表达Tie2的单核巨噬细胞在肿瘤微环境形成中的作用及机制研究进展

摘 要：表达Tie2的单核巨噬细胞（Tie2 expressing monocyte/macrophages,TEMs）是肿瘤相关巨噬细胞的重要亚群,存在于外周血、实体肿瘤等组织中。在肿瘤免疫抑制微环境中,TEMs能促进肿瘤生长、转移和复发,是肿瘤预后不良的新的指标,其作用机制主要通过促进血管生成、调节血管重塑、增加微血管密度、促进肿瘤微血管的形成;同时还可以抑制T细胞增殖、促进Treg的浸润、抑制抗肿瘤免疫应答。Ang-Tie2介导的Rheb/mTOR/p70S6K1信号通路是TEMs在肿瘤免疫微环境中促进肿瘤微血管生成的作用机制,对该细胞及相关通路的干预将成为新的肿瘤治疗靶点和策略。     

表达Tie2的单核细胞在肿瘤研究中的进展

表达Tie2的单核细胞(TEM)仅存在于外周血及肿瘤组织中,在肿瘤血管生成中发挥重要作用.TEM能够被血管生成素2(Ang2)及缺氧化学信号募集进入肿瘤组织,分化成表达Tie2的巨噬细胞,通过旁分泌作用参与肿瘤血管生成.肝癌、结肠癌、乳腺癌、恶性胶质瘤等肿瘤中检测到TEM水平升高,这对于肿瘤的诊断及预后判断有一定的提示作用.近年研究发现,TEM可用于抗肿瘤药物的靶向递送,能有效抑制肿瘤的生长和转移,同时TEM也是抗肿瘤治疗的潜在靶点.然而TEM在肿瘤微血管密度、临床分级及预后判断中的作用并不明确,目前针对TEM具体功能的探究引起了学者的广泛关注.     

Tie2受体在直肠癌组织中的表达与调控作用

目的：探讨Tie2在直肠癌中的表达及其与血管生成的关系。方法：利用免疫组化S—P法，对40例直肠癌组织中的Tie2受体表达进行研究。结果：Tie2受体定位于癌组织中内皮细胞胞浆及胞核，部分癌细胞胞浆也存在阳性表达，直肠癌组织中的Tie2表达阳性率明显高于正常直肠组织（P〈0．05），Tie2受体的表达与临床病理中的分化程度、浸润深度、Dukes分期无关（P〉0．05），而与淋巴转移相关（P〈0．05）。结论：Tie2受体在直肠癌肿瘤组织的生成、分化、生长过程中具有重要调控作用。     

Tie2受体在直肠癌组织中的表达与调控作用

目的:探讨Tie2在直肠癌中的表达及其与血管生成的关系.方法:利用免疫组化S-P法,对40例直肠癌组织中的Tie2受体表达进行研究.结果:Tie2受体定位于癌组织中内皮细胞胞浆及胞核,部分癌细胞胞浆也存在阳性表达,直肠癌组织中的Tie2表达阳性率明显高于正常直肠组织(P＜0.05),Tie2受体的表达与临床病理中的分化程度、浸润深度、Dukes 分期无关(P>0.05),而与淋巴转移相关(P＜0.05).结论:Tie2受体在直肠癌肿瘤组织的生成、分化、生长过程中具有重要调控作用.     

Tie-2受体在大肠癌组织中的表达与血管生成

目的　探讨Tie 2在大肠癌组织中的表达及其与血管生成的关系。方法　利用免疫组化SABC法 ,对 10 6例大肠癌组织及 2 0例正常大肠组织中的Tie 2受体表达进行研究。结果　Tie 2受体主要表达于癌组织及癌组织旁的血管内皮细胞上 ,Tie 2受体在大肠癌组织中的表达阳性率显著高于正常组织 (P <0 .0 1) ,Tie 2受体的表达与病理类型、分化程度及临床分期无关 (P >0 .0 5 )。结论　Tie 2受体在大肠癌的血管生成调控中具有重要作用。     

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…     

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...     

