肿瘤微环境与趋化因子家族

肿瘤微环境中趋化因子及其受体在以下几个方面影响着肿瘤的生长与转移：调控免疫细胞向肿瘤组织的迁移；影响机体对肿瘤细胞的清除能力；调节肿瘤组织的血管新生；刺激肿瘤以自分泌或旁分泌形式产生生长分子；影响肿瘤细胞的浸润和转移。现综述近年来有关趋化因子及其受体与肿瘤细胞免疫逃逸，以及在肿瘤免疫治疗等方面的研究进展。     

肿瘤微环境与趋化因子家族

肿瘤微环境中趋化因子及其受体在以下几个方面影响着肿瘤的生长与转移调控免疫细胞向肿瘤组织的迁移;影响机体对肿瘤细胞的清除能力;调节肿瘤组织的血管新生;刺激肿瘤以自分泌或旁分泌形式产生生长分子;影响肿瘤细胞的浸润和转移.现综述近年来有关趋化因子及其受体与肿瘤细胞免疫逃逸,以及在肿瘤免疫治疗等方面的研究进展.     

微环境中间质细胞通过趋化因子对乳腺癌生长和转移的影响

摘 要 大量研究表明，微环境中的多种间质细胞对肿瘤细胞的生长和转移具有多方面的影响，而在此过程中趋化因子及其受体则发挥着至关重要的作用。乳腺癌中的肿瘤相关性巨噬细胞在趋化因子CCL2及其受体CCR2作用下向肿瘤部位大量聚集，发挥促肿瘤血管形成的作用；癌症相关性成纤维细胞通过CXCL12/CXCR4生物轴作用于乳腺癌细胞，促进肿瘤生长和转移；间充质干细胞以旁分泌的方式分泌CCL5，作用于CCR5阳性的乳腺癌细胞，增强肿瘤细胞的运动、浸润和转移能力。除此之外，骨髓来源的细胞、造血前驱细胞、肿瘤浸润性树突状细胞、肿瘤浸润性淋巴细胞以及其他白细胞也能借助趋化因子及其受体在肿瘤微环境中发挥着重要作用。由此可见，对肿瘤微环境中间质细胞及趋化因子的深入研究，可能为肿瘤的生物学治疗提供新的靶点。     

趋化因子与肿瘤侵袭转移

趋化因子是一类具有趋化作用的分泌型小分子蛋白质,其受体属于G蛋白偶联的7次跨膜受体超家族.越来越多的证据表明趋化因子与肿瘤生长、侵袭和转移密切相关.现综述趋化因子在肿瘤细胞增殖、迁移、粘附、降解细胞外基质、肿瘤血管生成及肿瘤器官特异性转移等过程中的作用.     

趋化因子受体与肿瘤转移

目前认为肿瘤细胞转移和淋巴细胞迁移具有相似机制,但趋化因子及其受体参与肿瘤转移的机制尚未完全阐明。由于其在肿瘤细胞器官选择性转移中的重要作用,趋化因子受体有希望成为肿瘤治疗的靶标并具有预后价值。现综述趋化因子受体与肿瘤侵袭和转移的研究进展。     

趋化因子与肿瘤生长和转移

趋化因子是一个促炎多肽细胞因子的超家族，具有激活和趋化白细胞的作用，许多疾病的发生发展均需趋化因子的参与。在肿瘤的发生发展过程中，趋化因子表现出两方面的作用：一部分趋化因子可能增强宿主抗肿瘤侵入的固有或特异性免疫反应，另一部分可能通过促进肿瘤细胞的增殖和肿瘤组织中血管的生成，而促进肿瘤的生长和转移。本文主要     

红细胞趋化因子受体在抗肿瘤免疫反应中的作用

红细胞趋化因子受体是一个G蛋白非偶联的杂性趋化因子受体,可作为趋化因子"清除槽"或诱骗受体,吸附肿瘤局部过多的血管生成性趋化因子,使肿瘤血管生成减少,阻止肿瘤生长和转移.肿瘤患者红细胞趋化因子受体活性有明显下降,使肿瘤局部免疫状态低下,利于肿瘤细胞生长和转移.     

趋化因子CXCL12/CXCR4与肿瘤关系的研究进展

CXCL12及其受体CXCR4不仅在许多生命过程中发挥着重要的调控作用而且与肿瘤细胞的生长、增殖、侵袭、转移有密切的关系。本文将围绕CXCR4、CXCL12以及CXCL12/CXCR4轴在肿瘤增殖、侵袭、转移、肿瘤血管生成中的作用以及作用原理以及临床应用作一综述。     

pH值调控肿瘤细胞生长转移的机制

实体瘤存在一个显著的特征是肿瘤胞内呈碱性和胞外呈酸性的微环境,这种酸性微环境能促进肿瘤细胞的生长、侵袭转移.调节肿瘤酸性微环境的主要因子是膜离子交换体,这些离子交换体如NHE和VHA不仅是肿瘤酸性微环境的主要调节者,而且能促进肿瘤细胞的生长转移.通过调节肿瘤胞内外pH值变化可以抑制肿瘤细胞生长转移,但pH值的变化对肿瘤细胞生长转移的调控机制尚不清楚.全文对肿瘤细胞转移的发生机制、肿瘤酸性微环境的形成和膜离子交换体对其调节作用以及三者的关系进行阐述.     

