乳腺癌微环境中趋化因子CCL20作用的研究进展

趋化因子是一类低分子量细胞因子,在调节肿瘤微环境中发挥重要作用。肿瘤微环境中的趋化因子不仅能够趋化白细胞,也能诱导附近的反应细胞影响肿瘤生长、侵袭、转移和血管生成。趋化因子与炎症和肿瘤疾病的发生发展密切相关,其中CC家族中的趋化因子CCL20在多种恶性肿瘤的侵袭和转移中发挥重要作用。近年发现,趋化因子CCL20在乳腺癌免疫抑制、血管生成及诱导上皮间质转化和肿瘤侵袭转移中起重要的调控作用。然而,CCL20在乳腺癌中的作用机制尚未明确。本文重点阐述趋化因子CC亚家族成员CCL20在乳腺癌微环境中的功能,探讨CCL20与乳腺癌微环境之间的关系,以期为乳腺癌靶向治疗提供新的思路。     

乳腺癌肿瘤微环境中间质细胞介导的化疗耐药性研究进展

乳腺癌是一种具有异质性的全身性疾病,其微环境主要由肿瘤细胞及多种非肿瘤细胞组成。其中间充质干细胞在肿瘤的发生发展中发挥着重要作用。间充质干细胞可直接通过缝隙连接、膜受体和微管或间接通过可溶性分子与肿瘤细胞及其微环境相互作用。肿瘤相关成纤维细胞来源于癌旁成纤维细胞或间充质干细胞,在肿瘤耐药过程中发挥重要作用。在乳腺癌中,肿瘤干细胞与其所处微环境处于动态平衡状态,其表型受细胞因子的密切调控。间质细胞通过与乳腺癌细胞的相互作用,进而对其生物学特性产生重要影响。另外,间质细胞可改变肿瘤细胞对化疗药物的敏感性,进而使其产生耐药。因此,解决肿瘤间质细胞介导的化疗耐药是成功治疗中晚期乳癌的关键。本文主要阐述了间质细胞在乳腺癌微环境中介导化疗耐药的研究进展。     

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。     

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     

趋化因子结合蛋白与乳腺癌

趋化因子与乳腺癌的发生、发展过程密切相关，针对趋化因子受体的抗体及小分子拮抗剂可能具有抗乳腺癌作用。然而，肿瘤微环境中的趋化因子网络十分复杂，一些多靶点高效调节分子似乎发挥着至关重要的作用，现就趋化因子结合蛋白与乳腺癌的关系作扼要综述。     

炎性乳腺癌中肿瘤微环境的研究进展

炎性乳腺癌（IBC）是一种罕见且进展迅速的高侵袭性乳腺癌亚型。因其在起病初期常被误诊,对标准治疗反应较差以及缺少大样本的前瞻性研究,IBC患者的生存率明显低于非炎性乳腺癌患者。国内外一直致力于阐释IBC的各方面生物学机制,而作为肿瘤免疫最直接的表现形式,肿瘤微环境（TME）参与了IBC的各种恶性生物学行为。IBC的TME中包括淋巴管、血管、肿瘤相关成纤维细胞、肿瘤细胞外基质及浸润性免疫细胞等组成成分,但无明确特征,各种调控TME中免疫细胞的分子机制和信号通路在很大程度上仍不清楚。全文就IBC的TME与IBC发病机制及其预后的相关性进行综述。     

电离辐射对雌激素受体阴性乳腺癌微环境的影响

雌激素受体阴性乳腺癌具有好发于青年、BRCA1基因突变及暴露于电离辐射女性等的特点。此外,童年时期受到辐射的女性有更大的风险发展为三阴性乳腺癌（triple—negative breast cancer,TNBC）。最近研究发现,电离辐射能够诱导体内微环境中的某些过程的发生,从而促进了雌激素受体阴性肿瘤的发展。因此,了解电离辐射在雌激素受体阴性乳腺癌发生发展中的作用,有助于通过对年龄、药物和暴露等个体化因素的预防,以降低侵袭性乳腺癌的发病风险。     

