趋化因子及其受体在乳腺癌中的研究进展

乳腺癌已成为妇女最常见的恶性肿瘤,其发病率占妇女恶性肿瘤第一位,且有逐年上升趋势。乳腺癌的远处转移缩短了无病生存期,增加了病死率,也是目前临床上的治疗难点。而肿瘤的侵袭与转移是一个主动过程,与白细胞迁移有许多相似之处,由趋化因子及其受体严密调控。     

趋化因子5及其受体与乳腺癌

趋化因子CCL5及其受体CCR5作为趋化因子家族之一参与多种疾病过程,尤其与乳腺癌关系密切.研究表明趋化因子CCI5及其受体CCR5在乳腺癌的发生、浸润、转移、治疗和预后方面都发挥重要作用.     

乳腺癌趋化因子受体CXCR4的表达及其意义

目的研究趋化性细胞因子受体CXCR4在乳腺癌中的表达,探讨其与淋巴结转移、远处转移及预后的关系。方法84例正常乳腺组织及84例乳腺癌组织、43例区域淋巴结转移癌组织标本（依据组织类型及临床病理特性分组）,取自福建医科大学附属第二医院2000年1月至2002年12月手术切除的病理存档蜡块,应用免疫组化方法（二步法）分别检测3组标本CXCR4的表达情况。对计数资料采用χ^2检验,对生存率采用时序检验进行统计学分析。结果正常乳腺组织、乳腺癌组织、区域淋巴结转移癌组织CXCR4阳性率分别为11．9％、53．6％、74．4％;转移组织CXCR4阳性表达率明显高于原发肿瘤。乳腺癌组织CXCR4阳性表达率与淋巴结转移、HER-2表达、临床分期密切相关（P〈0．05）,而与患者年龄、肿瘤直径、ER表达、PR表达、组织学类型及肿瘤分化程度无关（P〉0．05）。发生远处转移组CXCR4表达水平（74．1％）高于未发生远处转移组（43．9％,P〈O．01）。CXCR4阳性表达组5年生存率66．7％（30／45）明显低于阴性表达组87．2％（84／89,P〈0．05）。结论CXCR4阳性表达与乳腺癌的淋巴结转移、远处转移有关,有助于预后判断。     

趋化因子CXCL12及其受体CXCR4介导乳腺癌转移分子机制

趋化因子CXCL12及其受体CXCR4之间的相互作用在乳腺癌转移中起着枢轴作用.新近研究发现,CXCR4-CXCL12介导的乳腺癌转移与缺氧诱导因子-1(HIF-1)、Her-2、核因子-κB(NFκB)、尿激酶型纤维蛋白酶原激活剂受体(uPAR)等分子密切相关,明确CXCL12-CXCR4介导的乳腺癌转移分子机制,进而逐个阻断上游分子对二者的调控作用,开发出靶点明确、作用特异的抗转移药物将使乳腺癌患者获益.     

乳腺癌组织趋化因子受体CCR7表达及其与淋巴管浸润关系的研究

目的:研究乳腺癌组织内趋化因子受体CCR7的表达及其与淋巴管浸润和淋巴结转移的关系.方法: 对102例乳腺癌组织标本分别进行CCR7和podoplanin免疫组化染色,观察CCR7的表达与临床病理参数之间的关系;并对57例淋巴管浸润标本进行CCR7和podoplanin双标免疫组化染色,观察CCR7在淋巴管内癌栓的表达情况.结果:在乳腺癌组织中CCR7阳性表达率为60.8%,CCR7的表达与患者的年龄、肿瘤大小、病理类型和雌孕激素受体(ER、PR)的表达无关,P>0.05;而与淋巴管的浸润及淋巴结的转移相关,P<0.01;双标免疫组化染色可见蓝黑色的淋巴管内CCR7阳性(红色)的癌细胞,并且CCR7在淋巴管内癌栓的表达强度为4.98±2.84,高于其周围相应的癌组织(3.84±2.51),P=0.037.结论:CCR7在介导乳腺癌细胞淋巴管浸润及淋巴结转移中可能起重要作用.     

