Mechanisms of angiogenesis in gliomas

Summary Gliomas are the most frequent primary tumors of the central nervous system in adults. Glioblastoma multiforme, the most aggressive form of astrocytic tumors, displays a rapid progression that is accompanied by particular poor prognosis of patients. Intense angiogenesis is a distinguishing pathologic characteristic of these tumors and in fact, glioblastomas are of the most highly vascularized malignant tumors. For this reason, research and therapy strategies have focused on understanding the mechanisms leading to the origin of tumor angiogenic blood vessels in order to develop new approaches that effectively block angiogenesis and cause tumor regression. We discuss here some important features of glioma angiogenesis and we present molecules and factors and their possible functions and interactions that play a role in neovascularization. In spite of the great progress that molecular biology has achieved on investigating tumor angiogenesis, many aspects remain obscure and the complexity of the angiogenic process stands for an obstacle in identifying the exact and complete molecular pathways orchestrating new blood vessels formation, which are necessary for the survival and expansion of these tumors.     

Anti-angiogenic Treatment Strategies for Malignant Brain Tumors

The use of angiogenesis inhibitors may offer novel strategies in brain tumor therapy. In contrast to traditional cancer treatments that attack tumor cells directly, angiogenesis inhibitors target at the formation of tumor-feeding blood vessels that provide continuous supply of nutrients and oxygen.With respect to brain tumor therapy, inhibitors of angiogenesis display unique features that are unknown to conventional chemotherapeutic agents. The most important features are independence of the blood–brain barrier, cell type specificity, and reduced resistance. Malignant brain tumors, especially malignant gliomas, are among the most vascularized tumors known. Despite multimodal therapeutic approaches, the prognosis remains dismal. Thus, angiogenesis inhibitors may be highly effective drugs against these tumors. In a clinical setting, they could be applied in the treatment of multiple tumors or postsurgically as an adjuvant therapy to prevent recurrence.This article provides an overview of current anti-angiogenic treatment strategies with emphasis on substances already in clinical trials or candidate substances for clinical trials. The cellular and molecular basis of these substances is reviewed.     

Molecular Mechanisms of Tumor Angiogenesis and Tumor Progression

The formation of new blood vessels (angiogenesis) is crucial for the growth and persistence of primary solid tumors and their metastases. Furthermore, angiogenesis is also required for metastatic dissemination, since an increase in vascular density will allow easier access of tumor cells to the circulation. Induction of angiogenesis precedes the formation of malignant tumors, and increased vascularization seems to correlate with the invasive properties of tumors and thus with the malignant tumor phenotype. In the last few years, the discovery and characterization of tumor-derived angiogenesis modulators greatly contributed to our understanding of how tumors regulate angiogenesis. However, although angiogenesis appears to be a rate-limiting event in tumor growth and metastatic dissemination, a direct connection between the induction of angiogenesis and the progression to tumor malignancy is less well understood. In this review, we discuss the most recent observations concerning the modulation of angiogenesis and their implications in tumor progression, as well as their potential impact on cancer therapy.     

抗肿瘤血管靶向药物的研究进展

肿瘤血管生成对大多数实体瘤的生长和转移具有重要意义,是多步骤多因素参与的复杂病理过程.选择肿瘤血管生成中的一些关键环节或参与的重要因子作为靶点,研制应用特异性肿瘤血管生成抑制剂或抗体,以靶向调控肿瘤血管生成,控制肿瘤的生长和转移,达到治疗肿瘤的目的.本文对近年来肿瘤血管生成机制和肿瘤血管生成抑制剂的研究进展进行综述.     

血管内皮生长因子和Dll4-Notch信号通路在肿瘤血管发生中的作用

抗肿瘤血管发生是一种全新的抗肿瘤治疗策略,目前研究最多的是寻找有效抗血管内皮生长因子(VEGF)信号通路的药物.然而VEGF抑制剂并不是对所有肿瘤有效,因此,有必要进一步探索血管发生的其他信号通路.目前,Dll4-Notch信号通路被认为是抗肿瘤血管发生的新靶点,而且VEGF和Dll4-Notch信号通路在多方面相互作...     

