CXCL4及其受体与结直肠肿瘤

CXC趋化因子配体4(CXCL4)是一类血小板衍生的趋化因子,属于CXC亚家族.CXCL4的受体CXC趋化因子受体3(CXCR3)为七次跨膜的G蛋白耦联受体,其辅助受体为糖胺聚糖.CXCL4及其受体参与调控体内许多生物学过程,如免疫调节、炎症反应、内皮细胞增殖迁移及血管新生等.近年来研究表明,CXCL4及其受体对结直肠肿瘤的细胞生长、血管生成、浸润和转移等过程有显著影响.这为探讨结直肠肿瘤的发生机制及靶向治疗提供了新视角.     

肿瘤微环境中CXC型趋化因子及其受体的研究进展

趋化因子是一种可以由肿瘤细胞和基质细胞产生的小分子分泌蛋白,趋化因子受体在肿瘤细胞和基质细胞表面也均有表达,趋化因子和其相配对的同源受体结合通过直接和间接方式调控肿瘤生长,包括激活信号通路直接调控肿瘤细胞的增殖与转移、作用于血管内皮细胞间接调控肿瘤及协调免疫细胞在组织内的迁移和定位后影响免疫反应调控肿瘤。趋化因子分为CXC、CC、CX3C及C四大类,研究较多的亚型为CXC和CC。鉴于CXC趋化因子及其受体在恶性肿瘤中作用广泛,且与免疫系统关系密切,有望成为一个有潜力的治疗靶标,其与免疫检查点抑制剂联合作用于肿瘤微环境（tumor microenvironment,TME）,改善肿瘤免疫反应。本文对CXC亚型的趋化因子/趋化因子受体轴研究进展进行综述,包括促肿瘤轴CXCR2/CXCLs、CXCR4/CXCL12 和抑肿瘤轴CXCR3/CXCL9~11 的基本生物学特性、对肿瘤的直接作用、对TME的间接作用、靶向治疗以及这3 个轴所包含的受体及配体的预测预后意义。     

CXCL12／CXCR4对肿瘤生物学行为的影响

恶性肿瘤细胞的侵袭转移是影响恶性肿瘤预后的根本原因。大量的研究发现趋化因子及其受体在肿瘤侵袭转移中发挥重要作用。其中关于趋化因子CXCL12及其受体CXCR4对肿瘤侵袭转移的影响的研究较多，本文通过国内外文献复习就CXCL12／CXCR4的生物学特性及其对肿瘤生物学行为的影响作一综述。     

趋化因子及其受体在肿瘤转移中的作用

近年来，由于分子生物学、分子免疫学及其相关高技术学科的飞速发展，使人们对趋化因子及其受体的结构与功能有了更深入的了解，对其生物学作用也有了更深入的研究。许多研究表明趋化因子及其受体与肿瘤生物学行为密切相关。本文对趋化因子及其受体在肿瘤转移方面的研究作一简要阐述。     

SDF-1/CXCR4及CCL19/21-CCR7与肿瘤的关系

趋化因子(Chemokine)是一类可诱导的,由多种细胞产生,有激活和趋化白细胞作用,分子量为7KDa～10KDa的促炎细胞因子,它们在抗感染和免疫中有至关重要的作用.根据其前两个半胱氨酸残基的相对位置不同,将它们分为了四大类:CXC趋化因子,CC趋化因子,C趋化因子和CX3C趋化因子.相应的趋化因子受体则分为CXC趋化因子受体(CXCR),CC趋化因子受体(CCR),C趋化因子受体(CR)和CX3C趋化因子受体(CX3CR),但它们都为GPCR家族成员(一类介导趋化因子使功能性GTP-蛋白耦连的七次跨膜受体).     

趋化因子与肿瘤免疫

趋化因子是细胞因子超家族成员中一大类可特异性激活和募集白细胞的小分子蛋白多肽 ,其氨基酸组成具有特异的半胱氨酸 (Cys)基序[1] 。根据特征性保守Cys基序的组成排列差异分为CXC、CC、C、CX3 C四类趋化因子。CXC类趋化因子又按有无ELR基序 (Glu Leu Arg)分为ELR CXC趋化因子和non ELR CXC趋化因子。趋化因子受体属G蛋白偶联的 7次跨膜型受体超家族 ,目前已经得以鉴定的达 19种[2 ] ,根据其特异性结合的相应配体而命名。包括 6种CXC趋化因子受体 (CXCR1CXCR6 )、11种CC趋化因子受体 (CCR1CCR11)、一种C趋化因子受体…     