趋化因子与乳腺癌

趋化因子参与乳腺癌细胞的生长、血管生成及远处转移过程。然而,近年来单靶点趋化因子受体拮抗剂的临床试验多以失败告终,彰显了肿瘤微环境中趋化因子网络的复杂性,因此基于多向药理学原理确立多靶点调控策略势在必行。多靶点非典型性趋化因子受体(ACR)作为内源性和生理性的调节分子,有可能成为捕获高表达的多种促肿瘤性趋化因子、有效控制乳腺癌的利器。     

趋化因子CXCL12及其受体CXCR4与乳腺癌

 趋化因子CXCL12及其受体CXCR4在乳腺癌发生发展的多个过程中受到多种因素调控并表达,并且多项研究证实CXCL12及CXCR4不但有助于判断乳腺癌患者的预后,而且针对CXCR4的治疗更为乳腺癌患者提供了新的联合治疗方案,给患者更为理想的治疗。     

趋化因子及其受体与肿瘤

趋化因子及其受体在肿瘤的发生、生长和转移等各个阶段都有复杂的网络性表达，研究表明趋化因子CXCL12及受体CXCR4介导乳腺癌、结肠癌、膀胱癌和前列腺癌等肿瘤的转移和发展，这为深入探讨肿瘤的发病及转移机制提供了新视角。现对近年来有关趋化因子及其受体与肿瘤之间的研究进展作一综述。     

趋化因子受体CXCR4在乳腺癌中表达的研究

目的探讨趋化受体CXCR4在乳腺癌中的表达及其与肿瘤转移的关系,以及脂多糖(LPS)对其表达的影响.方法采用流式细胞仪和RT-PCR法检测23例乳腺癌患者的癌组织、癌旁组织、正常组织以及MDA-MB-231细胞中CXCR4在蛋白质和mRNA水平的表达情况,以及LPS对MDA-MB-231细胞 CXCR4表达的影响;用Transwell板检测经LPS作用前后MDA-MB-231对趋化因子SDF-1趋化活性的影响.结果乳腺癌组织MDA-MB-231细胞的趋化因子受体CXCR4在蛋白质和mRNA水平的表达均显著高于癌旁组织和正常组织(P<0.05),并且CXCR4的表达与乳腺癌的转移密切相关;脂多糖(LPS)能下调CXCR4的表达,经LPS作用后乳腺癌细胞趋化活性降低.结论趋化因子受体在乳腺癌的转移中起重要作用,下调乳腺癌细胞CXCR4的表达水平,可减少或抑制其转移.     

Duffy抗原趋化因子受体参与人乳腺癌的淋巴结转移

目的探讨Duffy抗原趋化因子受体(DARC)与乳腺癌患者淋巴结转移的关系。方法乳腺癌原发灶组织标本75例,按淋巴结转移情况分为阳性组和阴性组,通过免疫组化技术检测DARC表达,并探讨其与乳腺癌淋巴结转移的关系。结果淋巴结转移阳性组中DARC强表达18例(48．6％),淋巴结转移阴性组中DARC强表达31例(81．6％),两组间差异有统计学意义(P< 0．01)。DARC强表达组与弱表达组的微血管密度(MVD)分别为(35．67±17．96)／HP和(53．38±20．29)／HP,差异有统计学意义(P<0．01)。此外,远处转移的13例患者中,有9例DARC弱表达(69．2％),4例DARC强表达(30．8％)。DARC表达与MVD、淋巴结转移状态及肿瘤远处转移呈负相关,而与患者的存活时间呈正相关。结论人原发乳腺癌组织中DARC表达降低和MVD增加可能易化肿瘤向淋巴结等远隔部位的转移。     

CXC趋化因子亚族及其受体与乳腺癌相关性的研究进展

趋化因子及其受体在肿瘤生物学中具有多方面的作用,与肿瘤的发生、进展和转移有着密不可分的关系。CXC趋化因子亚族及其受体可通过一系列作用机制调控肿瘤的生物学行为,已成为近年来研究的热点。本文就CXC亚族趋化因子及其受体在乳腺癌中的复杂作用作一综述。     

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.     

