nutrients to the tumour. Other GPCR agonists, such as chemokines, PGE2 and S1P also contribute to tumour-induced angiogenesis through the regulation of extracellular matrix degradation and endothelial cell permeability, proliferation and migration.
7. Many GPCRs represent suitable biomarkers for the early diagnosis of cancer, and the pharmacological inhibition of GPCRs and their downstream targets might provide an opportunity for the development of new, mechanism-based strategies for cancer prevention and treatment.

要点翻译：

1. G蛋白偶联受体（GPCRs）构成一个庞大的细胞表面受体家族，它们调控多种细胞功能（包括细胞增殖、存活与运动），并近年来被发现在肿瘤生长、血管生成和转移过程中发挥关键作用。
2. 尽管某些内分泌肿瘤由组成性激活的GPCR及G蛋白突变体引发，但更常见的是癌细胞通过异常过表达GPCR，并利用肿瘤或基质细胞释放的激动剂进行自分泌与旁分泌激活，从而刺激GPCR及其信号网络。
3. 由环氧合酶2（COX2）活性产生的前列腺素E2（PGE2）、趋化因子（如基质细胞衍生因子1/SDF1/CXCL12和白介素8/IL8/CXCL8）、脂质介质（如溶血磷脂酸LPA和1-磷酸鞘氨醇S1P）以及神经肽（如胃泌素释放肽GRP和内皮素）均参与基质-癌细胞相互作用，共同促进肿瘤生长、新生血管形成及转移扩散。
4. 肿瘤细胞增殖受多种神经肽、PGE2、凝血酶、S1P、LPA和IL8的调控。这些物质通过其特异性受体激活Gαs、Gαi、Gαq和Gα12信号通路，进而启动包含第二信使生成系统、Ras和Rho家族小GTP酶以及调控促生长基因核表达的MAPK级联反应在内的信号网络。
5. 表达CXCR4受体的肿瘤细胞会循着趋化因子SDF1的浓度梯度定向迁移，该趋化因子由作为癌细胞继发 colonization 靶点的器官释放。
6. 癌细胞和内皮细胞释放的IL8通过作用于CXCR2受体促进血管生成，为肿瘤提供营养。其他GPCR激动剂（如趋化因子、PGE2和S1P）则通过调控细胞外基质降解及内皮细胞通透性、增殖与迁移，共同参与肿瘤诱导的血管生成过程。
7. 许多GPCR可作为癌症早期诊断的适宜生物标志物，而针对GPCR及其下游靶点的药理抑制有望为开发基于机制的新型癌症防治策略提供契机。

英文摘要：

G-protein-coupled receptors (GPCRs), the largest family of cell-surface molecules involved in signal transmission, have recently emerged as crucial players in tumour growth and metastasis. Malignant cells often hijack the normal physiological functions of GPCRs to survive, proliferate autonomously, evade the immune system, increase their blood supply, invade their surrounding tissues and disseminate to other organs. This Review will address our current understanding of the many roles of GPCRs and their signalling circuitry in tumour progression and metastasis. We will also discuss how interfering with GPCRs might provide unique opportunities for cancer prevention and treatment.

摘要翻译： 

G蛋白偶联受体（GPCRs）是参与信号传导的细胞表面分子中最大的家族，近期被发现是肿瘤生长和转移中的关键角色。恶性细胞常常劫持GPCRs的正常生理功能，以维持自身存活、自主增殖、逃避免疫系统监视、增加血液供应、侵袭周围组织并扩散至其他器官。本文将回顾我们目前对GPCRs及其信号网络在肿瘤进展和转移中多重作用的理解，并探讨干预GPCRs如何为癌症预防和治疗提供独特机遇。

原文链接：

G-protein-coupled receptors and cancer