肿瘤相关巨噬细胞与结肠肿瘤微环境关系的研究进展

摘 要：肿瘤微环境（tumor microenvironment,TME）是肿瘤细胞与人体免疫系统相互作用的首要场所,包含肿瘤细胞、免疫细胞、间质细胞及其分泌的活性因子等,深深地影响着肿瘤的产生、发展和转移。巨噬细胞是非常可塑的细胞,TME中的巨噬细胞被称为肿瘤相关巨噬细胞（tumor-associated macrophages,TAMs）,在结肠癌发生发展的不同阶段,对TME的刺激能表达不同的功能。近年来TAMs在TME中的作用也得到了更多的关注。因此了解TAMs与结肠癌TME的关系,对深入研究TAMs在结肠肿瘤中的作用具有重要意义。全文对TAMs与结肠癌TME的关系进行综述,以期为深入探究TAMs在结肠癌中的作用提供新的线索。     

肿瘤相关巨噬细胞的研究进展

既往多认为,巨噬细胞是抗肿瘤免疫调节过程中的一种重要细胞群,可以直接杀伤肿瘤细胞,或者通过呈递肿瘤相关抗原诱导机体免疫应答从而清除肿瘤。但是近年来逐渐认识到,肿瘤间质中的巨噬细胞即肿瘤相关巨噬细胞(tumor-associated macrophages,TAM)并非发挥抗肿瘤作用,而是参与了肿瘤发生、生长、侵袭和转移的过程,尤其是与肿瘤血管生成和淋巴管生成密切相关。因此,研究TAM在肿瘤进程中的功能状态和动态变化具有重要意义,TAM有望成为肿瘤治疗的新靶点。1TAM的来源自从Rudolf Virchow首次发现肿瘤组织中有大量炎症细胞浸润后,有学者由此…     

结肠癌中肿瘤相关巨噬细胞与肿瘤浸润转移的关系

[目的]了解结肠癌组织中肿瘤相关巨噬细胞的浸润情况,探讨其与结肠癌侵袭转移的相关性。[方法]采用免疫组化染色的方法,对69例结肠癌标本中巨噬细胞的浸润情况进行检测,同时行巨噬细胞、淋巴管计数,并对巨噬细胞数量与临床病理参数之间的关系进行统计分析。[结果]结肠癌组织中有大量的肿瘤相关巨噬细胞浸润。结肠癌巨噬细胞计数与Duke’s分期有相关性(P=0.023),分期偏晚者巨噬细胞计数高于分期偏早者。巨噬细胞计数在年龄、性别、肿瘤分化程度等方面不存在差异(P>0.05)。巨噬细胞数量也与淋巴管数量相关(r=0.432,P<0.01)。[结论]结肠癌肿瘤组织中肿瘤相关巨噬细胞与淋巴管生成及肿瘤的侵袭转移有关。     

肿瘤相关巨噬细胞的研究进展

在多种恶性肿瘤中,巨噬细胞是浸润到肿瘤中的主要白细胞,被称为肿瘤相关巨噬细胞( tumor-associated macrophage,TAM).TAM主要来源于血液循环中的单核细胞,属于一类倾向M2型的、分化并不完全的巨噬细胞,具有高度的可塑性.在不同肿瘤,甚至在同一类肿瘤的不同部位、不同生长阶段,TAM膜分子及细胞...     

肿瘤相关巨噬细胞在膀胱癌中的研究进展

肿瘤相关巨噬细胞广泛存在于各种肿瘤微环境中,也是肿瘤微环境中较为丰富的免疫细胞之一,其在各种肿瘤的进展中起着重要的作用.膀胱癌是较为常见的实体肿瘤,已有大量文献报道肿瘤相关巨噬细胞与膀胱癌的发生?发展具有密切的联系.本文将总结以往研究成果从肿瘤相关巨噬细胞的极化以及肿瘤相关巨噬细胞促进膀胱癌的生长?侵袭和转移等多个方面...     

