肿瘤相关巨噬细胞在多发性骨髓瘤中作用的研究进展

骨髓微环境是肿瘤周围高度复杂的环境，在多发性骨髓瘤(MM)细胞存活、增殖、耐药、迁移等方面具有重要作用。肿瘤相关巨噬细胞(TAM)作为肿瘤微环境中重要的细胞成分，由于在肿瘤进展和耐药等方面发挥关键作用而受到关注。靶向TAM在癌症治疗中已显示出潜在的价值。为了明确巨噬细胞在MM进展中的作用，有必要了解TAM分化及其促进MM的特性。本文对TAM在MM中如何编程及促进肿瘤发展和耐药的机制研究进展作一综述。     

肿瘤相关巨噬细胞调节肿瘤免疫治疗作用的研究进展

<正>2018年最新的全球肿瘤统计结果显示,我国每天约有1万人确诊肿瘤,我国肿瘤患病率在全球处于中等偏上水平~([1])。肿瘤相关巨噬细胞(TAM)是肿瘤微环境的重要组成部分,并在肿瘤微环境中发挥重要的免疫调节作用,成为肿瘤靶向免疫治疗的研究热点。TAM主要分为经典活化的巨噬细胞(M1型)和替代性活化的巨噬细胞(M2型),两种细胞使TAM可能同时具有抗肿瘤和促肿瘤作用:M1型巨噬细胞     

慢性胃炎及微环境与胃癌

肿瘤微环境在肿瘤的发生、发展、转移中扮演着重要的角色。随着人们对慢性炎症的认识,肿瘤间质中大量炎性细胞以及炎性细胞因子在恶性肿瘤中的生物学作用逐渐受到重视。对慢性胃炎、微环境的研究有助于进一步认识胃癌发生发展的机制,并为临床上预防、诊断、治疗胃癌提供相关依据。本文综述了慢性胃炎、微环境中炎症信号通路及多种炎症递质在胃癌发生、发展及转移中的作用。     

肿瘤相关巨噬细胞作用和靶向治疗的研究进展

肿瘤微环境是一种复杂的细胞生态环境,其在向恶性肿瘤过渡期间与肿瘤细胞一起进化并提供支持。巨噬细胞特别富集并且存在于肿瘤进展的所有阶段,在原发性肿瘤中,肿瘤相关巨噬细胞(tumor associated macrophage,TAM)可以刺激血管生成并增强肿瘤细胞的侵袭,运动、内渗和耐药等能力,这些活动中的每一项都有不同的作用机制。     

肿瘤微环境下HMSC分化为肿瘤相关成纤维细胞及其对肿瘤生长作用的观察

摘要：目的：鉴定人骨髓间充质干细胞（human bone marrow-derived mesenchymal stem cell,HMSC）在肿瘤微环境下分化为肿瘤相关成纤维细胞（tumor associated fibroblast,TAF）及对肿瘤生长作用的观察。 方法：用Transwell实验鉴定HMSC向人胃腺癌细胞株（SGC-7901）迁移的能力。对与人胃癌组织或SGC-7901培养上清液（TCM）长期共培养后的HMSC细胞,用免疫荧光染色检测肌动蛋白微丝(F-actin)的表达、免疫细胞化学染色检测α-平滑肌肌动蛋白（α-smooth muscle actin,α-SMA）及波形蛋白（vimentin）的表达。用实时定量PCR法检测与胃癌组织及TCM共培养后的HMSC细胞中α-SMA表达水平。分别以SGC-7901细胞、SGC-7901细胞＋HMSC细胞、胃癌组织与HMSC共培养细胞＋SGC-7901细胞、TCM与HMSC共培养细胞＋SGC-7901细胞接种裸鼠,构建裸鼠致瘤模型,测定4组模型致瘤时间及瘤体大小。 结果：Transwell实验结果表明HMSC在肿瘤微环境诱导下具有向肿瘤迁移的能力,诱导后的HMSC细胞高表达TAF细胞表面特征蛋白F-actin、α-SMA及vimentin,实时定量PCR结果表明与胃癌组织及TCM共培养后的HMSC细胞α-SMA mRNA表达水平分别为(0.58±0.05)和(0.52±0.06),与对照组(0.35±0.04)相比明显增高（F=4.72,F=5.31,P均<0.05）。 裸鼠致瘤模型显示经肿瘤微环境诱导后的TAF可促进体内肿瘤生长。 结论：肿瘤微环境诱导下HMSC活化并可分化为TAF,并对肿瘤生长起到促进作用。     

