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。     

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。     

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。     

趋化因子与肿瘤

趋化因子在不同肿瘤生长、转移或者抑制过程中有其相应的表达方式,未来可能成为诊断肿瘤重要的标准和预后标志,应用趋化因子对肿瘤的临床评估尤其重要.通过对趋化因子在不同肿瘤中表达类型的研究,可以更深入地了解肿瘤在微观领域的动态,而将之与临床结合,有助于对特定肿瘤采取恰当的治疗方法和治疗手段.     

趋化因子CCL18与肿瘤

趋化因子CCL18通过招募炎症细胞参与机体的免疫和炎症过程,发挥免疫调控作用.在肿瘤患者血清及某些肿瘤组织中CCL18蛋白表达明显增加.然而CCL18在肿瘤中是发挥促癌作用还是抑癌作用尚存在争议.研究CCL18的作用及作用机制能够为肿瘤诊治提供新的靶向目标.     

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…     

趋化因子与肿瘤和炎症

趋化因子是指一组相对分子质量为8×104￣12×104,至少存在2个保守的Cys,能使白细胞向炎症部位迁移的因子,可调节白细胞的功能和运动方向,不仅在免疫系统的反应中起重要作用,而且参与调节T,B淋巴细胞的发育和血管新生。趋化因子与炎症和肿瘤密切相关。现已开发各种新型治疗分子,包括趋化因子及其衍生物、受体拮抗剂、受体的阻断抗体以及与受体有关的低分子量复合物,用于多种疾病的治疗。     

The tumor microenvironment

The concept of the tumor microenvironment, developed from Paget's "seed and soil" theory is made up of the cancer cells, the stromal tissue, and the extracellular matrix. In this mini-review, each of the components of this dynamic network will be examined. We will show that there are a multitude of complex interactions and a host of molecules involved in tumorogenesis and metastasis. We will further illustrate this notion with examples from the tumor microenvironment of breast cancer. Lastly, we conclude with thoughts about how this will influence the surgical field with examples of therapeutic agents already in use that target aspects of this microenvironment.     

Role of the tumor immune microenvironment in tumor immunotherapy

Tumor immunotherapy is considered to be a novel and promising therapy for tumors and it has recently become a hot research topic. The clinical success of tumor immunotherapy has been notable, but it has been less than totally satisfactory because tumor immunotherapy has performed poorly in numerous patients although it has shown appreciable efficacy in some patients. A minority of patients demonstrate durable responses but the majority of patients do not respond to tumor immunotherapy as the tumor immune microenvironment is different in different patients for different tumor types. The success of tumor immunotherapy may be affected by the heterogeneity of the tumor immune microenvironment and its components, as these vary widely during neoplastic progression. The deepening of research and the development of technology have improved our understanding of the complexity and heterogeneity of the tumor immune microenvironment and its components, and their effects on response to tumor immunotherapy. Therefore, investigating the tumor immune microenvironment and its components and elucidating their association with tumor immunotherapy should improve the ability to study, predict and guide immunotherapeutic responsiveness, and uncover new therapeutic targets.     

Melanoma and the tumor microenvironment

Melanoma arises through the accrual of mutations in genes critical for proliferation and survival. Although melanoma had been traditionally conceptualized as a cell-autonomous event, increasing evidence supports the notion that these tumors are not isolated entities but rather depend, interact with, and react to the adjacent microenvironment. Melanoma is composed of not only the malignant cells but also the supporting stroma, which includes fibroblasts, endothelial cells, immune cells, soluble molecules, and the extracellular matrix (ECM). Tumor cells actively interact with the microenvironment in a bidirectional manner through molecular signals that modulate the malignant phenotype. This article briefly reviews the molecular basis of melanomagenesis as well as the interplay of melanoma with other cells of the tumor microenvironment and components of the ECM. It also discusses the influence of the microenvironment on therapeutic targeting of melanoma, highlighting recent studies that propose novel strategies to target tumor-microenvironment interactions.     

Epigenetic changes in tumor microenvironment

The drama of cancer is not the solo performance of the malignant cells. Microenvironment of the tumor has significant contribution in carcinogenesis. Recent evidences show distinct gene promoter methylation in stromal cells of various malignant and pre-malignant tumors. These changes probably create unique tumor microenvironment, which is responsible for initiation, proliferation, invasion, and metastasis of tumor cells. In this mini review the role of epigenetic changes of tumor microenvironment in carcinogenesis has been discussed.     

趋化因子与肿瘤的定向转移

肿瘤转移预后不良,其形成涉及许多病理机制.近来研究表明,肿瘤细胞表达特定的趋化因子受体,而其转移好发部位高表达相应的配体,后者对肿瘤细胞有化学趋向性,由此形成了肿瘤细胞定向转移的"归巢"理论.这一理论提示,通过干预受体与配体间的相互作用,可能成为抗肿瘤转移治疗的新途径.     

T cells in tumor microenvironment

Tumors progress in a specific area, which supports its development, spreading or shrinking in time with the presence of different factors that effect the fate of the cancer cells. This specialized site is called “tumor microenvironment” and has a composition of heterogenous materials. The immune cells are also residents of this stromal, cancerous, and inflammatory environment, and their types, densities, or functional differences are one of the key factors that mediate the fate of a tumor. T cells as a vital part of the immune system also are a component of tumor microenvironment, and their roles have been elucidated in many studies. In this review, we focused on the immune system components by focusing on T cells and detailed T helper cell subsets in tumor microenvironment and how their behaviors affect either the tumor or the patient’s outcome.     

