Cancer neovascularization and proinflammatory microenvironments

Tumor neovascularization plays critical roles for the development, progression and metastasis of cancers via utilizing blood flow to supply nutrients and oxygen. Recent cumulative information on biology of tumor neovascularization from both laboratory and clinical studies has opened us to develop new therapeutic approaches to treat malignancies by controlling angiogenic activities; i.e., a humanized monoclonal antibody bevacizumab specifically targeting VEGF (vascular endothelial growth factor), as well as several tyrosine kinase inhibitors targeting VEGF-related pathways. It is obvious that VEGF is a key molecule for tumor neovascularization, however, strategies targeting VEGF may be a milestone and not a goal for antiangiogenic approach, because it has been elucidated the complexity of cancer microenvironments that mediate neovascularization and blood-borne metastasis. Specific subsets of chemoattractants recruit hematopoietic cells from the BM (bone marrow) that support tumor neovascularization in the primary lesion, and these mobilized cells are suggested to participate in pre-metastatic niche formation for circulating tumor cells. To establish safe and effective antiangiogenic therapies, it is important to understand the cross-communication between tumors and hosts that mediate proinflammatory milieu of both primary and metastatic lesions. This review discusses special features of tumor angiogenic vessels and their microenvironments, and in addition, recent topics including contribution of BM-derived cells, special mesenchymal cells and their chemoattractants that activate tumor vascular beds are summarized.     

肿瘤血管生成机制及抗肿瘤血管新生的靶向药物研究进展

抗肿瘤血管新生治疗是以血管内皮细胞为靶点,通过降低血管活性因子的活性、抑制内皮细胞增殖和迁移、改变肿瘤生长微环境,从而抑制肿瘤生长过程中的血管新生,切断肿瘤的供养,最终达到遏制肿瘤生长和转移的目的,是一种全新的靶向肿瘤治疗方法.该方法具有高效特异性、不易产生耐药性、药物易于到达靶部位和毒副作用小等优点,可以有效地抑制肿瘤的转移和复发,现在已成为抗肿瘤血管生成药物研究的热点之一,该文综述了肿瘤血管生成的机制及抗血管新生治疗药物的最新研究进展.     

The rationale and future potential of angiogenesis inhibitors in neoplasia.

Malignant tumours are angiogenesis-dependent diseases. Several experimental studies suggest that primary tumour growth, invasiveness and metastasis require neovascularisation. Tumour-associated angiogenesis is a complex multistep process under the control of positive and negative soluble factors. A mutual stimulation occurs between tumour and endothelial cells by paracrine mechanisms. Angiogenesis is necessary, but not sufficient, as the single event for tumour growth. There is, however, compelling evidence that acquisition of the angiogenic phenotype is a common pathway for tumour progression, and that active angiogenesis is associated with other molecular mechanisms leading to tumour progression. Experimental research suggests that it is possible to block angiogenesis by specific inhibitory agents, and that modulation of angiogenic activity is associated with tumour regression in animals with different types of neoplasia. The more promising angiosuppressive agents for clinical testing are: naturally occurring inhibitors of angiogenesis (angiostatin, endostatin, platelet factor-4 and others), specific inhibitors of endothelial cell growth (TNP-470, thalidomide, interleukin-12 and others), agents neutralising angiogenic peptides (antibodies to fibroblast growth factor or vascular endothelial growth factor, suramin and analogues, tecogalan and others) or their receptors, agents that interfere with vascular basement membrane and extracellular matrix [metalloprotease (MMP) inhibitors, angiostatic steroids and others], antiadhesion molecules antibodies such as antiintegrin alpha v beta 3, and miscellaneous drugs that modulate angiogenesis by diverse mechanisms of action. Antiangiogenic therapy is to be distinguished from vascular targeting. Gene therapy aimed to block neovascularisation is also a feasible anticancer strategy in animals bearing experimental tumours. Antiangiogenic therapy represents one of the more promising new approaches to anticancer therapy and it is already in early clinical trials. Because angiosuppressive therapy is aimed at blocking tumour growth indirectly, through modulation of neovascularisation, antiangiogenic agents need to be developed and evaluated as biological response modifiers. Therefore, adequate and well designed clinical trials should be performed for a proper evaluation of antiangiogenic agents, by determination and monitoring of surrogate markers of angiogenic activity.     

