血管内皮生长因子及受体与血液恶性肿瘤

血管内皮生长因子(VEGF)在实体瘤的发生、发展及转移过程起重要作用,但在血液恶性肿瘤中的作用研究较少,本文介绍多种血液恶性肿瘤细胞高表达VEGF,不同程度表达VEGF受体,血液恶性肿瘤患者骨髓血管新生明显,VEGF及受体在血液恶性肿瘤过程亦起重要作用。     

血管内皮生长因子及受体与血液恶性肿瘤

血管内皮生长因子（VEGF）在实体瘤的发生、发展及转移过程起重要作用，但在血液恶性肿瘤中的作用研究较少，本文介绍多种血液恶性肿瘤细胞高表达VEGF，不同程度表达VEGF受体，血液恶性肿瘤患者骨髓血管新生明显，VEGF及受体在血液恶性肿瘤过程亦起重要作用。     

血管内皮生长因子及其受体在肿瘤研究的概况

血管新生是肿瘤生长、转移扩散的一个关键因素。VEGF及其受体是这一过程的最重要调控因素，大量研究显示VEGF及其受体在多种恶性肿瘤中呈高水平表达，并与不良的预后及肿瘤复发相关，被认为是一个有用的临床检测指标用于评估预后及疗效。随着肿瘤靶向治疗的进展，VEGF及其受体成为抗肿瘤治疗中的一个热点。     

血清VEGF及其受体在消化道肿瘤预后中的研究进展

血管生成是实体瘤生长和转移的前提条件,而且与肿瘤的预后密切相关.血管生成的调节通过肿瘤细胞分泌的血管生成因子而实现.近年来研究发现,许多血管生成因子与肿瘤的血管生成有关,其中血管内皮生长因子(VEGF)是目前发现最重要的促进肿瘤血管形成的因子.在生理情况下,人体组织和血液中VEGF的表达水平很低,低氧、缺血和实体肿瘤可使VEGF合成增加,并与消化道肿瘤、呼吸系统肿瘤、妇科肿瘤的生长、转移以及预后密切相关[1-2].因此,血清VEGF(S-VEGF)水平在一定程度上反映肿瘤组织血管的生成能力.本文综述S-VEGF及其受体在消化道肿瘤预后中的研究进展. 1食管癌 血清VEGF(S-VEGF)水平是食管鳞癌重要的独立预后因素.Shimada等[3]报道,原发性食管癌患者S-VEGF水平升高,并与肿瘤体积、病理分级、淋巴结及远处转移有关,而复发与痊愈的食管癌患者S-VEGF水平基本正常.Nomiya等[4]认为S-VEGF水平与食管鳞状细胞癌的大小、浸润深度、淋巴结及远处转移和TNM分期密切相关.     

内抑素的研究进展

新生血管的生成是实体瘤生长和转移所必需的 ,肿瘤能够分泌一系列的促血管生成因子 ,如成纤维细胞生长因子 (a FGF和 b FGF)和血管内皮细胞生长因子 (VEGF)以刺激血管的生成。而有的研究表明恶性肿瘤也能产生抑制血管生成因子而抑制其转移灶的生长。内抑素 (endostatin)正是基于这种假设从小鼠内皮瘤细胞株的培养液中分离出来的。内抑素是一种内皮细胞增殖的特异性抑制剂 ,具有很强的抑制血管生成的作用。因而内抑素能够抑制肿瘤的生长和转移 ,另有研究表明内抑素能够阻断动脉粥样硬化的发展。1　内抑素的结构O′ Reilly等 1994年从 L…     

非霍奇金淋巴瘤患者血浆血管内皮细胞生长因子浓度测定的临床意义

血管新生机制是恶性肿瘤的重要发病机制.血管内皮生长因子(vascular endothelial growth factor, VEGF)是参与血管新生作用最强最具特征性的促血管生成介质,它可刺激血管生成,促进内皮细胞的增殖与迁移,使血管通透性增加.国外的许多研究证实在非霍奇金淋巴瘤中存在着血管新生,而且VEGF及受体在非霍奇金淋巴瘤的多种细胞系中表达,血清VEGF水平已成为非霍奇金淋巴瘤(non-Hodgkin lymphoma, NHL)的一项独立预后因素.本研究中我们主要应用酶联免疫吸附测定(ELISA)的方法检测NHL患者血浆VEGF浓度,旨在探讨NHL患者血浆VEGF(P-VEGF)与临床病情的关系.     