趋化因子及其受体与肿瘤

在最近的五年中 ,生物信息学和ＥＳＴ数据库的发展使得许多新型趋化因子 (ｃｈｅｍｏｋｉｎｅ)及其受体基因不断地被发现 ,人们对于多种趋化因子及其受体的生物学活性和作用机理有了更深入的研究 ,对趋化因子超家族的结构与功能有了更全面的了解 ,例如趋化因子受体被发现是ＨＩＶ感染的共同受体、趋化因子及其受体在炎症反应、树突状细胞成熟、Ｔ ,Ｂ细胞发育、Ｔｈ1和Ｔｈ2应答、感染、血管形成、肿瘤中都起着非常重要的作用。目前转基因和基因敲除小鼠的不断应用有助于研究趋化因子的体内作用。本文主要介绍近年来关于趋化因子及其受体在…     

趋化因子及其在肿瘤免疫治疗中的应用

趋化因子是一类调节白细胞迁移的超家族。其在肿瘤的生物学行为中表现出双向的调节作用。部分趋化因子通过趋化和调节免疫效应细胞的功能来发挥抗肿瘤免疫作用。全文综述了趋化因子及其受体的结构与功能,并阐述了其在肿瘤免疫治疗中的应用。     

CXC趋化因子受体3变体及其配体在肿瘤微环境中作用的研究进展

恶性肿瘤是严重威胁人类生命的疾病之一,近年来免疫治疗已经成为肿瘤治疗的焦点,解决免疫治疗只对部分患者 有效的问题迫在眉睫。在肿瘤微环境（tumor microenvironment,TME）中趋化因子介导细胞的定向移动,同时具有多种调节功能, 既可以作用于免疫细胞,也可直接作用于肿瘤细胞,发挥了复杂的生物学作用。CXC趋化因子受体3（CXC chemokine receptor 3, CXCR3）通过与其同源CXC趋化因子配体9（CXC chemokine ligand 9,CXCL9）/10/11结合,不仅参与了肿瘤发生、侵袭并促进肿 瘤相关血管的形成,同时也介导了免疫细胞向肿瘤组织中浸润,为无免疫反应性或免疫反应性差的“冷肿瘤”转变为免疫反应性 的“热肿瘤”提供了新的思路,并且可能成为治疗的新靶点。这种抗肿瘤和促肿瘤的双重作用,似乎与CXCR3变体（CXCR3-A、 CXCR3-B）发挥相反的作用密切相关。本文就近年来CXCR3变体CXCR3-A、CXCR3-B及其配体CXCL9/10/11在TME中作用的 研究进展展开综述。     

趋化因子及其受体与乳腺癌相关性的研究现状

目的：探讨趋化因子及其受体在乳腺癌发展过程中所起的作用，以及在此过程中其他细胞因子对趋化因子及受体的影响。方法：以乳腺肿瘤、趋化因子和受体为关键词检索CHKD系列全文数据库和MEDLINE数据库，筛选2002～2007年相关文献，重点是有关研究较多的CXCR4、CCR7及其配体，VEGF和MMP等的调控机制，以及趋化因子及受体与临床病理学参数的关系。结果：在乳腺癌的发展过程中，其他细胞因子及基因突变导致的自身结构的变化都会影响趋化因子及其受体的表达。趋化因子和受体结合，作用于改变肿瘤生物学特性的蛋白，进而调控乳腺癌细胞的发展。通过抗体抑制这些趋化因子及其受体的作用，就可以抑制乳腺癌的发生及转移，提示趋化因子及其受体有望成为乳腺癌靶向治疗的新途径。结论：趋化因子及其受体在乳腺癌组织或细胞上高表达，对乳腺癌的生长、侵袭及转移有重要作用，其信号的活化受到多种因素的影响。     

The role of CXC chemokines and their receptors in cancer

Chemokines, or chemotactic cytokines, and their receptors have been discovered as essential and selective mediators in leukocyte migration to inflammatory sites and to secondary lymphoid organs. Besides their functions in the immune system, they also play a critical role in tumor initiation, promotion and progression. There are four subgroups of chemokines: CXC, CC, CX(3)C, and C chemokine ligands. The CXC or alpha subgroup is further subdivided in the ELR(+) and ELR(-) chemokines. Members that contain the ELR motif bind to CXC chemokine receptor 2 (CXCR2) and are angiogenic. In contrast, most of the CXC chemokines without ELR motif bind to CXCR3 and are angiostatic. An exception is the angiogenic ELR(-)CXC chemokine stromal cell-derived factor-1 (CXCL12/SDF-1), which binds to CXCR4 and CXCR7 and is implicated in tumor metastasis. This review is focusing on the role of CXC chemokines and their receptors in tumorigenesis, including angiogenesis, attraction of leukocytes to tumor sites and induction of tumor cell migration and homing in metastatic sites. Finally, their therapeutic use in cancer treatment is discussed.     