Integrin alpha4beta1 promotes monocyte trafficking and angiogenesis in tumors

Monocytes and macrophages extensively colonize solid tumors, where they are thought to promote tumor angiogenesis. Here, we show that integrin alpha4beta1 (VLA4) promotes the invasion of tumors by myeloid cells and subsequent neovascularization. Antagonists of integrin alpha4beta1, but not of other integrins, blocked the adhesion of monocytes to endothelium in vitro and in vivo as well as their extravasation into tumor tissue. These antagonists prevented monocyte stimulation of angiogenesis in vivo, macrophage colonization of tumors, and tumor angiogenesis. These studies indicate the usefulness of antagonists of integrin alpha4beta1 in suppressing macrophage colonization of tumors and subsequent tumor angiogenesis. These studies further indicate that suppression of myeloid cell homing to tumors could be a useful supplementary approach to suppress tumor angiogenesis and growth.     

血管内皮生长因子和D114-Notch信号通路在肿瘤血管发生中的作用

抗肿瘤血管发生是一种全新的抗肿瘤治疗策略,目前研究最多的是寻找有效抗血管内皮生长因子（VEGF）信号通路的药物。然而VEGF抑制剂并不是对所有肿瘤有效,因此,有必要进一步探索血管发生的其他信号通路。目前,DH4-Nmch信号通路被认为是抗肿瘤血管发生的新靶点,而且VEGF和DH4-N0tch信号通路在多方面相互作用,在调控血管发生过程中发挥重要作用,对这两条通路的探索和研究,将会使治疗肿瘤的手段更为丰富。     

The selective Cox-2 inhibitor Celecoxib suppresses angiogenesis and growth of secondary bone tumors: An intravital microscopy study in mice

Background  

The inhibition of angiogenesis is a promising strategy for the treatment of malignant primary and secondary tumors in addition to established therapies such as surgery, chemotherapy, and radiation. There is strong experimental evidence in primary tumors that Cyclooxygenase-2 (Cox-2) inhibition is a potent mechanism to reduce angiogenesis. For bone metastases which occur in up to 85% of the most frequent malignant primary tumors, the effects of Cox-2 inhibition on angiogenesis and tumor growth remain still unclear. Therefore, the aim of this study was to investigate the effects of Celecoxib, a selective Cox-2 inhibitor, on angiogenesis, microcirculation and growth of secondary bone tumors.     

Antiangiogenic cancer therapy

Like most embryonic tissues, tumors have the ability to build up their own blood vessel networks. However, the architecture of tumor vessels is fundamentally different from that found in healthy tissues. Tumor vessels are usually irregular, heterogeneous, leaky, and poorly associated with mural cells. Endothelial cells in tumor vessels are also disorganized and express imbalanced surface molecules. These unusual features may provide some molecular and structural basis for selective inhibition or even destruction of tumor vessels by angiogenesis inhibitors. In animal tumor models, several angiogenesis inhibitors seem to inhibit tumor angiogenesis specifically without obvious effects on the normal vasculature. As a result, these inhibitors produced potent antitumor effects in mice. Excited by these preclinical studies, more than 60 angiogenesis inhibitors are being evaluated for their anticancer effects in human patients. Although the ultimate outcome of antiangiogenic clinical trials remains to be seen, several early observations have reported some disappointing results. These early clinical data have raised several important questions. Can we cure human cancers with angiogenesis inhibitors? Have we found the ideal angiogenesis inhibitors for therapy? What is the difference between angiogenesis in an implanted mouse tumor and in a spontaneous human tumor? What are the molecular mechanisms of these angiogenesis inhibitors? Should angiogenesis inhibitors be used alone or in combinations with other existing anticancer drugs? In this review, we will discuss these important issues in relation to ongoing antiangiogenic clinical trials.     