血管生成素-2：癌症治疗抑制剂的发展

血管生成素-2（angiopoietin-2,Ang2）是血管生成素家族的一员,在人类肿瘤发生和生长的血管生成中起了重要作用。Ang2在血管生成中的作用一般认为是Angl激活的Tie2信号转导对血管成熟和血管稳定起关键作用而Ang2拮抗这种效应。Ang2与另一个重要血管生成因子VEGF-A以一种协调作用的方式调控血管生成。遗传学研究显示Ang2在淋巴管生成中也起重要作用。然而．新的证据表明,Ang2在人类肿瘤进展中的血管生成过程和肿瘤细胞侵袭性表型方面起更复杂的作用,本文综述了Ang2在血管生成过程中的一些最新研究进展,并讨论了针对肿瘤患者Ang2作为一个潜在抗血管生成治疗靶点和潜在抑制剂的应用。     

巨噬细胞与肿瘤血管生成的研究进展

浸润到肿瘤组织内的巨噬细胞即肿瘤相关巨噬细胞(TAMs)。TAMs与肿瘤细胞共生,肿瘤细胞为TAMs提供存活因子,TAMs产生血管生成因子来响应肿瘤的微环境。本文综述了TAMs与血管生成的关系和在肿瘤发展过程中的作用,以及TAMs在肿瘤治疗中的作用。1巨噬细胞与肿瘤肿瘤一旦产生血管,就     

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。     

Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2

Recent findings indicate that tumor-associated macrophages are important drivers of tumor angiogenesis. Here, we review the essential role played by Tie2-expressing monocytes (TEM) in this phenomenon. TEMs are present in human blood and tumors and their elimination in various tumor models suppresses tumor angiogenesis. A ligand for Tie2, angiopoietin-2 (Ang-2), is produced by angiogenic tumor vessels and is a chemoattractant for TEMs. Hypoxia up-regulates Tie2 expression on TEMs and, together with Ang-2, down-regulates their antitumor functions. Learning more about the regulation of TEMs by the tumor microenvironment may yield new strategies to ablate the tumor vasculature.     

Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors

Bone marrow-derived cells contribute to tumor angiogenesis. Here, we demonstrate that monocytes expressing the Tie2 receptor (Tie2-expressing monocytes [TEMs]) (1) are a distinct hematopoietic lineage of proangiogenic cells, (2) are selectively recruited to spontaneous and orthotopic tumors, (3) promote angiogenesis in a paracrine manner, and (4) account for most of the proangiogenic activity of myeloid cells in tumors. Remarkably, TEM knockout completely prevented human glioma neovascularization in the mouse brain and induced substantial tumor regression. Besides TEMs and endothelial cells (ECs), Tie2 expression distinguished a rare population of tumor stroma-derived mesenchymal progenitors representing a primary source of tumor pericytes. Therefore, Tie2 expression characterizes three distinct cell types required for tumor neovascularization: ECs, proangiogenic cells of hematopoietic origin, and pericyte precursors of mesenchymal origin.     

Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells

Tumor-infiltrating myeloid cells convey proangiogenic programs that counteract the efficacy of antiangiogenic therapy. Here, we show that blocking angiopoietin-2 (ANG2), a TIE2 ligand and angiogenic factor expressed by activated endothelial cells (ECs), regresses the tumor vasculature and inhibits progression of late-stage, metastatic MMTV-PyMT mammary carcinomas and RIP1-Tag2 pancreatic insulinomas. ANG2 blockade did not inhibit recruitment of MRC1(+) TIE2-expressing macrophages (TEMs) but impeded their upregulation of Tie2, association with blood vessels, and ability to restore angiogenesis in tumors. Conditional Tie2 gene knockdown in TEMs was sufficient to decrease tumor angiogenesis. Our findings support a model wherein the ANG2-TIE2 axis mediates cell-to-cell interactions between TEMs and ECs that are important for tumor angiogenesis and can be targeted to induce effective antitumor responses.     