Tyrosine kinase signalling in breast cancer: Insulin-like growth factors and their receptors in breast cancer

The insulin-like growth factor (IGF) system exerts pleiotropic effects on mammalian cells. This review focuses on type I IGF receptor (IGF1R)-mediated signal transduction and its relevance in breast cancer. Upon activation by the IGFs, IGF1R, a transmembrane tyrosine kinase receptor, undergoes autophosphorylation, and then binds and phosphorylates additional signaling molecules. These intermediates initiate a series of downstream signaling events that are involved in multiple physiologic processes for cells. Recent data demonstrate that the IGF receptor system actively interacts with the estrogen receptor and integrin receptor systems. Cross-talk among these pathways regulates breast cancer proliferation, protection from cell death, and metastasis. Better understanding of IGF biochemical signaling pathways is of utmost importance for developing therapies for breast cancer.     

Correlation between steroid hormone receptors and prognostic factors in human breast cancer

Knowledge of the tumor content of estrogen (ER) and progesterone (PgR) receptors has proved to be of significant value in human breast cancer. Relative determinations were performed in 589 specimens in our laboratory. The positivity of ER and PgR is correlated with the patients' age at diagnosis, tumor size and relative grade. In particular, the significance of PgR versus ER status and the possible prognostic role of these receptors are investigated.     

Structural and functional studies of insulin receptors in human breast cancer

Summary We characterized the structure and the function of insulin receptors isolated from 10 human breast cancer specimens. We observed that the insulin receptor content, as determined by a specific radioimmunoassay, was four fold increased in human breast cancer tissue when compared to normal breast tissues. In both cancer and normal breast tissues, insulin receptor mRNA consisted of two major species of approximately 11.0 and 8.5 kilobases. The size of the insulin receptor alpha subunit was determined by¹²⁵I-insulin cross-linking followed by immunoprecipitation and polyacrylamide gel electrophoresis; a value of 135 kDa was observed for receptors from both breast cancer and normal breast tissues. The functional binding ability of insulin receptors from cancer tissues was slightly lower as compared to normal tissue derived insulin receptor (% B/T= 2.22±0.50 per ng of insulin receptor as determined by radioimmunoassay vs. 2.96±0.49, mean±S.E.M.). The concentration of insulin that caused half maximal inhibition of¹²⁵I-insulin binding was very similar for both cancer and normal breast receptors (80pM).The size of the insulin receptor beta subunit as determined by receptor autophosphorylation was 95kDa. Basal and maximal insulin (100nM) stimulated receptor tyrosine kinase activity, in terms of both receptor autophosphorylation and phosphorylation of an exogenous substrate, was similar in malignant and normal breast tissue derived insulin receptor. Also, a very similar insulin stimulated Km value for ATP was showed by the tyrosine kinase of insulin receptors from breast cancer and normal breast tissue (11.1 and 10.8µM ATP, respectively). However, in insulin receptors from breast cancer tissue the average tyrosine kinase sensitivity to insulin, as calculated on the exogenous substrate, was higher, although not significantly, with respect to normal breast tissue (ED₅₀ at 0.28±0.09 and 1.08±0.33 nM insulin, respectively). A similarly different sensitivity to insulin was observed also for receptor autophosphorylation.In conclusion, this study demonstrates that breast cancer tissues have an increased number of structurally and functionally normal insulin receptors. In some breast cancer tissues, however, the sensitivity of the receptor tyrosine kinase activity to insulin is greatly increased. These data suggest that, in vivo, the mitogenic effect of insulin may play a role in the biology of certain breast cancers.     

趋化因子及受体在结直肠癌中的研究进展

结直肠癌是最常见的消化道恶性肿瘤之一, 其发病率及死亡率均位居恶性肿瘤第3位。肝、肺转移是导致死亡的主要原因。肿瘤转移的机制目前尚不明确, 近年来的研究证实趋化因子及受体在肿瘤的转移行为中发挥着重要作用。趋化因子是一类小分子细胞因子蛋白家族, 通过与趋化因子受体结合而发挥趋化作用。趋化因子及受体除了能在炎性反应中定向趋化炎性细胞, 近来被发现在肿瘤的转移行为中也发挥着重要作用。现对趋化因子及受体在结直肠癌中的研究进展做一综述。      

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。