子宫内膜癌肿瘤微环境的研究进展

肿瘤微环境是决定肿瘤细胞发生发展的主要影响因素,由肿瘤细胞、基质细胞、细胞外基质共同构成的肿瘤局部的病理微环境。成纤维细胞、血管内皮细胞及免疫炎症细胞等称为基质细胞,在肿瘤进展过程中,基质细胞可通过自分泌、旁分泌的方式分泌多种可溶性因子,与微环境中肿瘤细胞及其他基质细胞相互作用,促进肿瘤细胞的发生、发展、浸润和转移。本文就肿瘤微环境中相关基质细胞与子宫内膜癌恶性行为的关系做一综述。     

模式识别受体与肿瘤微环境研究进展

肿瘤微环境的组成与肿瘤发生发展的关系备受瞩目,免疫系统参与肿瘤微环境形成并在其中发挥重要作用,天然免疫细胞对肿瘤的免疫监视以及免疫耐受的形成具有双向功能。模式识别受体(pattern recognition receptors,PRRs)是天然免疫细胞识别病毒、细菌等病原体以启动免疫与炎症过程的受体,在肿瘤免疫中也发挥双向的调控功能,其既能维持宿主寄生菌群平衡、清除死亡或突变细胞以抑制肿瘤发生,又能诱导慢性炎症、形成炎性微环境以促进肿瘤发生;既能识别危险信号启动天然免疫杀伤及后续的获得性免疫应答以抑制肿瘤进程,又能识别肿瘤释放的内源性配体以促进抑制性细胞亚群和细胞因子的产生,进而诱导肿瘤的免疫耐受与免疫抑制。此外,多种肿瘤细胞亦表达多种PRRs,肿瘤细胞本身PRR通路参与了肿瘤的发生、发展。本文将阐述肿瘤微环境中PRRs及其配体表达的特点,重点分析PRRs在肿瘤免疫调控中发挥的双向调控功能,以期为肿瘤免疫微环境形成的认识及肿瘤免疫治疗的设计提供新的视角。     

肿瘤微环境与炎症反应及溶瘤病毒治疗的关系

炎症反应在清除病原体、创伤愈合和抗肿瘤免疫中发挥重要作用,被肿瘤细胞劫持的炎性细胞和细胞因子也是肿瘤微环境重要的参与者;许多肿瘤起源于感染和慢性炎症,肿瘤微环境中炎症细胞和炎症介质的蓄积具有促进恶性细胞增殖和存活、促进血管生成和肿瘤转移,以及逆转获得性免疫反应的作用,也改变了肿瘤细胞对激素和化疗药物的敏感性。炎症反应在肿瘤的发生和消除中发挥的作用比较复杂。溶瘤病毒治疗肿瘤,是充分利用溶瘤病毒选择性感染和杀伤肿瘤细胞的特性。在肿瘤微环境中,溶瘤病毒所诱导的针对肿瘤细胞和病毒的天然免疫反应具有双重效应:既能引起肿瘤细胞的损伤,促进溶瘤病毒抗肿瘤的疗效,也能识别、清除隐藏于肿瘤组织内部的溶瘤病毒,降低溶瘤病毒的效应。     

肿瘤微环境中的炎性机制与肿瘤转移

炎性微环境是肿瘤微环境中影响肿瘤复发转移的关键因素之一.肿瘤炎性微环境可以通过调节上皮细胞向间充质细胞转变,启动肿瘤转移;可以通过降解细胞外基质从而破坏细胞外基质膜促进肿瘤细胞的侵袭;同时,炎性微环境促进肿瘤血管的新生为肿瘤的发生发展提供保障.     

