单核细胞趋化蛋白-1及其受体与肿瘤侵袭转移的研究进展

摘 要：趋化因子已被证实是肿瘤微环境中的核心调节因子,可募集多种免疫细胞至肿瘤微环境。趋化因子通过在多种类型癌细胞增殖、迁移、侵袭和血管生成中的作用而促进恶性肿瘤的进展。单核细胞趋化蛋白-1（monocyte chemoattractant protein-1,MCP-1/CCL2）是CC类趋化因子家族成员之一。CCL2可与其受体（以CC趋化因子受体2,CCR2为主）结合,通过多种信号传导通路促进恶性肿瘤的侵袭转移。深入研究CCL2/CCR2在恶性肿瘤中的作用机制,可能对恶性肿瘤的靶向治疗具有重大意义。全文就近年来研究较多的乳腺癌、前列腺癌、卵巢癌、结直肠癌等恶性肿瘤侵袭转移中CCL2/CCR2的作用机制进行综述。     

靶向CCL2-CCR2轴的肿瘤治疗研究进展

 单核细胞趋化蛋白-1（MCP-1/CCL2）是CC类趋化因子家族成员之一。CCL2作用广泛，主要结合CC类趋化因子受体2（CCR2）趋化单核细胞、巨噬细胞和T淋巴细胞。许多研究表明CCL2-CCR2轴参与肿瘤细胞生长存活、血管生成、肿瘤侵袭和转移的调控。本文综述了CCL2-CCR2轴在前列腺癌、乳腺癌、肝癌等肿瘤发生、发展、转移的作用和临床前动物模型实验以及靶向CCL2-CCR2轴的肿瘤治疗临床试验的进展、前景和挑战。     

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CCL8与肿瘤发生发展的研究进展

趋化因子CCL8是趋化因子CC家族中的一员，可以在炎症反应和肿瘤免疫等方面发挥重要作用。近来许多研究数据表明，CCL8与人类肿瘤的发生发展密切相关，它在肿瘤微环境中扮演了不可或缺的角色，一方面CCL8可以促进肿瘤细胞的浸润转移，另一方面又可以抑制肿瘤的发生发展。本文主要阐述了目前研究发现的CCL8在肿瘤中的作用，包括肿瘤的发生发展、浸润转移等，以上研究不仅可以帮助我们更加深入的了解肿瘤形成的机制，而且对于寻找更加有效的肿瘤新疗法有着重要的意义。     

趋化因子CCL20与恶性肿瘤之间的关系

趋化因子是一类控制细胞向炎性部位迁移的细胞因子,在调控免疫细胞分化、发育及定向迁移过程中起重要作用。CCL20是趋化因子家族中的重要成员之一,属于CC亚族,其受体为CCR6。CCL20在被激活的单核细胞、T细胞、树突状细胞及内皮细胞中表达;CCR6主要在肝、肺及淋巴组织中表达。CCL20的表达可被肿瘤坏死因子α(tumor necrosis factorα,TNFα)、白细胞介素1β(interleukin1β,IL-1β)、IL-17、CD40配体和干扰素γ(interferonγ,IFN-γ)等细胞因子诱导,在恶性肿瘤的生长及促进肿瘤细胞的侵袭和转移(主要是肝内转移)中发挥重要作用。     

CCL20及其受体CCR6与消化系肿瘤

趋化因子是一种小的结构相关的趋化性细胞因子,不仅在炎症反应中起重要作用,而且与肿瘤的发生发展有关。趋化因子CCL20是趋化因子CC家族中的一员,趋化因子受体CCR6是目前发现的CCL20唯一受体。近年,越来越多研究表明,趋化因子CCL20及其受体CCR6与消化系肿瘤密切相关。然而,人们对CCL20及其受体CCR6在消化系肿瘤的作用机制尚未完全认识。本文就趋化因子CCL20及其受体CCR6在消化系肿瘤研究中的进展进行综述,以期更好地理解两者之间的关系,并为CCL20及其受体CCR6成为消化系肿瘤治疗靶点的可能性提供依据。     

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.     