Anti-vascular endothelial growth factor therapy-induced glioma invasion is associated with accumulation of Tie2-expressing monocytes

The addition of anti-angiogenic therapy to the few treatments available to patients with malignant gliomas was based on the fact that these tumors are highly vascularized and on encouraging results from preclinical and clinical studies. However, tumors that initially respond to this therapy invariably recur with the acquisition of a highly aggressive and invasive phenotype. Although several myeloid populations have been associated to this pattern of recurrence, a specific targetable population has not been yet identified. Here, we present evidence for the accumulation of Tie2-expressing monocytes/macrophages (TEMs) at the tumor/normal brain interface of mice treated with anti-VEGF therapies in regions with heightened tumoral invasion. Furthermore, we describe the presence of TEMs in malignant glioma surgical specimens that recurred after bevacizumab treatment. Our studies showed that TEMs enhanced the invasive properties of glioma cells and secreted high levels of gelatinase enzymatic proteins. Accordingly, Tie2⁺MMP9⁺ monocytic cells were consistently detected in the invasive tumor edge upon anti-VEGF therapies. Our results suggest the presence of a specific myeloid/monocytic subpopulation that plays a pivotal role in the mechanism of escape of malignant gliomas from anti-VEGF therapies and therefore constitutes a new cellular target for combination therapies in patients selected for anti-angiogenesis treatment.     

Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis

The use of type I interferons (IFNs) in cancer therapy has been limited by ineffective dosing and significant toxicity. Here, we exploited the tumor-homing ability of proangiogenic Tie2-expressing monocytes (TEMs) to deliver IFN-alpha to tumors. By transplanting hematopoietic progenitors transduced with a Tie2 promoter/enhancer-driven Ifna1 gene, we turned TEMs into IFN-alpha cell vehicles that efficiently targeted the IFN response to orthotopic human gliomas and spontaneous mouse mammary carcinomas and obtained significant antitumor responses and near complete abrogation of metastasis. TEM-mediated IFN-alpha delivery inhibited tumor angiogenesis and activated innate and adaptive immune cells but did not impair myelopoiesis and wound healing detectably. These results illustrate the therapeutic potential of gene- and cell-based IFN-alpha delivery and should allow the development of IFN treatments that more effectively treat cancer.     

Macrophage-derived SHP-2 inhibits the metastasis of colorectal cancer via Tie2-PI3K signals

This research aimed to explore the influence of Src homology-2 containing protein tyrosine phosphatase (SHP- 2) on the functions of tyrosine kinase receptors with immunoglobulin and EGF homology domains 2 (Tie2)-expressing monocyte/macrophages (TEMs) and the influence of the angiopoietin(Ang)/Tie2-phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) (Ang/Tie2-PI3K/Akt/mTOR) signaling pathway on the tumor microvascular remodeling in an immunosuppressive microenvironment. In vivo, SHP-2- deficient mice were used to construct colorectal cancer (CRC) liver metastasis models. SHP-2-deficient mice had significantly more metastatic cancer and inhibited nodules on the liver surface than wild-type mice, and the high-level expression of p-Tie2 was found in the liver tissue of the macrophages’ specific SHP-2-deficient mice (SHP-2MACKO) + planted tumor mice. Compared with the SHP-2 wild type mice (SHP-2WT) + planted tumor group, the SHP-2MAC-KO + planted tumor group experienced increased expression of p-Tie2, p-PI3K, p-Akt, p-mTOR, vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), matrix metalloproteinase 2 (MMP2), and MMP9 in the liver tissue. TEMs selected by in vitro experiments were co-cultured with remodeling endothelial cells and tumor cells as carriers. It was found that when Angpt1/2 was used for stimulation, the SHP-2MAC-KO + Angpt1/2 group displayed evident increases in the expression of the Ang/Tie2-PI3K/Akt/mTOR pathway. The number of cells passing through the lower chamber and the basement membrane and the number of blood vessels formed by cells compared with the SHP-2WT + Angpt1/2 group, while these indexes were subjected to no changes under the simultaneous stimulation of Angpt1/2 + Neamine. To sum up, the conditional knockout of SHP-2 can activate the Ang/Tie2-PI3K/Akt/mTOR pathway in TEMs, thereby strengthening tumor micro angiogenesis in the microenvironment and facilitating CRC liver metastasis.     