趋化因子受体与肿瘤转移

目前认为肿瘤细胞转移和淋巴细胞迁移具有相似机制,但趋化因子及其受体参与肿瘤转移的机制尚未完全阐明。由于其在肿瘤细胞器官选择性转移中的重要作用,趋化因子受体有希望成为肿瘤治疗的靶标并具有预后价值。现综述趋化因子受体与肿瘤侵袭和转移的研究进展。     

趋化性细胞因子与乳腺癌的转移

远处转移是乳腺癌致死和预后较差的重要原因，而在乳腺癌转移中，趋化性细胞因子扮演着重要角色，乳腺癌细胞高表达某些趋化性细胞因子及某些受体，通过趋化性细胞因子与其受体的相互作用，趋化吞噬细胞及淋巴细胞浸润，促使癌细胞侵入正常组织及血管生成，形成转移肿瘤。本文主要综述了近年研究较多的趋化性细胞因子受体CXCR4及趋化性细胞因子RANTES、IL-8、MCP-1等在乳腺癌转移中的作用。     

SDF-1/CXCR7在肝细胞癌中的表达及临床意义

目的：研究趋化因子SDF-1及其受体CXCR7在肝细胞癌组织中的表达,探讨其表达水平与临床病理特征的关系。方法：采用SP免疫组织化学法检测55例肝细胞癌标本及28例正常肝组织标本中SDF-1、CXCR7的表达。结果：SDF-1、CXCR7在正常肝组织表达均阴性,癌组织中二者阳性表达率分别为63.6%和78.2%;SDF-1表达于癌细胞及间质上皮细胞,CXCR7主要表达于间质内皮细胞,SDF-1表达与门静脉癌栓有关,CXCR7表达与肝内病灶数目、门静脉癌栓有关。结论：SDF-1/CXCR7生物学轴通过促进新生血管生成,参与肝细胞癌的侵袭和转移。有望成为判断肝细胞癌侵袭性及预后的指标。     

趋化因子与肿瘤

本文就趋化因子及其受体家族在肿瘤生长和转移中的作用以及肿瘤生物治疗中的应用等方面的进展作一综述。     

HP 感染和趋化因子及受体 CXCL12 / CXCR4 与胃癌关系研究的最新进展简

幽门螺杆菌（helicobacter pylori,HP）感染在胃黏膜癌变过程中是一个重要致病因素,趋化因子及受体CXCL12／CXCR4与胃癌关系密切。本文综述了HP感染、趋化因子及受体CXCL12／CXCR4与胃癌及癌前病变的相互关系,为临床胃癌的癌前病变监控提供有实用价值的监控预测标志物,同时为HP的除菌治疗提供有用的实验室依据。     

Manipulating the expression of chemokine receptors enhances delivery and activity of cytokine-induced killer cells

Background:

Cytokine-induced killer (CIK) cells are ex vivo-expanded immune cells that express NK-cell and T-cell markers and that are routinely used in the treatment of many cancers. One key advantage of CIK cells is their ability to efficiently traffic to many solid tumours. Although likely to be mediated by chemokine receptor (CKR) expression, a thorough examination of the mechanism of tumour targeting has not been previously explored.

Methods:

Here, human CIK cell expansions were examined for the level, profile and kinetics of CKR expression.

Results:

It was found that CIK cells express a panel of CKRs, with considerable variation between donors. Importantly, CKR levels dropped considerably beyond 14 days in culture, being significantly reduced by day 28 (the time at which cytolytic activity peaked). As such, CIK preparations that are used clinically may not have optimal CKR expression. Several approaches were found to re-stimulate CKR cell-surface levels at these later time points. These approaches also enhanced cytolytic activity in vitro and were demonstrated to increase both in vivo tumour trafficking and anti-tumour activity in mouse models.

Conclusions:

Simple modifications of the CIK expansion protocol could therefore be used to significantly enhance the anti-tumour effects of this therapy.     

CXCL1, CXCL10 and CXCL12 Chemokines are Variously Expressed in Acute Myeloid Leukemia Patients Prior and Post Bone Marrow Transplantation

Aim: The chemokine-receptor axes play parts in development of leukemia, CXCL1, CXCL10 and CXCL12 are involved in immune responses. Thus, we have examined the serum levels of these chemokines in parallel with their related cognate receptors (CXCR1, CXCR3 and CXCR4) in AML (acute myeloid leukemia) patients prior and post BMT (bone marrow transplantation) therapy. Main methods: Clinical specimens were collected from 46 AML patients (23 M1 and 23 M3 subtypes) before/after BMT. CXCL1, CXCL10 and CXCL12 concentrations were determined by ELISA. The mRNA levels of the related receptors were detected by QRT_PCR. Data were analyzed by T-test, χ2 and ANOVA statistical methods in SPSS software version 18. A difference was regarded significant if P value < 0.05. Key findings: Our results indicated that the elevated levels of CXCL12 in AML patients were remained unchanged after transplantation.  The CXCL10 concentration was decreased in patients. All studied chemokines were elevated in BMT patients with history of 9 times PLT transfusion. In patients who received BMT from siblings CXCL1 and CXCL10 have been elevated, whereby they were compared to patients who received BMT from parents while CXCL12 sustained unchanged in groups. Serum measures of CXCL1 and CXCL10 were induced in acute and chronic GVHD patients in compare to these without GVHD. Significance: According to the results, it can be concluded that these chemokines play fundamental parts in pathogenesis of both AML and BMT. It is worthy to note that chemokines could be used as diagnostic markers alongside with possible promising therapeutic targets.     