胃癌组织TAM、MC和LV计数及其临床病理意义

[目的]研究胃癌组织中肿瘤相关巨噬细胞(TAM)、肥大细胞(MC)及淋巴管(LV)计数及相互关系和临床病理意义.[方法]60例胃癌组织常规制作石蜡包埋切片,TAM、MC和LV染色方法均为SP免疫组化法.[结果]60例胃癌TAM、MC和LV计数分别为18.4±5.6、15.2±4.3和13.5±4.8;高分化、侵袭肌层、无淋巴结转移及无远处转移病例TAM、MC、LV计数明显低于分化或未分化、侵袭浆膜层或浆膜外、淋巴结转移及远处转移病例(P＜0.05或P＜0.01);LV计数与TAM计数(r=0.43,P＜0.01)及MC计数(r=0.38,P＜0.01)均存在密切正相关,TAM计数与MC计数存在密切正相关(r=0.32,P＜0.05).[结论]TAM、MC和LV计数可能是反映胃癌进展、生物学行为和预后的重要标记物,TAM和MC可能具有促肿瘤淋巴管生成作用.     

血管内皮细胞生长因子-A及肿瘤相关巨噬细胞在多发性骨髓瘤中的研究进展

多发性骨髓瘤(MM)是一类浆细胞恶性克隆性疾病,发病机制复杂.MM的发生、发展与新生血管形成及骨髓微环境密切相关.新生血管形成受血管内皮细胞生长因子(VEGF)等血管形成调节因子调节,可促进MM细胞增殖、迁移.肿瘤相关巨噬细胞(TAM)活化后,亦可产生VEGF等促血管生成因子,从而促进骨髓新生血管形成,促进MM发展.笔者拟就VEGF-A、TAM在MM发病中的研究进展进行综述.     

肿瘤相关巨噬细胞靶向治疗宫颈癌研究进展

肿瘤相关巨噬细胞(TAMs)是肿瘤微环境(TME)中重要的免疫细胞,可分泌多种细胞因子参与和调控宫颈癌(CC)的生物学行为。详细了解TAM影响CC的生长和转移机制,是研发靶向治疗药物的关键。本文就近年来对TAM在CC中的治疗进展进行综述,重点探讨TAM靶向治疗CC的潜在治疗靶点、疫苗及药物,为CC新型靶向药物的研发提供理论依据,以期改善患者生存质量和延长其生存时间。     

外体（exosomes）对肿瘤微环境作用的研究进展

外体(exosomes)是体内来源的且能被多种类型的细胞释放到微环境的小囊泡,携带来自宿主的微小RNA(microRNA,miRNA)、mRNAs、DNA片段及蛋白质等成分。不同肿瘤微环境细胞(如免疫细胞、间充质干细胞和肿瘤自身细胞等)分泌的外体能介导肿瘤细胞与肿瘤微环境细胞间物质和信息的传递。研究表明,肿瘤细胞分泌的外体可募集和重建肿瘤微环境的相关成分,促进肿瘤的血管生成、肿瘤转移及执行免疫抑制功能。本文就目前外体对肿瘤微环境的研究进展作一综述。     