CXC chemokines and prostate cancer: growth regulators and potential biomarkers

CXC chemokines are a subset of chemotactic cytokines that possess angiogenic or angiostatic properties. Using genetically engineered mice lacking the receptors for these ligands, recent research has demonstrated a significant role for CXC chemokines in the development and growth of prostate tumors. The Duffy antigen/receptor for chemokines (DARC), which only binds to CXC chemokines that have angiogenic properties, is a nonsignaling receptor expressed on erythrocytes that appears to function by clearing these chemokines from sites of overproduction. The majority of men of African descent lack this receptor on their erythrocytes, suggesting that loss of this receptor may contribute to aggressive tumor phenotypes in these individuals. Thus, CXC chemokines and the erythrocyte DARC may serve as important growth regulators and biomarkers for prostate cancer stage and progression.     

Overexpression of the duffy antigen receptor for chemokines (DARC) by NSCLC tumor cells results in increased tumor necrosis

Background  

The Duffy antigen receptor for chemokines (DARC) is known to be a promiscuous chemokine receptor that binds a variety of CXC and CC chemokines in the absence of any detectable signal transduction events. Within the CXC group of chemokines, DARC binds the angiogenic CXC chemokines including IL-8 (CXCL8), GROα (CXCL1) and ENA-78 (CXCL5), all of which have previously been shown to be important in non-small cell lung carcinoma (NSCLC) tumor growth. We hypothesized that overexpression of DARC by a NSCLC tumor cell line would result in the binding of the angiogenic ELR+ CXC chemokines by the tumor cells themselves, and thus interfere with the stimulation of endothelial cells and induction of angiogenesis by the tumor cell-derived angiogenic chemokines.     

The multifaceted roles of chemokines in malignancy

Tumor development and progression are multifactorial processes, regulated by a large variety of intrinsic and microenvironmental factors. A key role in cancer is played by members of the chemokine superfamily. Chemokines and their receptors are expressed by tumor cells and by host cells, in primary tumors and in specific metastatic loci. The effects of chemokines on tumorigenesis are diverse: While some members of the superfamily significantly support this process, others inhibit fundamental events required for tumor establishment and metastasis. The current review describes the multifaceted roles of chemokines in malignancy, addressing four major aspects of their activities: (1) inducing leukocyte infiltration to tumors and regulating immune functions, with emphasis on tumor-associated macrophages (and the chemokines CCL2, CCL5), T cells (and the chemokines CXCL9, CXCL10) and dendritic cells (and the chemokines CCL19, CCL20, CCL21); (2) directing the homing of tumor cells to specific metastatic sites (the CXCL12–CXCR4 axis); (3) regulating angiogenic processes (mainly the ELR⁺–CXC and non-ELR–CXC chemokines); (4) acting directly on the tumor cells to control their malignancy-related functions. Together, these different chemokine functions establish a net of interactions between the tumor cells and their microenvironment, and partly dictate the fate of the malignancy cascade.     

Breast tumor cell soluble factors induce monocytes to produce angiogenic but not angiostatic CXC chemokines

Tumor cells are known to interact closely with nontumoral infiltrating cells in order to grow and proliferate. Monocyte-derived cells constitute a major component of the tumoral infiltrate and a high level of these cells has been associated with increased tumor growth and poor prognosis in patients with breast cancer. For their growth and metastatic propagation, solid tumors are dependant on angiogenesis and accumulated evidences suggest that monocyte-derived cells could also play an important role in this phenomenon. However, the precise nature of proangiogenic factors secreted by these cells in breast carcinomas, and their direct influence on vessel formation, has not been determined. In the present study, we show that soluble factors secreted by breast tumor cells induce monocytes to produce a variety of proangiogenic CXC chemokines without secretion of angiostatic CXC chemokines. Using in vitro tubule formation in Matrigel, we demonstrated that the CXC chemokines secreted by MTSs (monocytes cultured with tumor cell supernatants) were able to induce microvessel formation. The profile of secreted CXC chemokines was characteristic for each tumor cell line or fresh tumor cells. This last result points out that a precise profiling of secreted proangiogenic factors inside the tumor, by tumor cells themselves or tumor-infiltrating monocyte-derived cells, is important for a precise targeting of therapeutic agents against neovascularization.     

