微环境对肿瘤微血管内皮细胞异质性的影响

肿瘤微血管内皮细胞与正常组织来源的微血管内皮细胞相比，具有明显窗孔结构、对生长因子反应性高、粘附因子表达高等特点，是造成肿瘤血管通透性高且新生旺盛的重要原因，导致肿瘤的快速生长和转移。肿瘤微血管内皮细胞具有异质性，受宿主组织、肿瘤类型及肿瘤微环境的多重影响。了解肿瘤微血管内皮细胞发生、形态及功能上的异质性特点及其可能机制，对进行合理的、个性化的、以血管内皮细胞为靶的抗血管新生治疗意义重大。     

微环境对肿瘤微血管内皮细胞异质性的影响

肿瘤微血管内皮细胞与正常组织来源的微血管内皮细胞相比，具有明显窗孔结构，对生长因子反应性高，粘附因子表达等特点，是造成肿瘤血管透性高且新生旺盛的重要原因。导致肿瘤的快速生长和转移。肿瘤微血管内皮细胞具有异质性，受宿主组织，肿瘤类型及肿瘤微环境的多重影响。了解肿瘤微血管内皮细胞发生，形态及功能上的异质性特点及其可能机制，对进行合理的，个性化的，以血管内皮细胞为靶的抗血管新生治疗意义重大。     

胶皮质瘤血管发生发展机制研究

恶性胶质瘤是人体血管化程度最高的肿瘤，血管生成和增长在胶质瘤生长和侵袭过程中起重要作用，并与其恶性进展相关、内皮细胞在血管生成中起重要作用，内皮细胞与肿瘤细胞的相互作用是肿瘤血管生成的关键因素，血管生成因子以及微环境的改变主要调控胶质瘤的血管生成。组织重构的研究方法有助于对正常和病理性的血管生成分子机制进一步了解，胶质瘤血管生成机制将得以明确。     

胶质瘤血管发生发展机制研究

恶性胶质瘤是人体血管化程度最高的肿瘤,血管生成和增长在胶质瘤生长和侵袭过程中起重要作用,并与其恶性进展相关.内皮细胞在血管生成中起重要作用,内皮细胞与肿瘤细胞的相互作用是肿瘤血管生成的关键因素.血管生成因子以及微环境的改变主要调控胶质瘤的血管生成.组织重构的研究方法有助于对正常和病理性的血管生成分子机制进一步了解,胶质瘤血管生成机制将得以明确.     

肿瘤抗血管生成生物化疗的研究进展

传统的化疗通过杀伤肿瘤细胞抑制肿瘤的生长和侵袭,在对细胞毒化疗药物研究的同时发现,绝大多数药物在低剂量、高频率的给药方式下对肿瘤血管内皮细胞有持续抑制和杀伤作用,即后来所提出的抗血管生成的生物化疗。这种以肿瘤血管内皮细胞为作用靶点的化疗,其理论依据主要是肿瘤的生长和侵袭离不开新生血管的生成。目前认识到,许多化疗药物及一些抗肿瘤中药的有效成分在体外实验或体内实验中通过不同的作用机制发挥抗血管生成作用。     

肿瘤微环境异质性的研究进展

在肿瘤发生及发展过程中,肿瘤微环境起着至关重要的作用.已有研究证实肿瘤微环境异质性对肿瘤的疗效及耐药性有着巨大影响.本文综述了肿瘤微环境中免疫细胞及相关的免疫因子,以及血管内皮细胞异质性与肿瘤进展及预后的关系.从而更好的帮助我们理解肿瘤微环境异质性对于肿瘤的影响.有利于我们通过多种手段增强机体的抗肿瘤能力,从而抑制和杀伤肿瘤细胞.     