基质细胞衍生因子-1及其受体、血管内皮生长因子与肿瘤血管生成的研究进展

肿瘤侵袭转移是恶性肿瘤最基本的生物学特征,肿瘤血管形成又是肿瘤无限制增殖、侵袭性生长及转移的关键.因此,阻断新生血管的形成,是减少和预防肿瘤转移,进行肿瘤治疗的新策略.血管生成的过程是有多种因子参与的复杂过程,最近的研究发现基质细胞衍生因子-l(stromal cell-derived factor-1,SDF-1)及其特异性受体[趋化因子受体-4 chemokine(C-X-C motif)receptor 4,CXCR4]有促肿瘤血管新生的作用,而且这种血管化作用与血管内皮生长因子(vascular endothelial growth factor,VEGF)有着密切的联系,该文就SDF-1及其受体CXCR4与VEGF在肿瘤血管生成的相互作用和可能的机制作一综述.     

整合素受体示踪剂进行肿瘤靶向显像进展

实体瘤瘤组织由瘤细胞和问质构成，后者主要包括血管、淋巴管、结缔组织、炎细胞和细胞外基质等成分。肿瘤内的血管生成的过程是通过新生血管生成来完成。血管生成是指从已经存在的血管床产生新血管的过程。肿瘤血管生成是肿瘤细胞的侵润、迁移、增殖的重要过程，肿瘤血管生成不仅受到促血管生成的酶、生长因子及受体的控制，     

血管内皮生长因子及其受体与恶性血液病

血管内皮生长因子(vascular endothelial growth factor,VEGF)及其受体是血管新生的正调控因子,最近发现VEGF在多种恶性血液病细胞表达升高,是许多恶性血液病细胞生长转移的重要刺激因子之一,抑制VEGF及其受体的产生为治疗某些恶性血液病治疗新策略。     

血管新生与淋巴瘤关系的研究现状

血管新生(angiogenesis)指机体内新血管形成的基本过程,是近年来一个新兴的医学研究领域.目前血管新生在肿瘤中的作用已得到确认,主要包括实体瘤和某些血液系统的肿瘤,如白血病、多发性骨髓瘤.近年来对淋巴瘤的研究表明血管新生与淋巴瘤的发展及预后密切相关,抗血管新生疗法可能成为治疗淋巴瘤的另一种有效方法.笔者就血管新生的概况、血管新生与淋巴瘤发生、发展的关系及其在临床方面的应用进行综述.     

Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity

Various conventional chemotherapeutic drugs can block angiogenesis or even kill activated, dividing endothelial cells. Such effects may contribute to the antitumor efficacy of chemotherapy in vivo and may delay or prevent the acquisition of drug-resistance by cancer cells. We have implemented a treatment regimen that augments the potential antivascular effects of chemotherapy, that is devoid of obvious toxic side effects, and that obstructs the development of drug resistance by tumor cells. Xenografts of 2 independent neuroblastoma cell lines were subjected to either continuous treatment with low doses of vinblastine, a monoclonal neutralizing antibody (DC101) targeting the flk-1/KDR (type 2) receptor for VEGF, or both agents together. The rationale for this combination was that any antivascular effects of the low-dose chemotherapy would be selectively enhanced in cells of newly formed vessels when survival signals mediated by VEGF are blocked. Both DC101 and low-dose vinblastine treatment individually resulted in significant but transient xenograft regression, diminished tumor vascularity, and direct inhibition of angiogenesis. Remarkably, the combination therapy resulted in full and sustained regressions of large established tumors, without an ensuing increase in host toxicity or any signs of acquired drug resistance during the course of treatment, which lasted for >6 months. This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.     