趋化因子及趋化因子受体在骨肉瘤中的研究进展

骨肉瘤,又称成骨肉瘤,是最常见的恶性成骨性肿瘤之一,占恶性骨肿瘤总数的20%～45%,多数起源于骨间叶细胞。发病年龄多在15～25岁之间,男性多于女性。好发部位为长骨干骺端,其中以股骨远端和胫骨近端较多见,其次是肱骨和腓骨近端,随血液运行转移率高且早,发展迅速。骨肉瘤侵袭性强,约20%的患者发生转移,肺转移最为常见[1]。随着新辅助化疗、保肢手术等的开展,骨肉瘤患者5年生存率提高到60%～70%[2]。但由于化疗耐药性、转移率高等问题的存在,患者仍面临着复发及肺转移的困扰。基因治疗、免疫治疗和分子靶向治疗等生物治疗技术的发展也为骨肉瘤的治疗开辟了新的道路,为骨肉瘤患者带来新的希望[3]。     

脑胶质瘤中CXC趋化因子表达的预后意义及免疫细胞浸润分析

目的 分析多形性胶质母细胞瘤(GBM)中CXC趋化因子的表达,研究其在GBM中的预后价值及其作为治疗靶点的潜在作用.方法 利用GEPIA数据库筛选出差异表达的CXC趋化因子,并分析CXC趋化因子对GBM患者预后的影响.使用String数据库预测邻近基因,并构建蛋白互作网络(PPI).使用DAVID数据库进行GO富集分析...     

Virally encoded 7TM receptors

A number of herpes- and poxviruses encode 7TM G-protein coupled receptors most of which clearly are derived from their host chemokine system as well as induce high expression of certain 7TM receptors in the infected cells. The receptors appear to be exploited by the virus for either immune evasion, cellular reprogramming, tissue targeting or for cell entry. Through their efficient evolutionary machinery and through in vivo selection performed directly on the human cellular and molecular targets, virus have been able to optimize the encoded receptors for distinct pharmacological profiles to help in various parts of the viral life cyclus. Most of the receptors encoded by human pathogenic virus are still orphan receptors, i.e. the endogenous ligand is unknown. In the few cases where it has been possible to characterize these receptors pharmacologically, they have been found to bind a broad spectrum of either CC chemokines, US28 from human cytomegalovirus, or CXC chemokines, ORF74 from human herpesvirus 8. Nevertheless, US28 has been specifically optimized for recognition of the membrane bound chemokine, fractalkine, conceivably involved in cell-cell transfer of virus; whereas ORF74 among the endogenous CXC chemokines has selected angiogenic chemokines as agonists and angiostatic/modulatory chemokines as inverse agonists. ORF74 possess substantial cell-transforming properties and signals with high constitutive activity through the phospholipase C and MAP kinase pathways. Interestingly, transgenic expression of this single gene in certain lymphocyte cell lineages leads to the development of lesions which are remarkably similar to Kaposi's sarcoma, a human herpesvirus 8 associated disease. Thus, this and other virally encoded 7TM receptors appear to be attractive future drug targets.     

Macrophage migration inhibitory factor and CXC chemokine expression in non-small cell lung cancer: role in angiogenesis and prognosis.

PURPOSE: The purpose of this study was to determine whether expression of migration inhibitory factor (MIF) is increased in non-small cell lung cancer, and whether it correlates with angiogenesis and/or prognosis. EXPERIMENTAL DESIGN: We measured vessel density, and levels of MIF, angiogenic CXC chemokines, and vascular-endothelial growth factor (VEGF; by ELISA) in tumor and normal lung tissue from 87 patients after resection of lung cancer. We compared vessel density with levels of MIF, VEGF, or angiogenic CXC chemokines in the corresponding tumor homogenate. Disease-free survival was analyzed in a Cox proportional hazards model. RESULTS: Levels of MIF in lung cancer demonstrated a bimodal distribution, with some having "normal" values (relative to normal lung tissue) and a second cluster with markedly high values. The increased levels of MIF in lung cancer were statistically significant in both paired and unpaired comparisons (P < 0.05). The strongest correlation of vessel density was with the sum of angiogenic CXC chemokines. MIF correlated very strongly with levels of angiogenic CXC chemokines. Tumors in the high MIF group had a strong correlation between MIF level and vessel density. Risk of recurrence was associated with high levels of glutamic acid-leucine-arginine amino acid motif CXC chemokines, MIF, and/or VEGF in a Cox proportional hazards model. CONCLUSIONS: MIF expression in non-small cell lung cancer occurs in a bimodal distribution, and is closely associated with tumor levels of angiogenic CXC chemokines and with vessel density. High levels of tumor-associated CXC chemokines, MIF, or VEGF are associated with risk of recurrence after resection of lung cancer.