肿瘤血管内皮细胞异质性分子的研究进展

肿瘤血管与正常血管相比,其发生基础、表现形式及分子表达均存在明显差异,肿瘤血管内皮细胞的分子异质性是肿瘤抗血管生成靶向治疗的理论基础。深入研究肿瘤血管异质性分子对于肿瘤诊断、血管靶向治疗等具有重要意义。本文综述目前肿瘤血管内皮细胞异质性分子的研究进展,为相关研究提供参考。     

重组人血管内皮抑制素在乳腺癌治疗中的研究进展

大量研究表明抗血管生成治疗与放疗、化疗、免疫治疗及其他抗肿瘤药物联合使用可发挥协同增效作用。重组人血管内皮抑制素（恩度）是一种泛靶点类抗肿瘤血管生成靶向药物,其可通过抑制或调节肿瘤血管生成的多条信号通路,抑制内皮细胞的增殖、迁移,同时诱导内皮细胞的凋亡,抑制血管通透性的增加,使肿瘤血管“正常化”,重塑肿瘤微环境,从而改善肿瘤的综合治疗疗效,抑制肿瘤的生长和转移。近年来,恩度用于治疗乳腺癌的研究逐渐增多,并取得了可观的治疗效果,且不良反应小。全文就恩度的作用机制及其在乳腺癌治疗中的研究进展作一综述,旨在探讨恩度在乳腺癌治疗中的应用前景及优化手段,以期为乳腺癌患者尤其是三阴性乳腺癌患者带来更长远的生存获益。     

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...     

肿瘤抗血管生成治疗研究进展

肿瘤的生长和转移有赖于血管生成。抗血管生成治疗以血管内皮细胞为靶向,通过对抗肿瘤血管生成,切断肿瘤的供养,从而遏制肿瘤的生长和转移,其方法主要包括抑制或中和血管生成因子、应用血管生成抑制剂和针对特异性标记物应用素或抗体攻击肿瘤血管内皮细胞,它具有高效性、特异性、不易产生耐药和毒副作用小等优点。迄今,包括Ｅｎｄｏｓｔａｔｉｎ和Ａｎｇｉｏｓｔａｔｉｎ在内的多种抗血管生成药物在抗肿瘤实验研究中取得良好效果,并已开始走向临床。     

Tumor-associated endothelial cells with cytogenetic abnormalities

Tumor angiogenesis is necessary for solid tumor progression and metastasis. Tumor blood vessels have been shown to differ from normal counterparts, for example, by changes in morphology. An important concept in tumor angiogenesis is that tumor endothelial cells are assumed to be genetically normal, although these endothelial cells are structurally and functionally abnormal. However, we hypothesized that given the phenotypic differences between tumor and normal blood vessels, there may be genotypic alterations as well. Mouse endothelial cells were isolated from two different human tumor xenografts, melanoma and liposarcoma, and from two normal endothelial cell counterparts, skin and adipose. Tumor-associated endothelial cells expressed typical endothelial cell markers, such as CD31. They had relatively large, heterogeneous nuclei. Unexpectedly, tumor endothelial cells were cytogenetically abnormal. Fluorescence in situ hybridization (FISH) analysis showed that freshly isolated uncultured tumor endothelial cells were aneuploid and had abnormal multiple centrosomes. The degree of aneuploidy was exacerbated by passage in culture. Multicolor FISH indicated that the structural chromosomal aberrations in tumor endothelial cells were heterogeneous, indicating that the cytogenetic alterations were not clonal. There was no evidence of human tumor-derived chromosomal material in the mouse tumor endothelial cells. In marked contrast, freshly isolated normal skin and adipose endothelial cells were diploid, had normal centrosomes, and remained cytogenetically stable in culture even up to 20 passages. FISH analysis of tumor sections also showed endothelial cell aneuploidy. We conclude that tumor endothelial cells can acquire cytogenetic abnormalities while in the tumor microenvironment.     