Estrogen Disrupts Chemokine-Mediated Chemokine Release from Mammary Cells: Implications for the Interplay between Estrogen and IP-10 in the Regulation of Mammary Tumor Formation

Chemokines are pro-inflammatory cytokines that function to attract immune cells to the sites of tissue inflammation, injury or infection. We have formulated the hypothesis that release of one chemokine can serve, in a local paracrine or endocrine fashion, to induce the release of other chemokines from neighboring mammary cells. We set out to investigate whether specific chemokines could promote the release of other chemokine members from mammary cells, and whether estrogen could serve to disrupt the release of these chemokines from mammary cells. We found that treatment with the chemokine IP-10 resulted in significant increases in the amount of MIP-1alpha and MCP-1/JE released from murine mammary cells. Estrogen co-treatment significantly blocked the ability of IP-10 to trigger the release of MIP-1alpha and MCP-1/JE. Suppressive effects of estrogen were reversed upon co-treatment with 4-hydroxytamoxifen. Estrogen treatment significantly decreased expression of proteins corresponding to the chemokine receptors CXCR3 and CCR5 on mammary cells. Exposure of female mice to IP-10 in vivo significantly decreased the ability of estrogen to support the growth of CCL-51-based tumors in mammary tissue. Our results suggest that exposure of mammary tissue to estrogen may decrease the release of local chemokines from mammary cells, potentially increasing the risk of tumor growth through decreased immune surveillance. Ongoing studies are investigating the possible mechanisms through which IP-10 stimulates the release of chemokines from mammary cells, and how the action of IP-10 may serve to decrease mammary tumor formation.     

Inhibition of neutrophil infiltration into A549 lung tumors in vitro and in vivo using a CXCR2-specific antagonist is associated with reduced tumor growth

Neutrophils are important innate immune cells that are involved in microbial clearance at sites of infection and in wound healing. The microenvironment of tumors often resembles that of chronic inflammation and increased numbers of neutrophils have been observed in several tumors and, in some cases, these positively correlate with poor prognosis. Neutrophil recruitment into tumors appears to be dependent on chemokines that bind to CXCR1 and CXCR2 expressed by neutrophils. In our study, we used lung adenocarcinoma A549 multicellular tumor spheroids and A549 tumor xenografts along with a CXCR2-specific small molecule inhibitor (AZ10397767) to investigate the recruitment and function of human neutrophils in tumors. We found that A549 spheroids constitutively secrete high levels of CXCL chemokines and that neutrophil recruitment into A549 tumors in vitro and in vivo is largely dependent on CXCR2 activation. AZ10397767 significantly reduced the numbers of infiltrating neutrophils into both in vitro and in vivo tumor models, which was associated with slower growing tumors. Neutrophil infiltration into A549 tumor spheroids increased their size compared to noninfiltrated spheroids and neutrophil-derived factors increased the proliferation of A549 tumor cells and induced endothelial cell tubule formation in vitro. In contrast, we saw no reduction in microvascular density in AZ10397767-treated A549 tumors or in tumors grown in CXCR2(-/-) mice, suggesting that angiogenesis in these tumors is CXCR2-independent. Our data show that neutrophils can contribute to lung tumor growth and that CXCR2 antagonists may be a useful therapeutic agent in the treatment of lung carcinomas.     

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。     

CCR4与肿瘤的关系及其临床意义

CCR4是CC趋化因子受体（CC chemokine receptor, CCR）家族中的一员,主要表达于多种淋巴细胞。其高亲和力配体为胸腺和活化调节的趋化因子 (thymus and activation regulated chemokine,TARC/CCL17)及巨噬细胞衍生的趋化因子(macrophagederived chemokine,MDC/CCL22/STCP1)。CCR4主要通过CCR4+ Treg细胞及CCR4+ Th2细胞发挥免疫效应。CCR4的高表达与多种血液系统肿瘤以及恶性实体瘤的浸润和预后相关,其机制为Treg细胞表面的CCR4通过与其配体TARC、MDC 的结合趋化Treg细胞,引起免疫逃逸,从而导致不良临床后果。多种恶性肿瘤转移模型的研究进一步揭示了CCR4与恶性肿瘤转移之间的关系。抗CCR4嵌合型单克隆抗体KM2760的研究已进入Ⅱ期临床试验阶段,阻断TARC/MDCCCR4信号通路,有可能成为恶性肿瘤分子靶向治疗的新策略。