肿瘤相关巨噬细胞在肺癌中的研究进展

肺癌是全球发病率和死亡率最高的恶性肿瘤之一.因此对于肺癌治疗手段的研究也在不断深入,目前临床上主要有全身化疗、针对驱动基因阳性的靶向治疗、免疫检查点抑制剂的应用、抗肿瘤血管生成治疗以及上述不同治疗方法的联合等,这些方案的使用明显改善了大多数肺癌患者的预后,但晚期患者预后仍然不尽如人意.近年来,与免疫相关的肿瘤微环境(t...     

肿瘤相关巨噬细胞的极化与肿瘤的发展

肿瘤相关巨噬细胞（TAM）在肿瘤微环境中扮演重要角色,它包含了两种可以相互极化的亚型:M1型(经典活化巨噬细胞)和M2型（替代活化巨噬细胞）。M1型TAM发挥着抑制肿瘤生长的作用,而M2型TAM对肿瘤的发生发展起促进支持作用。在特定的肿瘤微环境中,M2型TAM占据主导地位,促进肿瘤的发展。基于肿瘤相关巨噬细胞两种亚型的功能特点,如何诱导M2型向M1型极化是目前的研究热点,也将是肿瘤治疗的一个重要靶点。     

肿瘤相关巨噬细胞对肿瘤新生血管生成的作用及其机制的研究进展

肿瘤相关巨噬细胞(TAM)在恶性肿瘤的发生、发展以及血管生成中发挥着重要作用.TAM被认为是肿瘤微环境(TME)的主要成分,具有促进肿瘤生长、侵袭、转移和肿瘤新生血管生成的作用.肿瘤基质中TAM的浸润水平、极化状态与患者预后密切相关,是肿瘤免疫治疗的潜在靶点.此外,肿瘤的生长依赖肿瘤新生血管生成,了解TAM在血管生成中...     

肿瘤相关巨噬细胞在鼻咽癌中的研究进展

肿瘤相关巨噬细胞(tumor-associated?macrophages,?TAMs)是肿瘤微环境中重要的免疫细胞,主要分为两种类型,即经典活化的M1型巨噬细胞和替代性活化的M2型巨噬细胞.TAMs在许多肿瘤组织中发挥M2型作用,即促进肿瘤的增殖、血管生成,诱导肿瘤细胞侵袭和转移,目前有关肿瘤相关巨噬细胞与肿瘤细胞之...     

肿瘤相关巨噬细胞研究进展

巨噬细胞起源于骨髓造血干细胞和胚胎时期卵黄囊组织,根据其活化的状态、发挥的功能以及分泌因子的不同,将其分为经典活化的M1型巨噬细胞和选择性活化的M2型巨噬细胞。它们具有很强的可塑性,当局部微环境改变时,M1和M2之间可以发生相互转化。其中极化的M2型巨噬细胞被认为是肿瘤相关巨噬细胞(TAM),在肿瘤发生发展中起到重要作用,它通常由血液中单核祖细胞趋化至肿瘤组织,然后在肿瘤微环境的作用下诱导产生。而转录因子、细胞表面标记、分泌的细胞因子等标志物常被用来对其进行鉴定。近年来,TAM作为肿瘤研究中的热点,已经被证明在促进肿瘤生长、血管生成、肿瘤侵袭、抑制抗肿瘤免疫反应、耐药/耐放疗中发挥重要作用。     

自噬介导的肿瘤相关巨噬细胞调控机制的研究进展

肿瘤细胞及各种基质细胞、免疫细胞、细胞因子等构成了复杂的肿瘤微环境。其中,肿瘤相关巨噬细胞(TAMs)是最重要的基质细胞之一,积极参与肿瘤生长、浸润、转移过程。自噬活动不仅在细胞应激反应和维护内环境稳定中起关键作用,还与肿瘤关系密切,涉及肿瘤微环境中TAMs前体细胞的生成及募集、前体细胞向TAMs极化的重要调节步骤。研究自噬介导的TAMs调控机制有利于更全面的认识肿瘤微环境中复杂的调控网络系统,并可能打开肿瘤治疗的新局面。     

The role of tumor-associated macrophages in gastric cancer development and their potential as a therapeutic target