Inhibition of ovarian tumor growth by gene therapy with recombinant soluble vascular endothelial growth factor receptor 2

The growth and persistence of solid tumors and their metastases are angiogenesis dependent. Targeting angiogenesis represents a new strategy for the development of antitumor therapies. The extracellular immunoglobulin- like domain of VEGFR-2 (KDR/Flk-1), soluble VEGFR-2, may form a heterodimeric complex with a wild-type VEGF receptor and function as a dominant negative receptor. We assessed the effects of sFlk-1 on SKOV3 cell growth and proliferation in vitro. Furthermore, we investigated the effectiveness of recombinant soluble Flk-1 adenovirus on inhibition of tumor growth in an ovarian tumor (SKOV3) nude murine model, combined with cis-diamminedichloroplatinum (DDP). Nude mice bearing SKOV3 tumors received adsFlk- 1 (recombinant soluble Flk-1 adenovirus) and DDP, respectively or in combination, and tumor growth inhibition, microvessel density, and apoptosis in tumor tissue were assessed by immunohistochemical analysis. Our data revealed that sFlk-1 had little effect on tumor cell growth in vitro, whereas ad-sFlk-1 administration could inhibit tumor growth significantly (p < 0.05) in the nude murine model, accompanied by angiogenesis suppression and apoptosis induction, and augmented efficiency was observed in combination with DDP as well. The present findings suggest that gene therapy with ad-sFlk-1 is an efficient antiangiogenesis strategy, which may be important in further exploration and possible translation into a clinical trial.     

Angiogenesis in gynecology and obstetrics]

In current scientific discussion, increasing importance is being given to the clinical significance of the new formation of vessels (angiogenesis) in the course of physiological, inflammatory and neoplastic processes. Angiogenesis is best studied in the growth of malignant tumors, since cancer may be regarded as the most important angiogenesis-dependent disease in terms of social and economic aspects. The significance of angiogenesis in gynecological oncology is as follows: 1) Intratumoral vessel density is an indicator for the emergence and growth of malignant tumours and their precursor lesions, 2) intratumoral vessel density is an independent prognostic factor for solid malignancies and 3) the inhibition of tumor angiogenesis by means of anti-angiogenetic substances causes tumor growth to be suppressed. Angiogenesis also plays an important role in the regulation of the female menstrual cycle. Proliferation of the endometrium and the formation of the corpus luteum in the second half of the menstrual cycle are examples of angiogenesis in the physiological field. The function of angiogenetic factors in the emergence of endometriosis and in female and male infertility are currently under study. In obstetrics, the new formation of blood vessels is significant for the implantation of impregnated blastocysts and for the development and growth of the placenta. Preeclempsia (gestational toxicosis), for instance, is a typical pregnancy-related disease whose pathophysiological mechanism is attributed to a disturbed development and function of small placental vessels. The present paper is an overview of current knowledge and current approaches of research concerning angiogenesis in the field of gynecology and obstetrics. The paper is focused on the clinical significance of angiogenesis.     

VEGF as an inhibitor of tumor vessel maturation: implications for cancer therapy

Tumor angiogenesis is an important component of cancer biology driven in part by the thesis that inhibition of tumor vessel growth would be expected to starve and thereby disrupt tumor growth. A significant portion of research on tumor angiogenesis has focused on VEGF and its blockade with the expectation that dramatic results would be demonstrated in cancer patients as previously documented in animal models. However, to date, anti-VEGF (bevacizumab, Avastin) therapy alone has demonstrated little if any antitumor activity or survival benefit in humans. Interestingly, bevacizumab in combination with chemotherapeutic agents appears to result in a modest survival benefit in patients with various malignancies. This has prompted the re-evaluation of the biological effects resulting from VEGF blockade. Recent reports indicate that inhibition of VEGF and its receptor can have dramatic and unexpected effects on mural and perivascular cells in the tumor microenvironment, leading to vascular smooth muscle cell/pericyte activation and vessel normalization/maturation. Specifically, when VEGF levels in tumors are high, recent studies suggest that this leads to reduced responsiveness of the mural cell to the related growth factor, platelet-derived growth factor. This raises the possibility that in addition to the demonstrated anti-angiogenic effect of VEGF neutralization, mural cell recruitment and thus vascular maturation might be among the most critical activities of anti-VEGF agents. This review seeks to explore how VEGF blockade impacts tumor vascular maturation and considers its implications for cancer therapy.     

Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer

The molecular mechanisms that control the balance between antiangiogenic and proangiogenic factors and initiate the angiogenic switch in tumors remain poorly defined. By combining chemical genetics with multimodal imaging, we have identified an autocrine feed-forward loop in tumor cells in which tumor-derived VEGF stimulates VEGF production via VEGFR2-dependent activation of mTOR, substantially amplifying the initial proangiogenic signal. Disruption of this feed-forward loop by chemical perturbation or knockdown of VEGFR2 in tumor cells dramatically inhibited production of VEGF in vitro and in vivo. This disruption was sufficient to prevent tumor growth in vivo. In patients with lung cancer, we found that this VEGF:VEGFR2 feed-forward loop was active, as the level of VEGF/VEGFR2 binding in tumor cells was highly correlated to tumor angiogenesis. We further demonstrated that inhibition of tumor cell VEGFR2 induces feedback activation of the IRS/MAPK signaling cascade. Most strikingly, combined pharmacological inhibition of VEGFR2 (ZD6474) and MEK (PD0325901) in tumor cells resulted in dramatic tumor shrinkage, whereas monotherapy only modestly slowed tumor growth. Thus, a tumor cell-autonomous VEGF:VEGFR2 feed-forward loop provides signal amplification required for the establishment of fully angiogenic tumors in lung cancer. Interrupting this feed-forward loop switches tumor cells from an angiogenic to a proliferative phenotype that sensitizes tumor cells to MAPK inhibition.     

Antitumor and antimetastatic effect of warfarin and heparins.

Experimental and clinical studies have shown an anticancer effect of anticoagulant drugs. The aim of this study is to review the mechanisms by which the common types of anticoagulants influence the primary tumor and metastatic processes of solid tumors. The review evaluates the interference of unfractionated heparin (UFH), low molecular weight heparin (LMWH) and warfarin on the growth of primary tumors and on the development of metastases. The first part of the review evaluates the effect on the growth and development of primary tumors. Attention is paid to the interference with proliferation of cancer cells, tumor angiogenesis and to the interference with the immune system. The second part of the review describes the metastatic process and the effect of anticoagulants on the cell motility and cancer cell adhesion. The third part refers to the outcomes of clinical studies with anticoagulant treatment in patients with cancer. The problem of thromboembolic disease in patients with advanced cancer is also mentioned. The anticoagulants are more effective in inhibition of stages of the metastatic cascade than in the influence on primary tumors. They can interfere with tumor angiogenesis, immunity system, cancer cell motility and adhesion. The first clinical trials showed an effect on the development of primary tumors and survival of patients namely with lung cancer.     

Antiangiogenic activity of 4'-thio-beta-D-arabinofuranosylcytosine

4'-Thio-beta-D-arabinofuranosylcytosine (T-araC), a new-generation deoxycytidine nucleoside analogue, showed significant efficacy against numerous solid tumors in preclinical studies and entered clinical development for cancer therapy. It is a structural analogue of cytarabine (araC), a clinically used drug in the treatment of acute myelogenous leukemia, which has no or very limited efficacy against solid tumors. In comparison with araC, the excellent in vivo activity of T-araC against solid tumors suggests that, in addition to inhibition of DNA synthesis, T-araC may target cellular signaling pathways, such as angiogenesis, in solid tumors. We studied T-araC and araC for their antiangiogenic activities in vitro and in vivo. Both compounds inhibited human endothelial cell proliferation with similar IC50s. However, only T-araC inhibited endothelial cell migration and differentiation into capillary tubules. T-araC also abrogated endothelial cell extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, a key signaling molecule involved in cellular processes of angiogenesis. Results from chick chorioallantoic membrane angiogenesis assays revealed that T-araC significantly inhibited the development of new blood vessels in vivo, whereas araC showed much less effect. The findings of this study show a role of T-araC in antiangiogenesis and suggest that T-araC combines antiproliferative and antiangiogenic activity in one molecule for a dual mechanism of drug action to achieve the excellent in vivo efficacy against several solid tumors. This study also provides important information for optimizing dosage and sequence of T-araC administration in clinical investigations by considering T-araC as both an antiproliferative and an antiangiogenic agent.     

Inhibition of Src kinase activity by Ad-mda7 suppresses vascular endothelial growth factor expression in prostate carcinoma cells.