趋化因子受体4和间质细胞衍生因子1α与鼻咽癌器官特异性转移的相关性研究

目的 研究趋化因子受体4(CXCR4)在鼻咽癌细胞中的表达,间质细胞衍牛因子1α(SDF-1α)在鼻咽癌远处靶器官中的表达,探讨CXCR4和(或)SDF-1α在鼻咽癌器官特异性转移中的作用.方法 应用逆转录聚合酶链反应(RT-PCR)和免疫组织化学法分析30例鼻咽癌、15例正常鼻咽组织中CXCR4 mRNA和蛋白的表达及其同临床病理学因素之间的相关性,应用免疫组织化学法分析鼻咽癌患者的正常颈部淋巴结(包括颈深上和颈深下淋巴结)、骨髓、肺、肝脏和肾脏、结肠(各5例)中SDF-1α蛋白的表达.结果 RT-PCR检测结果显示,鼻咽癌组织中CXCR4 mRNA相对表达强度(0.71±0.22)显著高于正常鼻咽组织(0.14±0.07;F=27.94,P<0.05);免疫组织化学检测结果显示,鼻咽癌组织中CXCR4蛋白的表达(1.58±0.59)显著高于正常鼻咽组织(0.51±0.22;F=17.75,P<0.05).鼻咽癌组织中CXCR4 mRNA和蛋白的表达与临床分期、淋巴结转移、细胞分化程度显著相关(均P<0.05).SDF-1α蛋白在鼻咽癌患者的颈深上淋巴结、骨髓、肺、肝脏中表达较高(2.35±0.67),而在颈深下淋巴结、肾脏和结肠中表达较弱(0.68±0.23),差异有统计学意义(t=10.13,P<0.01).结论 CXCR4的表达与鼻咽癌的转移密切相关,CXCR4和(或)SDF-1α在鼻咽癌器官特异性转移中可能发挥重要作用.     

人类趋化因子与肿瘤生长,转移

白细胞向炎症部位的定向移动是由趋化因子诱导的。近年来发现趋化因子及其受体参与了许多病理过程 ,尤其在艾滋病和肿瘤的发病机制与治疗中有了新进展。本文重点阐述趋化因子及其受体在肿瘤生长与转移中的作用。     

子宫内膜癌微环境中间质细胞相关信号通路的研究进展

和子宫内膜癌上皮细胞相似，肿瘤微环境中主要细胞的间质细胞也表达雌激素受体（ER），同样也受到雌激素的调控。在雌激素和抑癌基因的作用下，间质细胞与肿瘤细胞的增殖、侵袭和转移等密切相关。间质细胞相关信号通路的研究，为探索雌、孕激素失衡的发病机制、肿瘤复发和化疗耐药等机制提供新的依据。     

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。      

Host microenvironment in breast cancer development: Inflammatory cells, cytokines and chemokines in breast cancer progression - reciprocal tumor–microenvironment interactions

A comprehensive overview of breast cancer development and progression suggests that the process is influenced by intrinsic properties of the tumor cells, as well as by microenvironmental factors. Indeed, in breast carcinoma, an intensive interplay exists between the tumor cells on one hand, and inflammatory cells/cytokines/chemokines on the other. The purpose of the present review is to outline the reciprocal interactions that exist between these different elements, and to shed light on their potential involvement in breast cancer development and progression.     

Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential

In addition to the role in regulating leukocyte trafficking, chemokines recently have been shown to be involved in cancer growth and metastasis. Chemokine network in tumor neovascularity may be regulated by decoy receptors. Duffy antigen receptor for chemokines (DARC) is a specific decoy receptor binding with the angiogenic CC and CXC chemokines. To investigate the effects of DARC on the tumorigenesis and the metastasis potential of human breast cancer cells, human DARC cDNA was reintroduced into the MDA-MB-231 and MDA-MB-435HM cells which have a high capability of spontaneous pulmonary metastasis. We demonstrated that DARC overexpression induced inhibition of tumorigenesis and/or metastasis through interfering with the tumor angiogenesis in vivo. This inhibition is associated with decreasing CCL2 protein levels, and MVD and MMP-9 expression in xenograft tumors. In human breast cancer samples, we also demonstrated that low expression of the DARC protein is significantly associated with estrogen receptor (ER) status, MVD, lymph node metastasis, distant metastasis and poor survival. Our results suggest for the first time that DARC is a negative regulator of growth in breast cancer, mainly by sequestration of angiogenic chemokines and subsequent inhibition of tumor neovascularity.     

Host microenvironment in breast cancer development: inflammatory cells,cytokines and chemokines in breast cancer progression: reciprocal tumor-microenvironment interactions

A comprehensive overview of breast cancer development and progression suggests that the process is influenced by intrinsic properties of the tumor cells, as well as by microenvironmental factors. Indeed, in breast carcinoma, an intensive interplay exists between the tumor cells on one hand, and inflammatory cells/cytokines/chemokines on the other. The purpose of the present review is to outline the reciprocal interactions that exist between these different elements, and to shed light on their potential involvement in breast cancer development and progression.     

The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer

Increasing evidence has shown that chemokines and chemokine receptors are associated with tumor growth and metastasis. CCR4, an important chemokine receptor for regulating immune homeostasis, is thought to be involved in hematologic malignancies and has also recently implicated in some solid tumors, such as gastric cancer. The possible role of CCR4 in breast cancer has not been well elucidated. In this study, we show that CCR4 is differentially expressed in human breast cancer cell lines. Specifically, we find that CCR4 is overexpressed in breast cancer cell lines with high metastatic potential. More importantly, we used a combination of overexpression and RNA interference to demonstrate that CCR4 promotes breast tumor growth and lung metastasis in mice. Furthermore, we find that microvessel density is significantly increased in tumors formed by CCR4-overexpressing cells and decreased in those formed by CCR4-knockdown cells. We find that overexpression of CCR4 can enhance the chemotactic response of breast cancer cells to CCL17. However, the expression of CCR4 does not affect the proliferation of breast cancer cells in vitro. Furthermore, we show that CCR4 expression is positively correlated with HER2 expression, tumor recurrence and lymph node, lung and bone metastasis (P < 0.05). Multivariate analysis showed that CCR4 expression is a significant independent prognostic factor for overall survival (P = 0.036) but not for disease-free survival in patients with breast cancer (P = 0.071). Survival analysis indicated a strong association between CCR4 expression and lower overall survival (P = 0.0001) and disease-free survival (P = 0.016) in breast cancer.     

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。     

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。     

Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response

The chemotactic cytokines called chemokines are a superfamily of small secreted cytokines that were initially characterized through their ability to prompt the migration of leukocytes. Attention has been focused on the chemokine receptors expressed on cancer cells because cancer cell migration and metastasis show similarities to leukocyte trafficking. CXC chemokine receptor 4 (CXCR4) was first investigated as a chemokine receptor that is associated with lung metastasis of breast cancers. Recently, CXCR4 was reported to be a key molecule in the formation of peritoneal carcinomatosis in gastric cancer. In the present review, we highlight current knowledge about the role of CXCR4 in cancer metastases. In contrast to chemokine receptors expressed on cancer cells, little is known about the roles of cancer cell-derived chemokines. Cancer tissue consists of both cancer cells and various stromal cells, and leukocytes that infiltrate into cancer are of particular importance in cancer progression. Although colorectal cancer invasion is regulated by the chemokine CCL9-induced infiltration of immature myeloid cells into cancer, high-level expression of cancer cell-derived chemokine CXCL16 increases infiltrating CD8⁺ and CD4⁺ T cells into cancer tissues, and correlates with a good prognosis. We discuss the conflicting biological effects of cancer cell-derived chemokines on cancer progression, using CCL9 and CXCL16 as examples. ( Cancer Sci 2007; 98: 1652–1658)