肿瘤微环境中肿瘤相关巨噬细胞与上皮间质化“对话”的研究进展

肿瘤微环境决定了许多癌症的发生和发展。肿瘤相关巨噬细胞是肿瘤微环境中协调炎症和癌症之间的关键因子。上皮间质化的激活通常需要肿瘤细胞与局部肿瘤微环境组分（包括肿瘤相关巨噬细胞）之间的“对话”。在本篇综述中,临床和实验证据证明肿瘤相关巨噬细胞促进肿瘤侵袭和转移以及它在肿瘤转移级联反应中与上皮间质化的相互作用。此外,本文总结了以介入肿瘤相关巨噬细胞和上皮间质化的肿瘤细胞“对话”的信号通路作为肿瘤转移治疗的潜在靶点的治疗策略。     

肿瘤转移分子机制研究进展

肿瘤转移过程非常复杂,转移的肿瘤细胞最终能在转移器官植入成功并生长成瘤,不仅仅取决于肿瘤细胞的自身特点,还取决于肿瘤微环境的炎性特征以及肿瘤细胞与微环境之间的相互作用.全文主要从肿瘤转移相关基因和肿瘤微环境等方面综述了近几年来肿瘤转移分子机制研究的最新进展.     

肿瘤微环境在肿瘤细胞有氧糖酵解中的作用

肿瘤的发生发展和细胞代谢异常密切相关。肿瘤细胞摄入大量的葡萄糖,即使有足够的氧份供应,也主要借助糖酵解途径产生能量满足快速生长的需求。肿瘤细胞糖酵解受多方面因素影响,肿瘤微环境即为其中之一。近年来,有证据表明在肿瘤细胞糖代谢中,肿瘤微环境的免疫/炎症因子,转化生长因子β(Transforming growth factor-β,TGF-β)、肿瘤坏死因子α(Tumor necrosis factor alpha,TNF-α)、白细胞介素-4(Interleukin,IL-4)和白细胞介素-6(Interleukin,IL-6)等通过调控肿瘤细胞有氧糖酵解产生的能量与物质使细胞快速增殖,在肿瘤细胞糖代谢中起着至关重要的作用。因此,从肿瘤微环境中的免疫/炎症因子调控肿瘤细胞糖酵解的角度关注肿瘤的发生发展,可能为肿瘤的控制及临床治疗提供新思路。     

肿瘤微环境与乳腺癌细胞糖代谢重编程研究进展

摘 要：乳腺癌的进展、转移能力除了取决于肿瘤细胞的特性之外,还取决于肿瘤微环境对肿瘤细胞葡萄糖代谢的重新编程。肿瘤细胞葡萄糖代谢重编程即在氧气存在的情况下肿瘤细胞更喜欢在细胞质进行糖酵解,称为“Warburg效应”或“有氧糖酵解”。肿瘤微环境成分如肿瘤相关成纤维细胞、巨噬细胞、免疫细胞等也可发生糖代谢重编程,且两者之间相互影响促进乳腺癌的发展。全文综述了微环境主要成分与肿瘤细胞葡萄糖代谢重新编程相互作用对乳腺癌生物学和进展的重要性。     

肿瘤相关成纤维细胞在肿瘤中作用的研究进展

[摘要] 肿瘤是由肿瘤细胞及其周围基质细胞和非细胞组分构成的复合体,肿瘤的发生发展是肿瘤细胞与其微环境相互促进、共同演化的一个动态过程,肿瘤微环境在肿瘤的生长转移过程中发挥至关重要的作用。肿瘤相关成纤维细胞（cancer associated fibroblasts, CAFs）,作为肿瘤微环境中最主要的组成成分之一,能够分泌多种细胞因子,从而促进肿瘤血管生成,诱导肿瘤细胞发生上皮间质转化,打破组织细胞之间的稳态,使微环境更有利于肿瘤生长。CAFs对乳腺癌、肝癌、胃癌、结直肠癌、卵巢癌、肺癌等多种常见癌有促进作用。本文就近年来CAFs对肿瘤的发生发展、耐药及其他方面的影响及作用机制加以讨论,以期为癌症的治疗提供新的思路。     

活血化淤中药干预肿瘤乏氧微环境在侵袭转移方面的研究进展

1 传统与现代医学对于肿瘤乏氧的认识 肿瘤的发生和发展是一个多因素、多步骤、多基因共同作用的综合病变过程.特殊的宿主微环境通过种种调节机制影响着肿瘤细胞的生成发展、侵袭转移.特殊的宿主微环境是肿瘤细胞生存、增殖的土壤.肿瘤细胞所处的宿主微环境主要是由基质细胞、基质细胞分泌的不溶性细胞外基质及各种细胞因子和生长凶子构成~([1]).     