Gastric cancer (GC) represents the fifth cause of cancer-related death worldwide. Molecular biology has become a central area of research in GC and there are currently at least three major classifications available to elucidate the mechanisms that drive GC oncogenesis. Further, tumor microenvironment seems to play a crucial role, and tumor-associated macrophages (TAMs) are emerging as key players in GC development. TAMs are cells derived from circulating chemokine- receptor-type 2 (CCR2) inflammatory monocytes in blood and can be divided into two main types, M1 and M2 TAMs. M2 TAMs play an important role in tumor progression, promoting a pro-angiogenic and immunosuppressive signal in the tumor. The diffuse GC subtype, in particular, seems to be strongly characterized by an immuno-suppressive and pro-angiogenic phenotype. No molecular targets in this subgroup have yet been identified. There is an urgent need to understand the molecular pathways and tumor microenvironment features in the GC molecular subtypes. The role of anti-angiogenics and checkpoint inhibitors has recently been clinically validated in GC. Both ramucirumab, a fully humanized IgG1 monoclonal anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody, and checkpoint inhibitors in Epstein Bar Virus (EBV) and Microsatellite Instable (MSI) subtypes, have proved beneficial in advanced GC. Nevertheless, there is a need to identify predictive markers of response to anti-angiogenics and immunotherapy in clinical practice for a personalized treatment approach. The importance of M2 TAMs in development of solid tumors is currently gaining increasing interest. In this literature review we analyze immune microenvironment composition and signaling related to M1 and M2 TAMs in GC as well as its potential role as a therapeutic target.     

The role of autocrine motility factor in tumor and tumor microenvironment

Autocrine motility factor (AMF) is a tumor-secreted cytokine and is abundant at tumor sites, where it may affect the process of tumor growth and metastasis. AMF is a multifunctional protein capable of affecting cell migration, invasion, proliferation, and survival, and possesses phosphoglucose isomerase activity and can catalyze the step in glycolysis and gluconeogenesis. Here, we review the role of AMF and tumor environment on malignant processes. The outcome of metastasis depends on multiple interactions between tumor cells and homeostatic mechanisms, therefore elucidation of the tumor/host interactions in the tumor microenvironment is essential in the development of new prevention and treatment strategies. Such knowledge might provide clues to develop new future therapeutic approaches for human cancers.     

肿瘤相关巨噬细胞在肿瘤微环境中的作用新进展

众所周知,在肿瘤发生发展的各个阶段都有单核细胞通过血管壁进入肿瘤组织,这些单核细胞可分化形成具有独特表型的巨噬细胞,即肿瘤相关巨噬细胞（tumor-associated macrophages,TAMs）。TAMs是肿瘤微环境的重要组成部分,参与了肿瘤的发生、生长、侵袭及转移过程,其中,向肿瘤组织的转移是肿瘤恶性发展的关键步骤。本文将TAMs在肿瘤微环境形成中发挥作用的最新进展进行了总结,特别值得注意的是,细胞及动物实验研究表明,TAMs可为肿瘤的发生发展进程提供一个有利的微环境;同时,临床病理实验表明,TAMs在肿瘤内的累积与较差的临床疗效相关。最后,本文讨论了靶向TAMs的治疗手段作为一种间接癌症治疗新方法的可行性。     

Mesenchymal stem cell signaling in cancer progression

Mesenchymal (multipotent) stem/stromal cells (MSCs) may affect cancer progression through a number of secreted factors triggering activation of various cell signaling pathways. Depending on receptor status, phosphatase and tensin homolog (PTEN) status, or Wnt activation in the cancer cells, the signals may either result in increased growth and metastasis or lead to inhibition of growth with increased cell death. Thus, MSCs can play a dual role in cancer progression depending on the cellular context wherein they reside. The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway has a central role in regulating tumor growth, and several MSC secreted factors stimulate activation of this pathway. A comprehensive understanding of the signals regulating MSC–tumor cross-talk is highly important for the development of MSCs as potential therapeutic vehicles. Thus, the presented review focuses on factors released by MSCs and on the dual role they may have on various stages of tumorigenesis.     

Cancer stem cells and tumor angiogenesis

Cancer stem cells (CSCs) have been identified in several human solid and hematological tumors. They are able to initiate tumor formation and metastasis and express specific cell surface markers. CSC tend to be more resistant to chemotherapeutic agents and radiation therapy than more mature cell types from the same tissue because of increased expression of antiapoptotic proteins. In this context, the development of agents that eliminate or control CSC may be an effective strategy for cancer prevention.     