The ability of an adenoviral vector expressing the melanoma differentiation-associated gene-7 (Ad-mda7) to mediate inhibition of vascular endothelial growth factor (VEGF) has recently been reported. However, the molecular mechanism by which Ad-mda7 inhibits VEGF is unknown. In an attempt to elucidate this mechanism, we studied the effects of Ad-mda7 on VEGF expression using human prostate cancer cells as a model. We found that Ad-mda7 treatment of prostate cancer cells (LNCaP and DU145) in vitro resulted in a significant (P < 0.05) inhibition of VEGF expression. Analysis of the VEGF signaling pathway showed that Ad-mda7 inhibited c-Src kinase activity and abrogated STAT-3 binding to the VEGF promoter. Correlating with these observations were reductions in VEGF mRNA and protein levels in Ad-mda7-treated cells. Furthermore, Ad-mda7 inhibited VEGF in Src(+/+) but not in Src(-/-) mouse embryo fibroblasts. These results showed that Ad-mda7 inhibited VEGF by inhibiting the Src signaling pathway. Finally, conditioned medium from Ad-mda7-treated tumor cells containing reduced VEGF inhibited VEGF receptor signaling, resulting in reduced endothelial cell proliferation and apoptosis. Our results provide evidence for the mechanism by which Ad-mda7 inhibits VEGF in tumor cells and of the effects of this VEGF inhibition on endothelial cell proliferation, a requirement for angiogenesis. Our findings demonstrate that MDA-7 protein, in addition to inhibiting tumor angiogenesis directly, inhibits angiogenesis indirectly by inhibiting VEGF production by tumor cells.     

VEGF-VEGF receptor complexes as markers of tumor vascular endothelium.

Vascular endothelial growth factor (VEGF) is a primary stimulant of the vascularization of solid tumors and has therefore been the focus of intense research aimed at blocking its activity in solid tumors. VEGF production by tumor cells is induced by oncogenic gene mutations and hypoxic conditions inside the tumor mass. VEGF receptor expression on endothelial cells lining blood vessels in the tumor is also induced by hypoxia and the increased local concentration of VEGF. Therefore in the tumor microenvironment there is an upregulation of both VEGF and its receptor leading to a high concentration of occupied receptor on tumor vascular endothelium. The VEGF-VEGF receptor complex (VEGF-VEGFR) presents an attractive target for the specific delivery of drugs or other effectors to tumor endothelium. Herein we review the development of monoclonal antibodies that selectively bind to the VEGF-VEGFR and their use as targeting agents that selectively bind to VEGF activated blood vessels. Additionally, we summarize the properties of 2C3, a novel monoclonal anti-VEGF antibody that blocks VEGF from binding to VEGFR2 but not VEGFR1. 2C3 may be utilized as both an anti-angiogenic agent by inhibiting VEGFR2 activity and potentially as a vascular targeting agent by binding to blood vessels that express the VEGF-VEGFR1 complex.     

Improvement by solid dispersion of the bioavailability of KRN633, a selective inhibitor of VEGF receptor-2 tyrosine kinase, and identification of its potential therapeutic window

KRN633 is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases. However, it is poorly water-soluble; consequently, relatively high doses are required to achieve substantial in vivo tumor growth suppression after oral administration. We subjected KRN633 to the solid dispersion technique to improve its solubility, absorption, and antitumor efficacy after oral administration. This technique transformed the drug into an amorphous state and dramatically improved its dissolution rate. It also enhanced the bioavailability of the drug in rats by approximately 7.5-fold. The solid dispersion form of KRN633 also dramatically inhibited human tumor growth in murine and rat xenograft models: similar rates of tumor growth inhibition were obtained with 10- to 25-fold lower doses of the solid dispersion preparation relative to the pure drug in its crystalline state. Histologic analysis of tumors treated with the solid dispersion preparation revealed a significant reduction in microvessel density at much lower doses when compared with the crystalline form preparation. In addition, a dose-finding study using the solid dispersion form in a rat xenograft model revealed that there was a substantial range of doses at which KRN633 in the solid dispersion form showed significant antitumor activity but did not induce weight loss or elevate total urinary protein levels. These data suggest that the solid dispersion technique is an effective approach for developing KRN633 drug products and that KRN633 in the solid dispersion form may be a highly potent, orally available drug with a wide therapeutic window for diseases associated with abnormal angiogenesis.