Epithelial ovarian tumor microecology

Epithelial ovarian cancer remains an insidious and fatal gynecological malignancy. They are associated with a poor prognosis mainly due to a late diagnosis and to acquired chemoresistance. Cancer cell environment profoundly influences tumor development. Tumor microenvironment consists of vascular component, stromal fibroblasts, inflammatory cells and extracellular matrix. The multisite development of epithelial ovarian cancer results from molecular and cellular cross-talks between cancer cells, stromal cells and their extracellular matrix environment. These interactions involve cytokines, adhesives molecules, and proteolytic systems. This review points out the importance of micro-ecology in epithelial ovarian cancer development. For this purpose the relationships between cancer cells and their encountered microenvironments are described with suggesting some potential therapeutic perspectives.     

Targeting inflammation in pancreatic cancer: Clinical translation

Preclinical modelling studies are beginning to aid development of therapies targeted against key regulators of pancreatic cancer progression. Pancreatic cancer is an aggressive, stromally-rich tumor, from which few people survive. Within the tumor microenvironment cellular and extracellular components exist, shielding tumor cells from immune cell clearance, and chemotherapy, enhancing progression of the disease. The cellular component of this microenvironment consists mainly of stellate cells and inflammatory cells. New findings suggest that manipulation of the cellular component of the tumor microenvironment is possible to promote immune cell killing of tumor cells. Here we explore possible immunogenic therapeutic strategies. Additionally extracellular stromal elements play a key role in protecting tumor cells from chemotherapies targeted at the pancreas. We describe the experimental findings and the pitfalls associated with translation of stromally targeted therapies to clinical trial. Finally, we discuss the key inflammatory signal transducers activated subsequent to driver mutations in oncogenic Kras in pancreatic cancer. We present the preclinical findings that have led to successful early trials of STAT3 inhibitors in pancreatic adenocarcinoma.     

Tumor microenvironment in gastric cancers

The tumor microenvironment favors the growth and expansion of cancer cells. Many cell types are involved in the tumor microenvironment such as inflammatory cells, fibroblasts, nerves, and vascular endothelial cells. These stromal cells contribute to tumor growth by releasing various molecules to either directly activate the growth signaling in cancer cells or remodel surrounding areas. This review introduces recent advances in findings on the interactions within the tumor microenvironment such as in cancer‐associated fibroblasts (CAFs), immune cells, and endothelial cells, in particular those established in mouse gastric cancer models. In mice, myofibroblasts in the gastric stroma secrete R‐spondin and support normal gastric stem cells. Most CAFs promote tumor growth in a paracrine manner, but CAF population appears to be heterogeneous in terms of their function and origin, and include both tumor‐promoting and tumor‐restraining populations. Among immune cell populations, tumor‐associated macrophages, including M1 and M2 macrophages, and myeloid‐derived suppressor cells (MDSCs), are reported to directly or indirectly promote gastric tumorigenesis by secreting soluble factors or modulating immune responses. Endothelial cells or blood vessels not only fuel tumors with nutrients, but also interact with cancer stem cells and immune cells by secreting chemokines or cytokines, and act as a cancer niche. Understanding these interactions within the tumor microenvironment would contribute to unraveling new therapeutic targets.     

The tumor microenvironment in hepatocellular carcinoma (review)

The tumor microenvironment has been largely studied as a dynamic system orchestrated by inflammatory cells, including cancer cells, stroma as well as the extracellular matrix. It is useful to describe and predict the phenotypic characteristics of cancer. Furthermore, a better understanding of its interplay with the various aspects of the tumor cells may be utilized for the discovery of novel molecular targets. Liver cancer is considered a model of the relation occurring between the tumor micro-environment and tumor development. The chronic inflammatory status of the liver, sustained by the infection of hepatitis viruses, as well as the production of cytokines and growth factors within the parenchyma, lead to an intricate microenvironment. The identification of novel molecular therapeutic targets may improve the outcome of patients with liver cancer as it remains the third leading cause of cancer death worldwide. In the present study, the tumor microenvironment in hepatocellular carcinoma (HCC) was explored by a review of the literature. Studies on hepatitis virus infections and the consequent chronic inflammatory status were examined. In this context, immune-mediated and/or virus-related molecular mechanisms have been hypothesized as being responsible for liver cancer development. The interlink among HCC microenvironment components, comprising cellular elements, cytokines, growth factors and several proteins is also described together with the role of matrix metalloproteinases in HCC development. Finally, the rationale for targeting tumor-stromal interface is summarized in the context of new therapeutic opportunities.     