肿瘤相关巨噬细胞与乳腺癌关系的研究进展

乳腺癌生长依赖肿瘤微环境,肿瘤相关巨噬细胞（TAMs）是其微环境中的一种重要炎症细胞。目前认为,大部分TAMs通过分泌多种趋化因子和细胞因子促进乳腺癌相关的血管生成、侵袭、浸润和转移,还可以降低放、化疗的敏感性。临床普遍应用CD68来识别活检组织中的TAMs,其他一些TAMs相关的标志物（包括CD163、血管内皮生长因子、缺氧诱导因子、增殖细胞核抗原等）也具有一定的实用性。临床证据表明TAMs大量浸润的乳腺癌预后不良。在本文中,我们综述了TAMs与乳腺癌关系的最新进展,TAMs可作为乳腺癌潜在的预后指标和治疗靶点,抗TAMs治疗为改善乳腺癌预后提供了新思路。     

癌相关成纤维细胞促进肿瘤进展机制的研究

肿瘤的发生发展过程与肿瘤微环境密切相关。癌相关成纤维细胞（carcinoma-associated fibroblasts,CAF）是肿瘤微环境中最丰富的细胞成分,并且具有来源、表型和功能异质性，它主要通过产生和分泌各种趋化因子以及促进上皮间充质转化从而在肿瘤的发生、血管生成、耐药性、侵袭和转移中发挥重要作用。近年来许多研究证实CAF在促进肿瘤进展中起重要作用，但其作用机制尚未明确。本文就CAF促进肿瘤进展的潜在机制进行概述，以期发现新的治疗靶点，为肿瘤的诊治提供新的思路。     

趋化因子及受体在肝癌侵袭转移中的研究进展

近年来趋化因子及其受体领域已经受到广泛关注。它们是一个促炎多肽细胞因子的超家族,具有众多成员。趋化因子及其相应的受体在多种生理和病理过程中发挥着重要作用。研究表明,它们与肿瘤的血管生成、发生发展、侵袭转移及治疗预后都有着密切关系。文章就趋化因子及其受体在肝癌侵袭转移中的机制及其研究进展作一综述。     

RKIP regulates CCL5 expression to inhibit breast cancer invasion and metastasis by controlling macrophage infiltration

Accumulating evidence suggests that presence of macrophages in the tumor microenvironment add to the invasive and tumor-promoting hallmarks of cancer cells by secreting angiogenic and growth factors. RKIP is a known metastasis suppressor and interferes with several steps of metastasis. However, the mechanistic underpinnings of its function as a broad metastasis suppressor remain poorly understood. Here, we establish a novel pathway for RKIP regulation of metastasis inhibition through the negative regulation of RANTES/CCL5 thereby limiting tumor macrophage infiltration and inhibition of angiogenesis. Using a combination of loss- and gain-of-function approaches, we show that RKIP hinders breast cancer cell invasion by inhibiting expression of the CC chemokine CCL5 in vitro. We also show that the expression levels of RKIP and CCL5 are inversely correlated among clinical human breast cancer samples. Using a mouse allograft breast cancer transplantation model, we highlight that ectopic expression of RKIP significantly decreases tumor vasculature, macrophage infiltration and lung metastases. Mechanistically, we demonstrate that the inhibition of the CCL5 expression is the cause of the observed effects resulting from RKIP expression. Taken together, our results underscore the significance of RKIP as important negative regulator of tumor microenvironment.     

Role of chemokines in tumor growth

Chemokines play a paramount role in the tumor progression. Chronic inflammation promotes tumor formation. Both tumor cells and stromal cells elaborate chemokines and cytokines. These act either by autocrine or paracrine mechanisms to sustain tumor cell growth, induce angiogenesis and facilitate evasion of immune surveillance through immunoediting. The chemokine receptor CXCR2 and its ligands promote tumor angiogenesis and leukocyte infiltration into the tumor microenvironment. In harsh acidic and hypoxic microenvironmental conditions tumor cells up-regulate their expression of CXCR4, which equips them to migrate up a gradient of CXCL12 elaborated by carcinoma-associated fibroblasts (CAFs) to a normoxic microenvironment. The CXCL12-CXCR4 axis facilitates metastasis to distant organs and the CCL21-CCR7 chemokine ligand-receptor pair favors metastasis to lymph nodes. These two chemokine ligand-receptor systems are common key mediators of tumor cell metastasis for several malignancies and as such provide key targets for chemotherapy. In this paper, the role of specific chemokines/chemokine receptor interactions in tumor progression, growth and metastasis and the role of chemokine/chemokine receptor interactions in the stromal compartment as related to angiogenesis, metastasis, and immune response to the tumor are reviewed.     