Targeting angiogenesis from multiple pathways simultaneously: BIBF 1120, an investigational novel triple angiokinase inhibitor

Angiogenesis is considered one of the major components of tumor progression and metastasis. Interfering with the formation and stabilization of tumor blood vessels could increase tumor response rates and may translate into improved clinical outcomes in cancer patients. The clinical efficacy demonstrated in phase III trials with bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor ligand, suggests that targeting angiogenesis is a rational approach to cancer management. Agents that target additional proangiogenic intracellular signaling pathways also have the potential to contribute to our anticancer armamentarium. Novel targeted agents that have antiangiogenic properties have been developed in recent years such as sorafenib, sunitinib, vandetanib, and others. Many of them inhibit additional pathways beyond vascular endothelial growth factor signaling. One of these investigational targeted agents is a triple angiokinase inhibitor known as BIBF 1120. This compound targets not only vascular endothelial growth factor receptors, but also fibroblast growth factor receptors, and platelet-derived growth factor receptors. The preliminary clinical efficacy of BIBF 1120 is discussed in the context of the most relevant clinical data in several malignancies including non-small cell lung cancer.     

Development of new drugs in angiogenesis

Angiogenesis, the growth of new capillaries from pre-existing vessels, contributes to the development and progression of a variety of physio-pathological conditions. There is growing evidence that anti-angiogenic drugs will improve future therapies of diseases like cancer, rheumatoid arthritis and ocular neovascularisation. Conversely, therapeutic angiogenesis is an important homeostatic response contributing to limit the damage to ischemic tissues. Molecular processes involved in angiogenesis include stimulation of endothelial growth by cytokine production (i.e. vascular endothelial growth factor, VEGF; fibroblast growth factor-2, FGF-2), degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs), and migration of endothelial cells mediated by integrins (cell membrane adhesion molecules). Drugs targeting pathologic angiogenesis have been designed to interfere with any of these steps and are currently undergoing evaluation in early clinical studies. Important therapeutic strategies are: suppression of activity and signaling pathways activated by the major angiogenic regulators like VEGF and FGF-2; inhibition of function of alphav-integrins and MMPs; exploitation of endogenous anti-angiogenic molecules like angiostatin and endostatin. The strategy to "silence" endothelium with antiangiogenic drugs to starve tumors, provides a novel approach for cancer treatment. The unique targets of these drugs (endothelium) make them distinct from traditional cytotoxic chemotherapeutic agents. Conversely, gene transfer of angiogenesis inducers is the new approach for therapeutic neovascularization, which is under investigation using a variety of growth factors and a wide array of potential delivery systems, including the application of the gene as naked DNA or by viral vector. The status of pro- and anti-angiogenic therapies is here presented and discussed.     

Angiogenesis inhibitors. New agents in cancer therapy

Tumours that do not develop a blood supply cannot grow larger than 1 to 2mm3. The growth of a tumour blood supply, called angiogenesis, is a complex process that greatly increases the likelihood of metastatic spread and aggressive tumour behaviour. Molecular processes involved in angiogenesis include stimulation of endothelial growth by tumour cytokine production (vascular endothelial growth factor), degradation of extracellular matrix proteins by metalloproteinases, and migration of endothelial cells mediated by cell membrane adhesion molecules called integrins. These processes are being targeted by several new types of agents broadly classified as angiogenesis inhibitors. Additionally, endogenous angiogenesis inhibitors have been discovered and one of them, endostatin, is currently undergoing clinical trials. The unique targets of these drugs make them distinct from traditional cytotoxic chemotherapeutic agents. Unlike cytotoxic chemotherapy, in which the biological effect of the drug produces the antitumour effect as well as the toxic effect, angiogenesis inhibitors may produce their biological effect independently of the toxic effect. This fact raises important questions among clinical investigators as to what is the most effective way to administer these drugs and monitor their effects. This paper details some of the scientific evidence making angiogenesis an important therapeutic target as well as issues regarding the structure of clinical trials with these new anticancer agents.     