Understanding tumor endothelial cell abnormalities to develop ideal anti-angiogenic therapies

Tumor angiogenesis is necessary for solid tumor progression and metastasis. Tumor blood vessels have been shown to differ from their normal counterparts, for example, by changes in morphology. An important concept in tumor angiogenesis is that tumor endothelial cells are assumed to be genetically normal, even though these endothelial cells are structurally and functionally abnormal. To date, many anti-angiogenic drugs have been developed, but, their therapeutic efficacy is not dramatic and they have also been reported to cause toxic side effects. To develop ideal antiangiogenic therapies, understanding tumor endothelial cell abnormalities is important. We have isolated tumor endothelial cells from mouse tumor xenografts and have shown that tumor-associated endothelial cells are abnormal. Tumor-associated endothelial cells upregulate many genes, such as epidermal growth factor receptor (EGFR). Tumor-associated endothelial cells are also more sensitive to EGF. They also have relatively large, heterogeneous nuclei. Unexpectedly, tumor endothelial cells are cytogenetically abnormal. Fluorescence in situ hybridization (FISH) analysis showed that freshly isolated uncultured tumor endothelial cells were aneuploid and had abnormal multiple centrosomes. The degree of aneuploidy was exacerbated by passage in culture. In marked contrast, freshly isolated normal skin and adipose endothelial cells were diploid. They had normal centrosomes and remained cytogenetically stable in culture even up to 20 passages. We conclude that tumor endothelial cells can acquire cytogenetic abnormalities while in the tumor microenvironment. Questions as to whether or not tumor endothelial cells become resistant to antiangiogenic drugs are thus raised. Our preliminary data show that tumor endothelial cells are more resistant to certain chemotherapeutic drugs. Studies to evaluate the mechanism for cytogenetic abnormalities in tumor endothelial cells are underway. It is becoming quite clear that the tumor vasculature is much more complex and unpredictable than initially perceived. Here, we provide an overview of the current studies on tumor endothelial cell abnormalities.     

Tumor endothelial cells accelerate tumor metastasis

Tumor metastasis is the main cause of cancer‐related death. Understanding the molecular mechanisms underlying tumor metastasis is crucial to control this fatal disease. Several molecular pathways orchestrate the complex biological cell events during a metastatic cascade. It is now well known that bidirectional interaction between tumor cells and their microenvironment, including tumor stroma, is important for tumor progression and metastasis. Tumor stromal cells, which acquire their specific characteristics in the tumor microenvironment, accelerate tumor malignancy. The formation of new blood vessels, termed as tumor angiogenesis, is a requirement for tumor progression. Tumor blood vessels supply nutrients and oxygen and also provide the route for metastasis. Tumor endothelial cells, which line tumor blood vessels, also exhibit several altered phenotypes compared with those of their normal counterparts. Recent studies have emphasized “angiocrine factors” that are released from tumor endothelial cells and promote tumor progression. During intravasation, tumor cells physically contact tumor endothelial cells and interact with them by juxtacrine and paracrine signaling. Recently, we observed that in highly metastatic tumors, tumor endothelial cells interact with tumor cells by secretion of a small leucine‐rich repeat proteoglycan known as biglycan. Biglycan from tumor endothelial cells stimulates the tumor cells to metastasize. In the present review, we highlight the role of tumor stromal cells, particularly endothelial cells, in the initial steps of tumor metastasis.     

Current concepts of tumor-induced angiogenesis

Tumor induced angiogenesis is responsible for the nutrition of the growing tumor and can also increase the probability of hematogenous tumor dissemination. Data obtained from morphological analysis of tumor angiogenesis can contribute to the development of new anti-angiogenic therapies. Based on in vitro and in vivo observations several models of angiogenesis were introduced, explaining the mechanism of lumen formation and the timing of basement membrane depositon. (1) Lumen is formed either by cell body curving or by fusion of intracellular vacuoles of nonpolarized endothelial cells. New basement membrane is deposited after lumen formation. (2) Slit-like lumen is immediately formed by migrating polarized endothelial cells. Basement membrane is continuously deposited during endothelial cell migration, only cellular processes of the endothelial cell migrating on the tip of the growing capillary are free of deposited basement membrane material. (3) Development of transluminal bridges in larger vessels - a process called intussusceptive growth - leads to the division of the vessels. These models, however, describe angiogenesis in tissues rich in connective tissue. Different processes of angiogenesis take place in organs - such as liver, lungs, adrenals, which are the most frequent sites of metastasis - having high vessel density without sufficient space for capillary sprouting. In the case of liver metastases of Lewis lung carcinoma the proliferation of endothelial cells was elicited only by direct contact between tumor and endothelial cells, leading to the development of large convoluted vessels inside the metastases. These vessels were continuous with the sinusoidal system, suggesting that these metastases have dual blood supply. This observation, among others, is in contrast to the generally accepted view that liver tumors have arterial blood supply. The increasing number of data demonstrating the dual or venous blood supply of liver metastases should be taken into consideration in the therapy of liver metastasis.     