Antiangiogenic activity of BAI1 in vivo: implications for gene therapy of human glioblastomas

Glioblastomas are the most common primary brain tumors in adults. These tumors exhibit a high degree of vascularization, and malignant progression from astrocytoma to glioblastoma is often accompanied by increased angiogenesis and the upregulation of vascular endothelial growth factor and its receptors. In this study, we investigated the in vivo antiangiogenic and antitumor effects of brain-specific angiogenesis inhibitor 1 (BAI1) using human glioblastoma cell lines. Glioblastoma cells were transduced with an adenoviral vector encoding BAI1 (AdBAI1), and Northern and Western blot analyses, respectively, demonstrated BAI1 mRNA and protein expression in the transduced tumor cells. Using an in vivo neovascularization assay, we found that angiogenesis surrounding AdBAI1-transduced glioblastoma cells transplanted into transparent skinfold chambers of SCID mice was significantly impaired compared to control treated cells. Additionally, in vivo inoculation with AdBAI1 of established subcutaneous or intracerebral transplanted tumors significantly impaired tumor growth and promoted increased mouse survival. Morphologically, the tumors exhibited signs of impaired angiogenesis, such as extensive necrosis and reduced intratumoral vascular density. Taken together, these data strongly indicate that BAI1 may be an excellent gene therapy candidate for the treatment of brain tumors, especially human glioblastomas.     

Interstitial fluid pressure in cervical cancer: guide to targeted therapy

Interstitial fluid pressure (IFP) is elevated in most malignant tumors, mainly as a result of the abnormal tumor vasculature that develops from unregulated angiogenesis. Theoretical models predict that IFP should correlate with capillary flow resistance in tumors, and therefore also with perfusion and oxygenation. However, a prospective clinical study in patients with cervical cancer at Princess Margaret Hospital failed to demonstrate a relationship between IFP and oxygenation. Despite this, high IFP was strongly associated with inferior survival after radiotherapy independent of clinical prognostic factors and tumor oxygen status. This suggests that IFP and direct needle oxygen measurements may provide information about different aspects of tumor oxygenation, such as chronic versus intermittent hypoxia. Alternatively, IFP may reflect an aspect of tumor biology that is largely unrelated to perfusion and oxygenation. One possibility is that tumors with high pretreatment angiogenesis levels, as indicated by high IFP, may be more radioresistant because the vascular endothelium is more likely to survive during and after treatment. The mechanistic link between elevated IFP and the abnormal tumor vasculature and the strong prognostic effect of IFP in our cervix study together suggest that drugs targeted at angiogenesis, when combined with radiotherapy, may lead to improved tumor control and patient survival.     

Hypoxia inducible factor-1 independent pathways in tumor angiogenesis.

Among the factors that can stimulate angiogenesis, vascular endothelial growth factor has emerged as one of the most important, and inhibition of vascular endothelial growth factor has recently shown efficacy in the treatment of advanced colorectal cancer. Hypoxia develops within solid tumors and is one of the most potent stimuli of vascular endothelial growth factor expression. This effect is mediated primarily by hypoxia inducible factor-1 (HIF-1), often considered a master regulator of angiogenesis in hypoxia. Consequently, inhibition of HIF-1 has been proposed as a strategy to block tumor angiogenesis therapeutically. However, accumulating evidence indicates that HIF-independent pathways can also control angiogenesis. This review highlights some of the key signaling pathways independent of HIF-1 that can stimulate angiogenesis in hypoxia. Understanding the full spectrum of molecular pathways that control tumor angiogenesis is critical for the optimal design of targeted therapies.     