Recent advances in tumor vasculature targeting using liposomal drug delivery systems

Tumor vessels possess unique physiological features that might be exploited for improved drug delivery. The targeting of liposomal anticancer drugs to tumor vasculature is increasingly recognized as an effective strategy to obtain superior therapeutic efficacy with limited host toxicity compared with conventional treatments. This review introduces recent advances in the field of liposomal targeting of tumor vasculature, along with new approaches that can be used in the design and optimization of liposomal delivery systems. In addition, cationic liposome is focused on as a promising carrier for achieving efficient vascular targeting. The clinical implications are discussed of several approaches using a single liposomal anticancer drug formulation: dual targeting, vascular targeting (targeting tumor endothelial cells) and tumor targeting (targeting tumor cells).     

Recent advances in antiangiogenic agents with VEGFR as target

Angiogenesis is required for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. Its inhibition may be a valuable approach to cancer therapy. Antiangiogenic agents are designed to attack the tumor vasculature and cut off the tumor's supply of nutrients. Systemic blockade of angiogenesis has been recently approved for the treatment of several types of human cancers. Antiangiogenic therapy presents various advantages as compared to conventional treatment. Vascular endothelial growth factor (VEGF) is considered to be one of the most important regulators of angiogenesis and a key target in anticancer treatment. VEGF binding to its receptor (VEGFR) leads to cell proliferation and new vascular formation by tyrosine kinase (TK) pathway. VEGF/VEGFR pathway is becoming attractive target for anticancer drug design. It is believed to be important in the control of angiogenesis. Antiangiogenic therapy based on inhibition of VEGFR was reported to be powerful clinical strategies. In this review, the authors describe the existing literature regarding VEGFR inhibitors in the last few years. We attempt to cover all essential publications on the medicinal chemistry in terms of chemical structure, pharmacological profile and structure-activity relationships.     

Angiogenesis inhibitors. Drug selectivity and target specificity

The critical role of angiogenesis in tumor development and progression has long been appreciated. The elucidation of the mechanisms of tumor angiogenesis and the emergence of anticancer drugs targeting the tumor vasculature has been a breakthrough in the treatment of several tumors in the last few years. Several novel molecules are being developed that target different aspects of angiogenesis. This review outlines the principle of anti-angiogenic therapies, illustrates the main mechanisms and complexity of growth signals involved in tumor angiogenesis, its interactions with hypoxia, stroma and tumor microenvironment. It provides a comprehensive review of clinical results obtained with anti-angiogenic agents (VEGF/VEGFR signaling inhibitors, direct angiogenesis inhibitors, vascular disrupting agents) and finally discusses the differences of the several approaches and their limitations due to the emergence of resistance.     

OSU-A9 inhibits angiogenesis in human umbilical vein endothelial cells via disrupting Akt–NF-κB and MAPK signaling pathways