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。     

精准靶向肿瘤局部的免疫治疗有可能成为治愈癌症的关键性策略

[摘要]肿瘤免疫治疗的两大重要进展：（1）在体外激活或通过基因修饰的T细胞进行体内输注;（2）通过抗体使体内被抑制的免疫细胞激活并处于相对持续作用状态。前者的基因修饰的T细胞主要是指嵌合抗原受体T（CAR-T）细胞,其对部分血液肿瘤产生了明显的疗效;后者主要指免疫检查点抗体,其对基因突变较多的肿瘤产生了明显的疗效。对于肿瘤患者而言,其肿瘤局部微环境的免疫抑制状态往往明显高于全身的免疫抑制状态。要将肿瘤局部微环境的免疫状况调整到正常或增强,全身用药时可能引发其它正常组织免疫反应过强,甚至导致严重损害,如间质性肺炎、急性心肌炎及严重肝损伤。本文通过总结肿瘤免疫微环境的形成和分类、肿瘤治疗和免疫治疗的发展历程,阐述靶向肿瘤微环境的重要性,提出了用自分泌抗体的CAR-T 细胞（白泽T细胞）高效精准靶向肿瘤局部,迅速提高肿瘤局部微环境的免疫功能,且有可能成为治愈癌症的关键策略。     

鼻咽癌与免疫逃逸

肿瘤的免疫逃逸是癌症的一大特征,目前所知的肿瘤逃逸机制主要包括肿瘤的直接免疫逃逸和肿瘤微环境介导的免疫逃逸.鼻咽癌的发生发展与其肿瘤细胞的免疫逃逸密切相关,其中与鼻咽癌相关的肿瘤的直接免疫逃逸主要包括肿瘤细胞表面主要组织相容性复合体-Ⅰ类分子表达下降或缺失、肿瘤细胞缺乏共刺激分子以及Fas/FasL系统介导的免疫逃逸;与鼻咽癌相关的肿瘤微环境介导的免疫逃逸则包括肿瘤相关免疫抑制分子和肿瘤相关免疫抑制性细胞.研究鼻咽癌免疫逃逸的作用机制能够为其治疗及预防提供新的研究方向.     

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.     

Mechanisms linking pathogens-associated inflammation and cancer

It has been estimated that chronic infections with viruses, bacteria and parasites are the causative agents of 8-17% of global cancers burden. Carcinogenesis associated with infections is a complex process, often mediated by chronic inflammatory conditions and accumulating evidence indicate that a smouldering inflammation is a component of the tumor microenvironment and represents the 7th hallmark of cancer. Selected infectious agents promote a cascade of events culminating in chronic inflammatory responses, thus predisposing target tissues to increased cancer susceptibility. A causal link also exists between an inflammatory microenvironment, consisting of inflammatory cells and mediators, and tumor progression. Tumor-Associated Macrophages (TAM) represent the major inflammatory population present in tumors, orchestrating various aspects of cancer, including: diversion and skewing of adaptive responses; cell growth; angiogenesis; matrix deposition and remodelling; construction of a metastatic niche and actual metastasis; response to hormones and chemotherapeutic agents. Recent studies on human and murine tumors indicate that TAM show a remarkable degree of plasticity and functional heterogeneity, during tumour development. In established tumors, TAM acquire an M2 polarized phenotype are engaged in immunosuppression and the promotion of tumor angiogenesis and metastasis. Being a first line of the innate defence mechanisms, macrophages are also equipped with pathogen-recognition receptors, to sense the presence of danger signals, including onco-pathogens. Here we discuss the evidence suggesting a causal relationship between selected infectious agents and the pro-tumoral reprogramming of inflammatory cells, as well as its significance in tumor development. Finally, we discuss the implications of this phenomenon for both cancer prevention and therapy.