Dissociation of angiogenesis and tumorigenesis in follistatin- and activin-expressing tumors

The transforming growth factor-beta superfamily member activin and its antagonist, follistatin, act as a pleiotropic growth factor system that controls cell proliferation, differentiation, and apoptosis. Activin inhibits fibroblast growth factor 2-induced sprouting angiogenesis in vitro (spheroidal angiogenesis assay) and in vivo (Matrigel assay). To further study the role of the activin/follistatin system during angiogenesis and tumor progression, activin- and follistatin-expressing R30C mammary carcinoma cells were studied in mouse tumor experiments. Surprisingly, activin-expressing tumors grew much faster than follistatin-expressing tumors although they failed to induce increased angiogenesis (as evidenced by low microvessel density counts). Conversely, follistatin-expressing tumors were much smaller but had a dense network of small-diameter capillaries. Qualitative angioarchitectural analyses (mural cell recruitment, perfusion) revealed no major functional differences of the tumor neovasculature. Analysis of activin- and follistatin-expressing R30C cells identified a cell autonomous role of this system in controlling tumor cell growth. Whereas proliferation of R30C cells was not altered, follistatin-expressing R30C cells had an enhanced susceptibility to undergo apoptosis. These findings in experimental tumors are complemented by an intriguing case report of a human renal cell carcinoma that similarly shows a dissociation of angiogenesis and tumorigenesis during tumor progression. Collectively, the data shed further light into the dichotomous stimulating and inhibiting roles that the activin/follistatin system can exert during angiogenesis and tumor progression. Furthermore, the experiments provide a critical proof-of-principle example for the dissociation of angiogenesis and tumorigenesis, supporting the concept that tumor growth may not be dependent on increased angiogenesis as long as a minimal intratumoral microvessel density is maintained.     

肿瘤源性IL-35促进肿瘤血管生成的研究进展

白细胞介素-35（interleukin-35，IL-35）是IL-12家族中新发现的异二聚体细胞因子，其与TGF-β、IL-10被认为是三种最重要的免疫抑制因子。IL-35广泛表达于多种免疫细胞及肿瘤细胞。近年来越来越多的研究表明，IL-35在恶性肿瘤中不仅发挥着免疫抑制作用，同时在肿瘤细胞增殖、凋亡、侵袭迁移、血管生成等恶性行为中发挥重要作用。肿瘤血管生成是实体肿瘤发生发展中不可或缺的环节，本文对IL-35在肿瘤血管生成中的作用进行分析总结，以供临床和基础研究参考。      

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.     

Tumor inflammatory angiogenesis and its chemoprevention

The importance of angiogenesis for the growth of tumors is widely recognized. Drugs that successfully target the endothelium, such as antivascular endothelial growth factor antibodies, are beginning to have an effect on the life expectancy of cancer patients. However, the endothelial cell is not the only possible target for antiangiogenic therapy or prevention of vascularization (angioprevention). It is evident from the literature that native immune cells recruited into tumors in turn stimulate the endothelium and are responsible for an indirect pathway of tumor vascularization. Inflammation-dependent angiogenesis seems to be a central force in tumor growth and expansion, a concept supported by the observation that the use of "classic" anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs, leads to angiogenesis inhibition. The mechanisms of inflammatory angiogenesis provide new approaches to target, cure, or even better, prevent tumor angiogenesis by treatment with synthetic or natural agents with anti-inflammatory properties. We propose chemoprevention of inflammatory angiogenesis as a way of checking the cancer before it progresses.     

Revisiting tumor angiogenesis：vessel co-option,vessel remodeling,andcancer cell-derived vasculature formation

Tumor growth and metastasis depend on the establishment of tumor vasculature to provide oxygen, nutrients, and other essential factors. The well?known vascular endothelial growth factor (VEGF) signaling is crucial for sprout?ing angiogenesis as well as recruitment of circulating progenitor endothelial cells to tumor vasculature, which has become therapeutic targets in clinical practice. However, the survival beneifts gained from targeting VEGF signal?ing have been very limited, with the inevitable development of treatment resistance. In this article, we discuss the most recent ifndings and understanding on how solid tumors evade VEGF?targeted therapy, with a special focus on vessel co?option, vessel remodeling, and tumor cell?derived vasculature establishment. Vessel co?option may occur in tumors independently of sprouting angiogenesis,and sprouting angiogenesis is not always required for tumor growth. The differences between vessel?like structure and tubule?like structure formed by tumor cells are also intro?duced. The exploration of the underlying mechanisms of these alternative angiogenic approaches would not only widen our knowledge of tumor angiogenesis but also provide novel therapeutic targets for better controlling cancer growth and metastasis.     