Since the introduction of angiogenesis as a useful target for cancer therapy, few agents have been approved for clinical use due to the rapid development of resistance. This problem can be minimized by simultaneous targeting of multiple angiogenesis signaling pathways, a potential strategy in cancer management known as polypharmacology. The current study aimed at exploring the anti-angiogenic activity of OSU-A9, an indole-3-carbinol-derived pleotropic agent that targets mainly Akt–nuclear factor-kappa B (NF-κB) signaling which regulates many key players of angiogenesis such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Human umbilical vein endothelial cells (HUVECs) were used to study the in vitro anti-angiogenic effect of OSU-A9 on several key steps of angiogenesis. Results showed that OSU-A9 effectively inhibited cell proliferation and induced apoptosis and cell cycle arrest in HUVECs. Besides, OSU-A9 inhibited angiogenesis as evidenced by abrogation of migration/invasion and Matrigel tube formation in HUVECs and attenuation of the in vivo neovascularization in the chicken chorioallantoic membrane assay. Mechanistically, Western blot, RT-PCR and ELISA analyses showed the ability of OSU-A9 to inhibit MMP-2 production and VEGF expression induced by hypoxia or phorbol-12-myristyl-13-acetate. Furthermore, dual inhibition of Akt–NF-κB and mitogen-activated protein kinase (MAPK) signaling, the key regulators of angiogenesis, was observed. Together, the current study highlights evidences for the promising anti-angiogenic activity of OSU-A9, at least in part through the inhibition of Akt–NF-κB and MAPK signaling and their consequent inhibition of VEGF and MMP-2. These findings support OSU-A9's clinical promise as a component of anticancer therapy.     

Antiangiogenic therapies in non-Hodgkin's lymphoma

The tumor microenvironment is critical in the initiation and progression of cancerous growth, which is dependent on the establishment of a functional vascular network supporting neoplastic proliferation. While the precise role of tumor angiogenesis in lymphoma pathogenesis remains under active investigation, emerging data on the proangiogenic properties of the neoplastic lymphoma cells and mechanism of vascular assembly suggest that angiogenesis is highly relevant to the biology and therapy of non-Hodgkin's lymphoma. Antiangiogenic therapies in non-Hodgkin's lymphoma are in various stages of clinical development aiming at distinct angiogenic pathways operative in endothelial cells and perivascular stromal cells. The major classes of available antiangiogenics include anti-VEGF, small molecule inhibitors targeting proangiogenic receptor tyrosine kinases and their downstream signal transduction pathways, as well as immunomodulatory compounds with antiangiogenic properties. Preliminary clinical data indicate therapeutic advantages associated with strategies targeting dual compartments of vascular cells and tumor cells, as well as multiple angiogenic pathways within the tumor microenvironment. This review summarizes recent applications of antiangiogenic strategies in non-Hodgkin's lymphoma based on current understanding of the biology of lymphoma angiogenesis.     

Angiogenesis: new targets for the development of anticancer chemotherapies

Angiogenesis is the process by which new blood vessels are formed from preexisting microvasculature. To ensure an adequate blood supply, tumor cells release angiogenic factors that are capable of promoting nearby blood vessels to extend vascular branches to the tumor. In addition, larger tumors have been shown to release angiogeneic inhibitory factors that prevent blood vessels from sending branches to smaller, more distant tumors that compete for oxygen and nutrients. Angiogenesis is a complex multistep biochemical process, and offers several potential molecular targets for non-cytotoxic anticancer therapies. Strategies for exploiting tumor angiogenesis for novel cancer drug discovery include: (i) inhibition of proteolytic enzymes that breakdown the extracellular matrix surrounding existing capillaries; (ii) inhibition of endothelial cell migration; (iii) inhibition of endothelial cell proliferation; (iv) enhancement of tumor endothelial cell apoptosis. There is also a host of miscellaneous agents that inhibit angiogenesis for which the specific mechanisms are not clear. Several methods have been developed for measuring antiangiogenic activity both in vitro and in vivo. Although there has been intensive research efforts focused at the phenomena of angiogenesis, as well as the search for antiangiogenic agents for more than two decades, many questions remain unanswered with regard to the overall biochemical mechanisms of the angiogenesis process and the potential therapeutic utility of angiogenic inhibitors. Nevertheless potent angiogenic inhibitors capable of blocking tumor growth have been discovered, and appear to have potential for development into novel anticancer therapeutics. However there are still hurdles to be overcome before these inhibitors become mainstream therapies.     