肿瘤细胞耐药分子机制的研究进展

临床上肿瘤患者在接受化疗和靶向治疗后体内形成耐药的肿瘤细胞。这类细胞具有增殖缓慢、细胞代谢调节性强、表型可塑性高和对肿瘤微环境的适应性强等特征。这些特征背后的分子机制与肿瘤细胞产生耐药相关。耐药细胞的减速机制可以发生在细胞内,也可以通过微环境介导。耐药细胞可以通过线粒体呼吸,调控蛋白质合成,和增强抗氧化途径的方式来调节细胞代谢。耐药细胞通过上皮间质转化和转分化来改变细胞表型。耐药细胞通过和肿瘤微环境中的肿瘤相关巨噬细胞、肿瘤相关成纤维细胞等其他细胞相互作用,增强其对微环境的适应能力。结合临床现状,开发可靠的临床前肿瘤耐药细胞模型对进一步研究肿瘤耐药细胞的特性和寻找临床治疗新策略具有重要意义。     

人脐静脉内皮细胞分离鉴定及其膜分子的表达

背景：肿瘤微环境作用于血管内皮细胞,影响其膜表面分子的表达,与肿瘤的生长、转移及免疫逃逸作用相关,但迄今相关机制尚不完全清楚。目的：分析肿瘤微环境下血管内皮细胞的膜表面分子表达量变化。方法：原代分离培养人脐静脉内皮细胞,采用不同肿瘤培养上清,用不同时间进行诱导。记录培养血管内皮细胞形态;利用免疫组织化学方法,鉴别Ⅷ因子相关抗原;荧光实时定量PCR法测定其膜表面分子mRNA表达量。结果与结论：肝癌smmc7721细胞培养上清处理后,内皮细胞抗原提呈会随着时间延长减弱,黏附白细胞能力随着时间延长而变化。胃癌SGC7901细胞培养上清处理后内皮细胞后,抗原提呈能力无明显变化;黏附能力有关分子中,CD31和细胞间黏附分子1表达降低,CD62E表达增高。说明肿瘤微环境可能通过上述黏附分子和抗原提呈分子表达的变化影响血管内皮细胞的相应功能。     

肿瘤相关巨噬细胞促进肿瘤转移的机制

浸入肿瘤微环境中的肿瘤相关巨噬细胞在不同因子的刺激下,可分化为具有抗肿瘤功能的M1型巨噬细胞和具有促肿瘤功能的M2型巨噬细胞。在大多数肿瘤中肿瘤相关巨噬细胞以M2型为主,它参与肿瘤新血管形成、基底膜破坏、细胞外基质重塑、肿瘤细胞上皮间质转化等与肿瘤细胞侵袭转移相关的过程,由此肿瘤相关巨噬细胞已经成为肿瘤靶向治疗的重要靶点。本文主要探讨肿瘤相关巨噬细胞与肿瘤细胞的相互作用,以及其在促进肿瘤转移的各个环节中的分子机制。     

Tamoxifen reduces P-gp-mediated multidrug resistance via inhibiting the PI3K/Akt signaling pathway in ER-negative human gastric cancer cells

Multidrug resistance (MDR), mediated by overexpression of drug efflux transporters such as P-glycoprotein (P-gp), is a major problem limiting successful chemotherapy of gastric cancer. Tamoxifen (TAM), a triphenylethylene nonsteroidal antiestrogen agent, shows broad-spectrum antitumor properties. Emerging studies demonstrated that TAM could significantly reduce the MDR in a variety of human cancers. Here we investigated the effects and possible underlying mechanisms of action of TAM on the reversion of MDR in ER-negative human gastric cancer cells. Our results demonstrated that in MDR phenotype SGC7901/CDDP gastric cancer cells TAM dramatically lowered the IC₅₀ of CDDP, 5-FU and ADM, increased the intracellular Rhodamine123 accumulation and induced G0/G1 phase arrest, while G2/M phase decreased accordingly. Furthermore, at the molecular level, TAM substantially decreased the expression of P-gp, p-Akt and the Akt-regulated downstream effectors such as p-GSK-3β, p-BAD, Bcl-XL and cyclinD1 proteins without affecting the expression of t-Akt, t-GSK-3β, t-BAD proteins in SGC7901/CDDP cells. Thus, our findings demonstrate that TAM reverses P-gp-mediated gastric cancer cell MDR via inhibiting the PI3K/Akt signaling pathway.     