Tumor angiogenesis—characteristics of tumor endothelial cells

Tumor blood vessels provide nutrition and oxygen to the tumor, resulting in tumor progression. They also act as gatekeepers, inducing tumor metastasis. Thus, targeting tumor blood vessels is an important strategy in cancer therapy. Tumor endothelial cells (TECs), which line the inner layer of blood vessels of the tumor stromal tissue, are the main targets of anti-angiogenic therapy. Because new tumor blood vessels generally sprout from pre-existing vasculature, they have been considered to be the same as normal blood vessels. However, tumor blood vessels demonstrate a markedly abnormal phenotype that includes several important morphological changes. The degree of angiogenesis is determined by the balance between the angiogenic stimulators and inhibitors released by the tumor and host cells. Recent studies have revealed that TECs also exhibit altered characteristics which depend on the tumor microenvironment. Here, we review recent studies on TEC abnormalities and heterogeneity with respect to tumor progression and consider their therapeutic implications.     

Vascular endothelial growth factor in ovarian cancer

Tumor growth requires nutrients and oxygen. Both nutrients and oxygen are provided via the vasculature. Thus, when a tumor increases in volume, new blood vessels must form and invade the expanding tumor. This process, called angiogenesis, has theoretical significance in the context of ovarian cancer for two reasons. First, the process of angiogenesis and vessel regression occurs in a tightly controlled way as part of normal ovarian function. This suggests that at least some ovarian cells are primed to produce the paracrine stimulus needed for new blood vessel growth and that, on tranformation, this capability is present early in tumor development. Second, the characteristically large size of ovarian tumors indicates that angiogenesis is mandatory to sustain the tumor. In this article, we review the experimental and clinical correlative data that support the hypothesis that ovarian cancers are highly angiogenic. Because a critical component of angiogenesis is the paracrine and autocrine production of vascular endothelial cell growth factor, there is substantial focus on this topic.     

Heterogeneity of tumor endothelial cells

Tumor blood vessels play important roles in tumor progression and metastasis. Thus, targeting tumor blood vessels is an important strategy for cancer therapy. Tumor endothelial cells (TECs) are the main targets of anti‐angiogenic therapy. Although tumor blood vessels generally sprout from pre‐existing vessels and have been thought to be genetically normal, they display a markedly abnormal phenotype, including morphological changes. The degree of angiogenesis is determined by the balance between the positive and negative regulating molecules that are released by tumor and host cells in the microenvironment. Reportedly, tumor blood vessels are heterogeneous with TECs differing from normal endothelial cells (in contrast to the conventional view). We recently compared characteristics of different TECs isolated from highly and low metastatic tumors. We found TECs from highly metastatic tumors had more proangiogenic phenotypes than those from low metastatic tumors. Elucidating the variety of TEC phenotypes and identifying TEC molecular signatures should lead to more complete understanding of the mechanisms of tumor progression, discovery of new therapeutic targets, and development of biomarkers. This review considers current studies on TEC heterogeneity and discusses the therapeutic implications of these findings.     