Design and development of polymer conjugates as anti-angiogenic agents

Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is one of the central key steps in tumor progression and metastasis. Consequently, it became an important target in cancer therapy, making novel angiogenesis inhibitors a new modality of anticancer agents. Although relative to conventional chemotherapy, anti-angiogenic agents display a safer toxicity profile, the vast majority of these agents are low-molecular-weight compounds exhibiting poor pharmacokinetic profile with short half-life in the bloodstream and high overall clearance rate. The “Polymer Therapeutics” field has significantly improved the therapeutic potential of low-molecular-weight drugs and proteins for cancer treatment. Drugs can be conjugated to polymeric carriers that can be either directly conjugated to targeting proteins or peptides or derivatized with adapters conjugated to a targeting moiety. This approach holds a significant promise for the development of new targeted anti-angiogenic therapies as well as for the optimization of existing anti-angiogenic drugs or polypeptides. Here we overview the innovative approach of targeting tumor angiogenesis using polymer therapeutics.     

抗肿瘤血管新药的研究进展

目前肿瘤血管靶向治疗新药的研究主要集中在两个方向,即肿瘤血管生成抑制剂(tumor angiogenesis inhibitor,TAI)和肿瘤血管靶向制剂(vascular targeting agent,VTA).TAI类旨在抑制肿瘤血管生成的过程,近年来研究较多的为血管内皮生长因子(VEGF)类、基质金属蛋白酶(MMP)类、血管抑素类、内皮抑素类等;而VAT类则是通过破坏肿瘤组织中已存在的血管从而使肿瘤坏死,主要包括小分子类VTA和生物类VTA.对近年来各类抗肿瘤血管治疗新药的种类、作用机制及各自的临床研究进展进行综述.     

Heparin derivatives as angiogenesis inhibitors

Angiogenesis is the process of generating new capillary blood vessels. Uncontrolled endothelial cell proliferation is observed in tumor neovascularization and in angioproliferative diseases. Tumors cannot growth as a mass above few mm(3) unless a new blood supply is induced. It derives that the control of the neovascularization process may affect tumor growth and may represent a novel approach to tumor therapy. Angiogenesis is controlled by a balance between proangiogenic and antiangiogenic factors. The angiogenic switch represents the net result of the activity of angiogenic stimulators and inhibitors, suggesting that counteracting even a single major angiogenic factor could shift the balance towards inhibition. Heparan sulfate proteoglycans are involved in the modulation of the neovascularization that takes place in different physiological and pathological conditions. This modulation occurs through the interaction with angiogenic growth factors or with negative regulators of angiogenesis. Thus, the study of the biochemical bases of this interaction may help to design glycosaminoglycan analogs endowed with angiostatic properties. The purpose of this review is to provide an overview of the structure/function of heparan sulfate proteoglycans in endothelial cells and to summarize the angiostatic properties of synthetic heparin-like compounds, chemically modified heparins, and biotechnological heparins.     

Perindopril: possible use in cancer therapy

Since angiogenesis is essential for the growth of any solid tumor, emerging efforts are being made to develop antiangiogenic therapy. To date, however, no antiangiogenic agent has become widely available for the clinical setting. Angiotensin I-converting enzyme (ACE) inhibitors are commonly used as antihypertensive agents and it has recently been suggested that they decrease the risk of cancer. Studies have found that an ACE inhibitor, perindopril, is a potent inhibitor of experimental tumor development and angiogenesis at a clinically comparable dose. The potent angiogenic factor, vascular endothelial growth factor (VEGF), is significantly suppressed by perindopril and also inhibits VEGF-induced tumor growth. In vitro studies showed that perindopril is not cytotoxic to either tumor cells or endothelial cells. Since perindopril is already in widespread clinical use without serious side effects, it may represent a potential new strategy for anticancer therapy.     