Ablation of peripheral dopaminergic nerves stimulates malignant tumor growth by inducing vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis

Many important physiological and pathological processes are modulated by angiogenesis. It has been shown that initiation of this angiogenic process is an essential early step in the progression of malignant tumors. We report here that ablation of peripheral dopaminergic nerves markedly increased angiogenesis, microvessel density, microvascular permeability, and growth of malignant tumors in mice. Endogenous peripheral dopamine acted through D2 receptors as significantly more angiogenesis and tumor growth was observed in D2 dopamine receptor knockout mice in comparison with controls. The vascular endothelial growth factor receptor 2 phosphorylation, which is critical for promoting angiogenesis, was also significantly more in tumor endothelial cells collected from the dopamine-depleted and D2 dopamine receptor knockout animals. These results reveal that peripheral endogenous neurotransmitter dopamine might be an important physiological regulator of vascular endothelial growth factor-mediated tumor angiogenesis and growth and suggest a novel link between endogenous dopamine, angiogenesis, and tumor growth.     

A single extra copy of Dscr1 improves survival of mice developing spontaneous lung tumors through suppression of tumor angiogenesis

The incidence of most solid tumors is remarkably reduced in individuals with Down syndrome. Using mouse models of Down syndrome, we have previously shown that this decrease in tumor incidence is due, in part, to suppression of tumor angiogenesis as a consequence of attenuated calcineurin signaling in endothelial cells. Our prior studies utilized xenografted tumors in a transgenic mouse model with three copies of the Down syndrome critical region-1 (Dscr1) gene, a chromosome 21-encoded endogenous calcineurin inhibitor. These data indicate that upregulated Dscr1 contributes to broad cancer protection by suppressing tumor angiogenesis through inhibiting the calcineurin pathway in the vascular endothelium. However, it still remains to be confirmed whether a single extra copy of Dscr1 is also sufficient to suppress tumor angiogenesis in slow growing spontaneous tumors that more accurately recapitulate molecular features of human malignancies. In this study, utilizing LSL-Kras^G12D mice, an inducible and autochthonous model of human lung adenocarcinoma, on a Dscr1 transgenic mouse background, we show that a single extra transgenic copy of Dscr1 provides a survival advantage in these mice developing spontaneous lung tumors driven by oncogenic Kras^G12D without affecting either initiation or progression of spontaneous lung tumors. Furthermore, we show that Dscr1 trisomy significantly reduces microvessel density in lung tumors and thus limits the growth of lung tumors through decreased proliferation and increased apoptosis of lung tumor cells. These data provide evidence that a single extra copy of Dscr1 is sufficient to suppress tumor angiogenesis during spontaneous lung tumorigenesis and further support our hypothesis that suppression of tumor angiogenesis by an additional copy of Dscr1 contributes to the reduced cancer incidence in individuals with Down syndrome and the calcineurin pathway in the tumor vasculature is a potential target for cancer treatment.     

Ｅｎｄｏｇｌｉｎ（ＣＤ１０５）在肿瘤新生血管靶向诊断及治疗中的应用

Ｅｎｄｏｇｌｉｎ（ＣＤ１０５）是最可靠的内皮细胞增殖标志物,在肿瘤新生血管中过表达。基于Ｅｎｄｏｇｌｉｎ的靶向显像可以了解恶性肿瘤的血管生成情况,并为新生血管靶向治疗提供依据。在生物治疗方面,单克隆抗体在恶性肿瘤治疗中的地位越来越重要,因而基于抗Ｅｎｄｏｇｌｉｎ抗体的肿瘤靶向治疗在近年来受到广泛关注。本文将对基于Ｅｎｄｏｇｌｉｎ的靶向诊断及治疗作一简要综述。