中性粒细胞与肿瘤的相关性

癌症的进展不仅与肿瘤细胞本身有关,还与其他相关的参与者有关,包括癌细胞募集的免疫细胞、免疫细胞释放的促炎因子和细胞外基质。这些分子构成了肿瘤的微环境,在肿瘤的发生发展中起重要的作用。中性粒细胞是循环系统中数量最多的白细胞,是肿瘤微环境的重要组成部分。中性粒细胞在炎症和癌症之间起着重要的联系作用,在肿瘤的进展和转移中起积极的作用。中性粒细胞可能被认为是多种癌症类型的新靶点之一。     

Tumor infiltrating lymphocytes and macrophages have a potential dual role in lung cancer by supporting both host-defense and tumor progression

A prerequisite to the developement of an efficient cell and/or gene therapy for lung cancer is a precise characterization of the inflammatory cell populations spontaneously present in the tumor stroma associated with this cancer. This study was designed to define the cytotoxic potential and the relationship with stroma development of tumor infiltrating lymphocytes (TIL) and tumor associated macrophages (TAM). Tumor samples from 48 patients undergoing surgery for non-small cell lung cancer (NSCLC) were analyzed, by immunohistochemistry and in situ hybridization, with a panel of antibodies and probes specific for cell proteins linked to cytotoxicity, cytokines, and growth factors, and the replication status of TIL and TAM was evaluated by in vivo 5-bromodeoxyuridine incorporation. It was shown that, in NSCLC: (1) tumor stroma inflammatory cells are mainly TIL (approximately 2/3) (among them, 80 % are T-cells) and TAM (approximately 1/3), with almost no natural killer (NK) cells, and a few dentritic cells; (2) TAM and TIL are poorly replicating, but mainly recruited to the tumor stroma; (3) more than half TAM show an antibody-dependent cytotoxic potential, and one third of T-cells are TIA-1 positive CD8 activated cytotoxic lymphocytes; (4) cancer cells from only a few tumor express HLA class I and II antigens; (5) TAM production of cytotoxic cytokines [interleukin-1alpha (IL-1alpha), IL-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha)] and of transforming growth factor-beta1 (TGF-beta1) is low, in contrast to their strong release of platelet-derived growth factor (PDGF). We concluded that, in NSCLC, TIL cytotoxicity is likely to be low because of a poor class I MHC expression by tumor cells, and TAM low production of cytotoxic cytokines is a major limit to their possible cytotoxic activity. In contrast, TAM may favor tumor progression by contributing to tumor stroma formation and angiogenesis through their release of PDGF, in conjunction with TGF-beta1 production by tumor cells.     

Exploring the role of FBXO5 in gastric cancer

Gastric cancer is one of the most common lethal malignancies in the world, especially in China. Due to the ineffective screening of early gastric cancer and drug resistance of the advanced, the prognosis of gastric cancer remains dismal. Based on bioinformatics and tissue microarray analyses, FBXO5 was selected for analysis in this study. Here, we report the function of FBXO5 in gastric cancer, showing for the first time that it contributes to tumor cell proliferation, clone formation, invasion and migration. In these preliminary findings, FBXO5 promoted the transition of the cell cycle from the G0/G1 to the G2/M phase, which likely resulted from FBXO5 interacting with CDK1 and NCAPG proteins. The relevant mechanism needs to be explored. In addition, FBXO5 participated in the tumor microenvironment and was negatively related to immune activation. FBXO5, an oncogene, plays a role in tumor initiation and progression, and is expected to be a potential target for gastric cancer treatment.     