靶向血管内皮生长因子及其受体的抗肿瘤药物研究进展

血管生成对肿瘤的生长和转移起着关键作用,血管内皮生长因子（VEGF）及其受体信号通路是调节肿瘤新生血管生成的重要途径,因此,近年来以VEGF及其受体为作用靶标的抗肿瘤血管生成治疗已经成为研究热点,目前已有多种药物上市或处于临床试验阶段。本文主要综述了VEGF及其受体在肿瘤血管生成调节机制中的作用,同时着重介绍靶向VEGF及其受体的抗肿瘤药物的新近研究进展、临床应用及存在的问题。     

Vascular targeting of ocular neovascularization with a vascular endothelial growth factor121/gelonin chimeric protein

Tumors provide an extremely abnormal microenvironment that stimulates neovascularization from surrounding vessels and causes altered gene expression within vascular cells. Up-regulation of vascular endothelial growth factor (VEGF) receptors has allowed selective destruction of tumor vessels by administration of a chimeric protein consisting of VEGF121 coupled to the toxin gelonin (VEGF/rGel). We sought to determine whether there is sufficient up-regulation of VEGF receptors in endothelial cells participating in ocular neovascularization to permit a similar strategy. After intravenous injection of 45 mg/kg VEGF/rGel, but not uncoupled recombinant gelonin (rGel), there was immunofluorescent staining for rGel within choroidal neovascularization in mice and regression of the neovascularization occurred, demonstrating successful vascular targeting via the systemic circulation. Intraocular injection of 5 ng of VEGF/rGel also caused significant regression of choroidal neovascularization and regression of retinal neovascularization in two models, transgenic mice with expression of VEGF in photoreceptors and mice with ischemic retinopathy, whereas injection of 5 ng of rGel had no effect. These data suggest that the strategy of vascular targeting can be applied to nonmalignant neovascular diseases and could serve as the basis of a new treatment to reduce established ocular neovascularization.     

The VEGF/Rho GTPase signalling pathway: a promising target for anti-angiogenic/anti-invasion therapy

It has become increasingly apparent that current antiangiogenic therapy elicits modest effects in clinical settings. In addition, it remains challenging to treat cancer metastasis through antiangiogenic regimes. Rho GTPases are essential for vascular endothelial growth factor (VEGF)-mediated angiogenesis and are involved in tumour cell invasion. This review discusses novel therapeutic strategies that interfere with Rho GTPase signalling and further explores this network as a target for anticancer therapy through interference with tumour angiogenesis and invasion. Recent findings describe the development of innovative Rho GTPase inhibitors. Positive clinical effects of Rho GTPase targeting in combination with conventional anticancer therapy is of increasing interest.     

Inhibition of tumor angiogenesis by antibodies, synthetic small molecules and natural products

Cancer remains one of the major causes of death worldwide. The switch to pathological angiogenesis is a key process in the promotion of cancer and consequently provides several new and promising targets to anticancer therapy. Thus, antagonizing angiogenesis cuts off the tumor's oxygen and nutrition supply. This review focuses on angiogenesis inhibitors as option for cancer treatment. Modes of action, adverse effects, mechanisms of resistance as well as new developments are highlighted. One approach in angiogenesis inhibition is intermitting the further VEGF (vascular endothelial growth factor) signal pathway with monoclonal antibodies. Bevacizumab is a highly specific recombinant humanized monoclonal IgG antibody targeting VEGF-A. An efficient antitumor therapy demands more specific antibodies that affect other signal molecules besides VEGF-A, which is in the focus of current research. In addition to antagonizing VEGF, there are also small molecules that inhibit receptor tyrosine kinases (RTKs). Many RTK inhibitors have been described, which exhibit different specificity profiles. The question, whether highly specific antagonists are necessary remains open, because other affected RTKs may also represent growth factor receptors that are essential for tumor growth. Therefore their inhibition may also contribute to anticancer activity. Secondary plant metabolites represent templates for the development of new small molecules. The identification of new drugs from plants has a long and successful history. There is convincing evidence for the beneficial effect of phytochemicals on cancer-related pathways, particularly with regard to anti-angiogenesis. Plant phenolics are the most important category of phytochemicals, including flavanoids. Prominent phytochemicals affecting different pathways of angiogenesis are green tea polyphenols (epigallocatechin gallate) and soy bean isoflavones (genistein).