肿瘤微环境中的起始细胞

探索肿瘤发生的起始阶段是理解肿瘤生物学的关键,肿瘤起始细胞(cells of origin)的研究已显示出这个领域的进步。现综述肿瘤前期细胞(progenitor cells)、祖细胞(progenitorcells)、癌前干细胞(pre-cancerous stem cells,pCSCs)和肿瘤干细胞(cancer stem cells,CSCs)等肿瘤起始细胞研究的新进展,讨论微环境对肿瘤起始细胞研究的影响。     

Visualizing movement in the tumor microenvironment landscape

The local microenvironment influences tumor progression in several important ways. A recent study by Nguyen-Ngoc and colleagues used explants of primary human and mouse mammary tumors to examine how the composition of the extracellular matrix modulates tumor cell invasion. Culture in the presence of a three-dimensional laminin-rich basement membrane, similar to the mammary basement membrane in vivo, resulted in minimal invasion. In contrast, identical tumor fragments in a collagen I matrix which resembles the interstitial breast stroma exhibited a pronounced protrusive migration and local dissemination. These data emphasize the importance of the laminin-rich basement membrane in constraining tumor cell invasion.The transition from carcinoma in situ to invasive disease is a pivotal event in the natural history of breast cancer and has a pronounced effect on the prognosis of the patient with cancer. Of particular significance is the efficiency with which the invasive tumor cells disseminate locally and to distant sites. It has become clear that, though indisputably important, the accumulation of mutations in key genes is necessary but not sufficient for full expression of the malignant phenotype. The influence of collaborating microenvironmental factors on this transition is an area of intense investigation. A considerable body of work has illuminated the role of the tumor-associated macrophage in eliciting invasive behavior [1]. Less studied has been the impact of the precise composition of the local tissue extracellular matrix on modulating breast cancer cell motility and dissemination. The basement membrane of non-malignant mammary epithelium is a thin layer of extracellular matrix composed primarily of laminins, collagen IV, nidogen, entactin, and proteoglycans [2], whereas the interstitial matrix beyond the mammary ducts is composed of collagen I. The basement membrane acts as a barrier to local tissue invasion but, once this barrier is breached, does the surrounding microenvironment simply provide a passive landscape through which the neoplastic cells can rampage, or do factors intrinsic to this microenvironment actively promote the invasive migratory behavior of these cells?Using time-lapse microscopy, Nguyen-Ngoc, Ewald, and colleagues [3] recently examined the impact of local extracellular matrix composition on regulating protrusive migration and cell dissemination. Epithelial fragments from either primary human or mouse mammary carcinomas cultured in a reconstituted basement membrane matrix (Matrigel) either were indolent or only occasionally exhibited a multilayered collective migration. In contrast, fragments explanted into collagen I gels showed extensive protrusive migration and cell dissemination. Dissemination was primarily mesenchymal, although amoeboid migration was also frequently observed. Collective dissemination of groups of cells was seen in a minority of cases. Isolation of organoids from one substrate and regrowth on the reciprocal matrix indicated that these changes in invasion mode are reversible. The inability of the malignant cells in collagen gels to deposit a laminin basement membrane, reminiscent of a much earlier study [4], was a major distinguishing feature between malignant and normal cells in this assay. Surprisingly, attempts to define matrix-dependent gene expression profiles by microarray analysis revealed minimal differences between Matrigel- and collagen I-cultured tumor fragments, suggesting that key mRNA differences may be restricted to a minority of cells or that the important alterations are post-translational.Several questions arise from this interesting study. Although a small number of primary human tumor specimens were used, the bulk of the analysis was performed with tumor explants from MMTV-PyMT mice, and MMTV-PyMT is an oncogene that does not have a straightforward parallel in human breast cancer. It would be interesting to expand this approach to additional models to determine the extent to which these findings can be generalized. Previous work from the Pearson laboratory [5] has indicated that fibroblast-dependent remodeling of collagen is key to inducing invasion in mixed cultures of Matrigel/collagen I and that basal, but not luminal, breast cancer cell lines preferentially invade under those conditions. In the clinic, cases of invasive breast cancer are frequently observed without lymph node metastasis. Almost all of the human tumors tested in this study were from node-positive patients and thus had already demonstrated a strong capacity for invasive migration in the original patient. Performing similar experiments with tumor explants from node-negative patients would help determine whether the migratory activity of both node-negative and -positive tumors is similarly influenced by the local extracellular matrix environment.A significant strength of this study is the extensive body of time-lapse imaging following the behavior of the explants for several days, and this allowed the quantification of disseminating cells and the analysis of their modes of invasion. It is striking how rare the disseminating cells are (only 612 disseminating cells from PyMT tumor fragments were observed in a total of 48 multi-day movies). This is consistent with an intravital imaging study of MMTV-PyMT tumors, which showed that motile cells comprise a very small proportion of the tumor bulk [6]. Given the relative rarity of migratory cells, it is perhaps not surprising that gene expression profiling of the bulk tumor fragments did not reveal a substantial number of differentially expressed genes between the two matrix environments. This issue high-lights the value of selectively isolating and profiling the invasive tumor cells, an approach recently reported in vivo by Patsialou and colleagues [7]. The nature of the mechanisms conferring a highly motile phenotype on some tumor cells while their neighbors remain indolent is another important question that remains to be resolved.Finally, the use of three-dimensional extracellular matrix culture models - usually laminin-rich matrices like Matrigel - for mammary gland biology and breast cancer research has undergone a rapid expansion over the past decade [8-10]. A provocative question raised by this study is whether our experimental approaches to study invasive breast cancer cells might more appropriately be directed toward three-dimensional collagen I cultures.