贲门癌中肿瘤相关巨噬细胞浸润及其对预后的影响

目的:探讨贲门癌组织中肿瘤相关巨噬细胞（TAM）与肿瘤侵袭、转移及预后的相关性。方法:收集2014年1月至2015年1月于莆田市第一医院行D2根治术的100例贲门癌患者癌组织及癌旁组织,以CD163标记M2型TAM。制作组织芯片,采用免疫组织化学法检测组织芯片中CD163的表达情况。以所有癌组织CD163阳性细胞计数的...     

The interaction between cancer associated fibroblasts and tumor associated macrophages via the osteopontin pathway in the tumor microenvironment of hepatocellular carcinoma

Background: Cancer-tumor associated macrophage (TAM)-cancer associated fibroblast (CAF) interactions are an important factor in the tumor microenvironment of hepatocellular carcinoma.Materials and Methods: Hepatic stellate cells (HSCs) were cultured with cancer cell-conditioned medium (Ca.-CM), TAM-CM and CAF-CM, and the expression of CAF markers were evaluated by RT-PCR. Whether HSCs cultured with Ca.-CM, TAM-CM and CAF-CM contributed to the enhanced malignancy of cancer cells was examined using proliferation, invasion and migration assays. Furthermore, the differences between these three types of CM were evaluated using cytokine arrays.Results: HSCs cultured with Ca.-CM, TAM-CM and CAF-CM showed significantly increased mRNA expression of αSMA, FAP and IL-6. All HSCs cultured with each CM exhibited significantly increased proliferation, invasion and migration of cancer cells. The osteopontin concentration was significantly higher in HSCs cultured with TAM-CM than the other CAF-CMs. Osteopontin inhibition significantly reduced osteopontin secretion from HSCs cultured with TAM-CM and suppressed the proliferation and invasion of cancer cells enhanced by HSCs cultured with TAM-CM.Conclusions: We observed enhanced osteopontin secretion from TAMs, and this increased osteopontin further promoted osteopontin secretion from HSCs cultured with TAM-CM, leading to increased malignancy. For the first time, we demonstrated the importance of cancer-TAM-CAF interactions via osteopontin in hepatocellular carcinoma.     

Tumor-associated macrophages provide a suitable microenvironment for non-small lung cancer invasion and progression

Objective

It remains largely unknown whether tumor-associated macrophages (TAMs) are involved in invasion and metastasis of human lung cancer. The aim of our study was to obtain an accurate overview of the broad range of changes occurring in monocytes that develop into TAMs, and the roles of TAMs during the progression of non-small cell lung cancer.

Methods

TAM was isolated from 98 primary lung cancer tissues by short term cultivation in serum-free medium. The mRNA expression levels of 9 genes, including EGF, Cathepsin K, Cathepsin S, COX-2, MMP-9, PDGF, uPA, VEGFA, HGF, were evaluated by real-time PCR in 98 NSCLC. The relationships between those gene expression levels and clinicopathological features were investigated. The effects of conditioned medium from TAMs on the invasive properties of different lung cancer cell lines were measured using Transwell chambers.

Results

We successfully achieved up to 95% purity of TAM, derived from 98 primary lung cancer tissues. TAM expressed high levels of Cathepsin K, COX-2, MMP-9, PDGF-B, uPA, VEGFA, and HGF. Phenotypic expression on TAMs, like MMP9, was shown to be correlated with disease progression by analyzing lung cancer tissues. Conditioned medium from TAM significantly increased cell migration and invasion in SPC-A1 cells, H460 cells and A549 cells. Anti-uPA and anti-MMP-9, but not anti-VEGF monoclonal antibodies, can inhibit TAM-induced invasion. The increase of invasiveness in the lung cancer cell lines was also correlated with their gelatinase activity, through MMP9.

Conclusions

Short-term culture in serum free medium is an effective way to isolate TAM in NSCLC. The results of this study also demonstrated that those up-regulated genes in TAMs contributed to suitable microenvironments for lung cancer invasion and metastasis. These findings may be useful in developing novel therapeutic strategies to prevent lung cancer progression.