Pro‐angiogenic TIE‐2‐expressing monocytes/TEMs as a biomarker of the effect of sorafenib in patients with advanced hepatocellular carcinoma

Sorafenib, a multi‐kinase inhibitor, inhibits tumor angiogenesis and is the first‐line systemic therapy for patients with advanced hepatocellular carcinoma (HCC). However, due to its limited effects and frequent occurrence of side effects, biomarkers are needed to predict the effects of sorafenib. We considered the possibility of using TIE‐2‐expressing monocytes (TEMs) to predict the response in sorafenib‐treated patients with advanced HCC. TEMs serve as a diagnostic marker of HCC and are related to angiogenesis. We analyzed 25 advanced HCC patients and prospectively evaluated TEMs before (Pre TEMs) and at 1 month after initial therapy (T1m TEMs). The radiologic response was evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Median survival time (MST) was significantly longer in the partial response/stable disease (PR/SD) group (21.8 months) than in the PD group (8.7 months). ΔTEMs (changes of T1m TEMs compared to Pre TEMs) were significantly lower in the PR/SD group than in the PD group. MST of the ΔTEMs low group (14.2 months) was significantly longer than that of the high group (8.7 months). Univariate and multivariate Cox regression analyses showed that ΔTEMs [hazard ratio (HR) = 8.53, 95% confidence interval (CI) = 1.51–48.16, p = 0.015] and Child‐Pugh class (HR = 5.59, 95% CI = 1.06–29.63, p = 0.043) were independently associated with overall survival. Our results suggest that ΔTEMs could serve as a biomarker for predicting radiologic response and overall survival in sorafenib‐treated patients with advanced HCC.     

Multitargeting strategy using lenvatinib and golvatinib: Maximizing anti‐angiogenesis activity in a preclinical cancer model

Almost all cancers show intrinsic and/or evasive resistance to vascular endothelial growth factor (VEGF) inhibitors by multiple mechanisms. Serum angiopoietin‐2 (Ang2) level has been proposed as a potential biomarker of VEGF inhibitor response in several cancers. From these clinical observations, the Ang2 and Tie2 (its receptor) axis has been focused on as a promising target. Here, we show a novel strategy to circumvent the resistance by combining multi‐tyrosine kinase inhibitors lenvatinib (VEGF receptor, fibroblast growth factor receptor, and RET inhibitor) and golvatinib (E7050; c‐Met, Tie2, and EphB4 inhibitor). Tie2 identifies a highly pro‐angiogenic macrophage subset, Tie2‐expressing macrophages (TEM). Angi‐Tie2 and EphB4‐EphrinB2 signaling plays critical roles in pericyte‐mediated vessel stabilization. In vitro analyses suggested that golvatinib combined with lenvatinib inhibited pericyte‐mediated vessel stabilization and TEM differentiation. In thyroid and endometrial cancer models, golvatinib and lenvatinib inhibited pericyte network development and TEM infiltration, resulting in severe perfusion disorder and massive apoptosis. Body weight loss was tolerable, and no macroscopic change was observed. These preclinical studies suggest that modulation of the tumor microenvironment by a strategic and well‐tolerated combination of multi‐targeting tyrosine kinase inhibitors may sensitize cancer to VEGF inhibitors.     

单核/巨噬细胞在非霍奇金淋巴瘤中的研究进展

非霍奇金淋巴瘤(Non-Hodgkin's lymphoma,NHL)是具有很强异质性的一组独立疾病的总称。近年来,人们发现在肿瘤微环境中,单核/巨噬细胞对肿瘤的生长、增殖、免疫逃逸及预后等都具有一定的影响,同时肿瘤也对单核/巨噬细胞产生刺激作用。本文对目前单核/巨噬细胞在几种常见NHL中的研究现状作简要综述,总结单核/巨噬细胞与NHL病人预后的相关性、单核/巨噬细胞与NHL肿瘤细胞的相互作用及机制,并对NHL的免疫疗法中单核/巨噬细胞可能扮演的作用进行阐述。