肿瘤微环境中外泌体在肿瘤发生发展中作用及机制

外泌体(exosomes)是直径在30~100 nm,内含RNA、脂质和蛋白质的纳米级囊泡,来源于细胞内溶酶体微粒内陷形成的多囊泡体,与细胞膜融合后释放到胞外,是肿瘤微环境中细胞间通讯和遗传物质的重要载体。肿瘤在发生、发展过程中可通过外泌体与肿瘤微环境中的免疫细胞、内皮细胞和肿瘤相关成纤维细胞之间相互作用从而促进肿瘤的进展,其携带蛋白质、脂质和核酸等内容物释放到细胞外随着体液运输改变肿瘤微环境、促进肿瘤细胞增殖、加快血管形成及促进癌症发展;肿瘤微环境是由肿瘤细胞、巨噬细胞、成纤维细胞及细胞外基质等共同构成的局部稳态环境,在癌症的发生、复发、转移和化疗耐药等过程中发挥重要的作用。本综述着重讨论外泌体的生物学特性及对肿瘤微环境的影响,为研究及诊断治疗肿瘤提供新的思路。     

CCL5 secreted by tumor associated macrophages may be a new target in treatment of gastric cancer

AimTo investigate the role of CCL5 secreted by tumor associated macrophages (TAMs) in gastric cancer, and to explore how CCL5/CCR5 axis modulates phenotypes of gastric cancer cells.MethodsExpression of CCL5 and TAM surface marker CD68 in gastric cancer tissues was examined using SP immunohistochemistry. Serum CCL5 levels of patients were assessed using ELISA. Cross-analyses of CCL5 and CD68 expression with clinicopathological data were done. Correlation between CCL5 and CD68 in gastric cancer tissues was also studied. In vitro functional characterization of CCL5 in gastric cancer was done in co-culture of AGS and THP-1 derived macrophages using MTS assay, plate clone formation assay, and transwell experiment. Expression of chemokines and its receptors were detected by RT-PCR, while Stat3 phosphorylation and downstream target proteins were studied using western blot.ResultsCCL5 and CD68 were both highly expressed in tissues gastric cancer, of which the expressions were positively correlated with each other, and of clinical importance, were associated with the depth of invasion, lymph node metastasis, TNM staging and tumor differentiation. Serum CCL5 was also elevated in patients with gastric cancer comparing to healthy volunteers. Co-culture of AGS cells with THP-1 derived macrophages increased cell proliferation, clone forming ability as well as migration of AGS cells. Migration of AGS cells across transwell membrane was also enhanced by increasing exogenous CCL5. Meanwhile, mRNA expression of CCL5, MMP2, MMP9, and CCR5 was also highly expressed in the cells. Stat3 signaling as reflected by its phosphorylation was also increased in AGS cells upon co-culture with THP-1 derived macrophages.ConclusionCCL5 secreted by TAMs may promote the proliferation, invasion and metastasis of gastric cancer cells, in which Stat3 signaling pathway is likely to play an important role. The correlation of CCL5 with clinicopathological parameters suggested CCL5 holds promise as important molecular marker of gastric cancer staging and disease progression.     

调节性T细胞在胰腺癌免疫治疗中的作用机制与应用策略

免疫治疗在胰腺癌的临床试验中疗效欠佳，主要原因在于胰腺癌具有高度免疫抑制的肿瘤微环境（tumor microenvironment, TME）。调节性T细胞（regulatory T cells, Tregs）是一类控制自身免疫反应的T细胞亚群，也是免疫抑制性肿瘤微环境的主要组成成分之一。研究发现Tregs能够调控机体免疫反应强度，抑制效应T细胞的功能和活性进而诱导免疫耐受，维持免疫应答稳态。在胰腺癌肿瘤微环境中，Tregs通过抑制机体免疫反应从而介导肿瘤细胞发生免疫逃逸，影响患者的预后与治疗效果。本综述通过总结Tregs在胰腺癌免疫微环境中的作用机制以及在胰腺癌中的临床意义，以期为胰腺癌免疫治疗提供更多的新思路。