SI-CLP inhibits the growth of mouse mammary adenocarcinoma by preventing recruitment of tumor-associated macrophages

Chitinase-like proteins (CLP) are chitin-binding proteins that lack chitin hydrolyzing activity, but possess cytokine-like and growth factor-like properties, and play crucial role in intercellular crosstalk. Both human and mice express two members of CLP family: YKL-40 and stabilin-1 interacting chitinase-like protein (SI-CLP). Despite numerous reports indicating the role of YKL-40 in the support of angiogenesis, tumor cell proliferation, invasion and metastasis, the role of its structurally related protein SI-CLP in cancer was not reported. Using gain-of-function approach, we demonstrate in the current study that the expression of recombinant SI-CLP in mouse TS/A mammary adenocarcinoma cells results in significant and persistent inhibition of in vivo tumor growth. Using quantitative immunohistochemistry, we show that on the cellular level this phenomenon is associated with reduced infiltration of tumor-associated macrophages (TAMs), CD4+ and FoxP3+ cells in SI-CLP expressing tumors. Gene expression analysis in TAM isolated from SI-CLP-expressing and control tumors demonstrated that SI-CLP does not affect macrophage phenotype. However, SI-CLP significantly inhibited migration of murine bone-marrow derived macrophages and human primary monocytes toward monocyte-recruiting chemokine CCL2 produced in the tumor microenvironment (TME). Mechanistically, SI-CLP did not affect CCL2/CCR2 interaction, but suppressed cytoskeletal rearrangements in response to CCL2. Altogether, our data indicate that SI-CLP functions as a tumor growth inhibitor in mouse breast cancer by altering cellular composition of TME and blocking cytokine-induced TAM recruitment. Taking into consideration weak to absent expression of SI-CLP in human breast cancer, it can be considered as a therapeutic protein to block TAM-mediated support of breast tumor growth.     

趋化因子CCL28在乳腺癌中的表达及意义

背景与目的：目前已知趋化因子在乳腺癌的发生、发展中扮演着重要的角色,但对CCL28在乳腺癌的功能报道较少,本研究旨在探讨趋化因子CCL28在人乳腺癌中的表达情况,并分析其与乳腺癌相关临床病理指标之间的关系。方法：采用免疫组织化学方法检测趋化因子CCL28在150例乳腺癌、相应癌旁正常乳腺组织的表达差异情况;分析乳腺癌中CCL28表达与患者年龄、临床分期、肿瘤直径、淋巴结转移状况、雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)、人表皮生长因子受体-2(humanepidermal growth factor receptor-2,HER-2)等临床病理指标的相关性。结果：①CCL28在乳腺癌组及癌旁正常乳腺组中均有表达,在乳腺癌组中CCL28的阳性表达率为54.6%,在癌旁正常乳腺组中的阳性表达率为9.3%;CCL28在乳腺癌组的表达明显高于癌旁正常乳腺组,差异有统计学意义(P＜0.001)。②CCL28的表达与患者的年龄、肿瘤直径、临床分期、淋巴结转移与否、ER、PR及HER-2的表达等临床病理指标无关(P＞0.05)。结论：CCL28在乳腺癌中呈现高表达而在癌旁正常乳腺组织则表达较少,CCL28可能与乳腺癌发生、发展有关。CCL28在乳腺癌中表达的高低与发生淋巴结转移无明显的相关性,CCL28能否作为预测淋巴结转移的指标有待于进一步的研究。     

CXCR2在肿瘤进展中的作用

CXCR2与人体免疫关系密切,多项研究表明CXCR2及其配体在结肠癌、乳腺癌、肝癌、肾细胞癌、黑色素瘤、胰腺癌、卵巢癌等多种肿瘤细胞中呈高表达,在促进肿瘤生长、转移、血管生成等肿瘤进展过程中发挥重要作用。CXCR2在多种肿瘤的诊断以及预后的判断上具有重要价值。包括CXCR2拮抗剂SB225002在内的多种趋化因子拮抗剂在多项研究中都表现出了抑制血管生成及抑制肿瘤细胞生长、转移等作用。文章对CXCR2及其配体在肿瘤进展中的作用进行综述,为肿瘤的靶向治疗提供新的思路。     

Stat3 orchestrates interaction between endothelial and tumor cells and inhibition of Stat3 suppresses brain metastasis of breast cancer cells

Brain metastasis is a major cause of morbidity and mortality in patients with breast cancer. Our previous studies indicated that Stat3 plays an important role in brain metastasis. Here, we present evidence that Stat3 functions at the level of the microenvironment of brain metastases. Stat3 controlled constitutive and inducible VEGFR2 expression in tumor-associated brain endothelial cells. Furthermore, inhibition of Stat3 by WP1066 decreased the incidence of brain metastases and increased survival in a preclinical model of breast cancer brain metastasis. WP1066 inhibited Stat3 activation in tumor-associated endothelial cells, reducing their infiltration and angiogenesis. WP1066 also inhibited breast cancer cell invasion. Our results indicate that WP1066 can inhibit tumor angiogenesis and brain metastasis mediated by Stat3 in endothelial and tumor cells.