Angiogenesis in malignant lymphoma

PURPOSE OF REVIEW: Angiogenesis plays an important role in the pathophysiology of both solid tumors and hematologic malignancies. Angiogenesis-associated parameters are important prognosticators, and tumor blood vessels are an emerging target for therapy. This review addresses the evidence of the role of angiogenesis in malignant lymphoma and discusses some therapeutic implications. RECENT FINDINGS: In angiogenesis assays, lymphoma cells show angiogenic properties. Tumor vascularization is higher in lymphoma tissue than in reactive lymph nodes and increases in step with clinically more aggressive lymphoma subtypes and advanced-stage disease. High levels of vascular endothelial growth factor in blood and tissue are associated with adverse prognosis. Vascular endothelial growth factor and vascular endothelial growth factor receptors are also present in lymphoma cells. Therapy against vascular endothelial growth factor in animal models is effective and points to both the tumor cell and the host endothelium as targets. Structural microvessel abnormalities are present in some lymphoma subtypes. The role of angiogenesis might vary in lymphoma subtypes because the prognostic value of microvessel density and the expression of angiogenesis-related molecules differ between lymphoma subtypes. There are also differences in blood vessel phenotype between lymphoma subtypes. This heterogeneity may have implications for antiangiogenic therapies. Antiangiogenic therapy in human lymphoma is still in its infancy. SUMMARY: The role of angiogenesis in malignant lymphoma is evident. Tumor vasculature is an attractive target for lymphoma therapy. Differences between lymphoma subtypes must be taken into account in the selection of the most suitable patients for trials with antiangiogenic agents.     

Lymphotoxin-α promotes tumor angiogenesis in HNSCC by modulating glycolysis in a PFKFB3-dependent manner

Tumor angiogenesis is critical for tumor progression as the new blood vessels supply nutrients and facilitate metastasis. Previous studies indicate tumor associated lymphocytes, including B cells and T cells, contribute to tumor angiogenesis and tumor progression. The present study aims to identify the function of Lymphotoxin-α (LT-α), which is secreted by the activated lymphocytes, in the tumor angiogenesis of head and neck squamous cell carcinoma (HNSCC). The coculture system between HNSCC cell line Cal27 and primary lymphocytes revealed that tumor cells promoted the LT-α secretion in the cocultured lymphocytes. In vitro data further demonstrated that LT-α promoted the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) by enhancing the PFKFB3-mediated glycolytic flux. Genetic and pharmacological inhibition of PFKFB3 suppressed the enhanced proliferation and migration of HUVECs. We further identified that LT-α induced PFKFB3 expression was dependent on the TNFR/NF-κB signaling pathway. In addition, we proved that PFKFB3 blockade decreased the density of CD31 positive blood vessels in HNSCC xenografts. Finally, the results from the human HNSCC tissue array revealed that the expression of LT-α in HNSCC samples positively correlated with microvessel density, lymphocytes infiltration and endothelial PFKFB3 expression. In conclusion, infiltrated lymphocyte secreted LT-α enhances the glycolysis of ECs in a PFKFB3-dependent manner through the classical NF-κB pathway and promotes the proliferation and migration of ECs, which may contribute to the aberrant angiogenesis in HNSCCs. Our study suggests that PFKFB3 blockade is a promising therapeutic approach for HNSCCs by targeting tumor angiogenesis.     

Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis

The mechanism of tumor cell killing by OXI4503 was investigated by studying vascular functional and morphological changes post drug administration. SCID mice bearing MHEC5-T hemangioendothelioma were given a single dose of OXI4503 at 100 mg/kg. Tumor blood flow, measured by microsphere fluorescence, was reduced by 50% at 1 hr, and reached a maximum level 6-24 hr post drug treatment. Tumor vascular permeability, measured by Evan's blue and hemoglobin, increased significantly from 3 hr and peaked at 18 hr. The elevated tumor vessel permeability was accompanied by an increase in vascular endothelial growth factor (VEGF) from 1 hr post drug treatment. Immunohistochemical staining for CD31 and laminin showed that tumor blood vessels were affected as early as 3 hr but more prominent from 6 hr. From 12 hr, the vessel structure was completely destroyed. Histopathological and double immunohistochemical staining showed morphological change and induction of apoptosis in endothelial cells at 1-3 hr, followed by tumor cell necrosis from 6-72 hr. There were no statistically significant changes of Evan's blue and hemoglobin contents in liver tissue over the time course. These results suggest that OXI4503 selectively targets tumor blood vessels, and induces blood flow shutdown while it enhances tumor blood vessel permeability. The early induction of endothelial cell apoptosis leads to functional changes of tumor blood vessels and finally to the collapse of tumor vasculature, resulting in massive tumor cell necrosis. The time course of the tumor vascular response observed with OXI4503 treatment supports this drug for development as a stand alone therapy, and also lends support for the use of the drug in combination with other cancer therapies.