血管内皮生长因子受体-1与肿瘤

血管内皮生长因子受体-1（VEGFR-1）通过其酪氨酸激酶活性调节肿瘤血管的新生从而影响肿瘤的发生、发展和转移。近年研究发现一些肿瘤细胞本身也可以表达VEGFR-1,抗VEGFR-1抗体不仅可以对表达VEGFR-1的肿瘤血管内皮发生直接的抗血管生成活性,也可以通过旁分泌的配体活化VEGFR-1阳性肿瘤细胞而直接影响肿瘤的发生、发展。     

Vascular endothelial growth factor signaling pathways: therapeutic perspective.

The establishment of a vascular supply is one of the earliest and most important events occurring during embryonic development. Growth and maturation of a functional vascular network are complex and still incompletely understood processes involving orchestrated activation of vascular progenitors in the early stages of embryonic development followed by vasculogenesis and angiogenesis. These processes require a tightly regulated activation of several growth factors and their receptors. The role of vascular endothelial growth factors (VEGF) and their receptors has been studied extensively due to their prominent role during blood vessel formation. Mice deficient in various VEGF ligands or receptors show serious defects in vascular formation and maturation. Moreover, members of the VEGF family are involved in other significant biological processes, including lymphangiogenesis, vascular permeability, and hematopoiesis. Importantly, VEGF is released by tumor cells and induces tumor neovascularization. It is now well established that the VEGF axis represents an important target for antitumor therapy. Aberrant VEGF signaling is also a feature of several other pathologic conditions, such as age-related macular degeneration and rheumatoid arthritis.     

Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications

Since the discovery that cancer development requires the growth of new blood vessels, many investigations have revealed the key molecules in the regulation of new vessel formation. One of the most important of these molecules is vascular endothelial growth factor (VEGF)--an endothelial-cell-specific mitogen and survival factor. VEGF also causes increased vascular permeability and recruits progenitor endothelial cells from the bone marrow. Clinical observations have confirmed that VEGF status is closely associated with the extent of neovascularisation and prognosis in many solid tumours. VEGF status is predictive of resistance to various treatments, including radiotherapy, chemotherapy, and endocrine therapy. Preliminary results also indicate that anti-VEGF treatment suppresses cancer progression without serious toxic effects. Various approaches for the control of cancers involving inhibition of the activity of VEGF are currently being investigated. This review considers the clinical implications of VEGF, particularly its prognostic, predictive, and therapeutic value.     

Vascular endothelial growth factor receptor-1 signaling promotes mobilization of macrophage lineage cells from bone marrow and stimulates solid tumor growth

Vascular endothelial growth factor and its receptors, including Flt-1 and Flk-1, are involved in angiogenesis under physiologic and pathologic conditions. Recently, Flt-1-expressing cells were reported to contribute to the intracranial growth of glioma cells. However, the role of Flt-1 signaling in solid tumor growth in s.c. tissue has not been elucidated. To investigate how Flt-1 signaling is involved in the proliferation of solid tumors, we implanted tumor cells into wild-type (Wt) and Flt-1 tyrosine kinase (TK)-deficient (Flt-1 TK(-/-)) mice. Growth of HSML and B16 but not Lewis lung carcinoma cell in s.c. tissue was significantly decreased in Flt-1 TK(-/-) mice. Angiogenesis in HSML and B16 tumors was remarkably reduced in Flt-1 TK(-/-) mice. Moreover, the infiltration of macrophage lineage cells into HSML and B16 tumors was clearly suppressed in Flt-1 TK(-/-) mice. Pericyte marker(+) cells were also reduced in Flt-1 TK(-/-) mice. However, in the border area of tumor, angiogenesis and the infiltration of macrophage lineage cell were basically similar between Wt and Flt-1 TK(-/-) mice. In bone marrow (BM) transplantation experiments, tumor angiogenesis, infiltration of macrophage lineage cells, and tumor growth were significantly suppressed in Wt/Flt-1 TK(-/-) mice implanted with Flt-1 TK(-/-) BM cells compared with those implanted with Wt BM cells. We conclude that Flt-1 signaling is involved in the function of BM-derived cell, such as the migration of macrophages into cancerous tissues, and significantly contributes to angiogenesis and tumor progression.     

Vascular endothelial growth factor-mediated decrease in plasma soluble vascular endothelial growth factor receptor-2 levels as a surrogate biomarker for tumor growth

Vascular endothelial growth factor (VEGF) is a potent proangiogenic protein that activates VEGF receptor (VEGFR) tyrosine kinases expressed by vascular endothelial cells. We previously showed that one of these receptors, VEGFR-2, has a truncated soluble form (sVEGFR-2) that can be detected in mouse and human plasma. Because activation of VEGFR-2 plays an important role in tumor angiogenesis, clinical interest in monitoring plasma sVEGFR-2 levels in cancer patients has focused on its potential exploitation as a surrogate biomarker for disease progression as well as assessing efficacy/activity of antiangiogenic drugs, particularly those that target VEGF or VEGFR-2. However, no preclinical studies have been done to study sVEGFR-2 during tumor growth or the mechanisms involved in its modulation. Using spontaneously growing tumors and both localized and metastatic human tumor xenografts, we evaluated the relationship between sVEGFR-2 and tumor burden as well as underlying factors governing protein level modulation in vivo. Our results show an inverse relationship between the levels of sVEGFR-2 and tumor size. Furthermore, using various methods of VEGF overexpression in vivo, including cell transfection and adenoviral delivery, we found plasma sVEGFR-2 decreases to be mediated largely by tumor-derived VEGF. Finally, in vitro studies indicate VEGF-mediated sVEGFR-2 modulation is the result of ligand-induced down-regulation of the VEGFR-2 from the cell surface. Taken together, these findings may be pertinent to further clinical exploitation of plasma sVEGFR-2 levels as a surrogate biomarker of VEGF-dependent tumor growth as well as an activity indicator of antiangiogenic drugs that target the VEGFR system.     

Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts

Antiangiogenic therapy can enhance radiation-induced tumor growth inhibition. However, the effects of combined antiangiogenic and radiation therapy on long-term tumor control and normal tissue response have not been reported. We treated mice bearing two different human tumor xenografts with anti-vascular endothelial growth factor receptor-2 antibody (DC101) and five dose fractions of local radiation and followed them for at least 6 months. DC101 significantly decreased the dose of radiation necessary to control 50% of tumors locally. The decrease was 1.7- and 1.3-fold for the moderately radiosensitive small cell lung carcinoma 54A and the highly radioresistant glioblastoma multiforme U87, respectively. In contrast to tumors, no increase in skin radiation reaction by the antibody was detected. Surprisingly, 44% of mice bearing 54A tumor developed clear ascites after DC101 treatment at its highest dose; this was fatal to 20% of mice. This adverse effect was seen only in mice that received whole-body irradiation 1 day before tumor implantation. The encouraging results on two human tumor xenografts suggest that vascular endothelial growth factor receptor-2 blockade merits further investigation to assess its potential as an enhancer of radiation therapy in the clinic.     

Vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) is a hypoxia-inducibleangiogenesis and vascular permeability factor which is expressedin high amounts in perinecrotic palisading cells inhuman glioblastomas. In vitro VEGF gene expression isenhanced approximately ten times by hypoxia. Current evidencesuggests, that hypoxia is also the driving forcefor VEGF gene expression in glioblastoma cells invivo and represents the most important trigger fortumor angiogenesis and edema. Our approaches to inhibittumor angiogenesis and edema formation in glioblastoma patientswill concentrate on the disruption of VEGF/VEGF receptorsignal transduction pathway in vivo.     

Vascular endothelial growth factor receptor-3 is a favorable prognostic factor in advanced gastric carcinoma

Vascular endothelial growth factor receptor (VEGFR)-3 is a receptor for VEGF-C and D and is implicated in the development of lymphatic vessels and metastasis. The purpose of this study was to investigate the expression of VEGFR-3 and its clinicopathological significance in primary gastric carcinoma (GC). Pathological and clinical findings from 109 GC cases were reviewed and VEGFR-3 expression was examined using immunohistochemistry. The clinicopathological implications of VEGFR-3 expression were analyzed statistically. VEGFR-3 expression was evaluated for intensity (0-3) and proportion (0-100%). A total score was obtained by multiplying the intensity by the proportion (0-300). A total score of 82 or more was considered positive for VEGFR-3. Of the 109 patients with GC, 19 (17.4%) were positive for VEGFR-3. VEGFR-3 expression was associated with Lauren classification (68.4% for intestinal type, 31.6% for diffuse type, p=0.058). It was more frequent in early gastric cancer (EGC), 28.0% in EGC, 16.2% in advanced gastric carcinoma (AGC), though this difference was not statistically significant. In 78 patients with AGC, VEGFR-3 expression was associated with good overall survival (p=0.052). In a multivariate analysis, the pTNM stage and VEGFR-3 were independent prognostic factors (OR=3.35, p=0.002 for pTNM stage; OR=0.23, p=0.044 for VEGFR-3). However, the expression of VEGFR-3 in EGC was not correlated with overall survival. In conclusion, the expression of VEGFR-3 was associated with the intestinal type (based on Lauren classification) and may be a favorable prognostic factor in AGC.     

血管内皮因子及其受体与胶质瘤

 血管内皮生长因子及其受体在肿瘤的生长和转移过程中可能是最关键的刺激因子。在胶质瘤血管形成过程中起促进作用，它们的表达与胶质瘤的分级相关,且在抗胶质瘤血管生成治疗中是比较理想的靶位。     

血管内皮生长因子与肿瘤

血管形成是肿瘤生长和转移的重要条件 ,而血管内皮生长因子 (VEGF)对肿瘤的血管形成具有很突出的作用 ,就VEGF与肿瘤予以综述     

Delphinidin, a dietary anthocyanidin, inhibits vascular endothelial growth factor receptor-2 phosphorylation

Epidemiological studies have shown that a diet rich in fruits and vegetables has a beneficial preventive effect on cardiovascular diseases and cancer by mechanisms that have not yet been elucidated. In this work, we investigated the antiangiogenic activities of anthocyanidins, a class of polyphenols present at high levels in fruits. Among the tested anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin), delphinidin was the most potent angiogenic inhibitor. In vitro, low concentrations of delphinidin inhibited vascular endothelial growth factor (VEGF)-induced tyrosine phosphorylation of VEGF receptor (VEGFR)-2, leading to the inhibition of downstream signaling triggered by VEGFR-2. Inhibition of VEGFR-2 by delphinidin inhibited the VEGF-induced activation of ERK-1/2 signaling and the chemotactic motility of human EC as well as their differentiation into capillary-like tubular structures in Matrigel and within fibrin gels. In vivo, delphinidin was able to suppress basic fibroblast growth factor-induced vessel formation in the mouse Matrigel plug assay. The identification of delphinidin as a naturally occurring inhibitor of VEGF receptors suggests that this molecule possesses important antiangiogenic properties that may be helpful for the prevention and treatment of cancer.     

血管内皮生长因子及其受体与骨肉瘤关系的研究进展

血管内皮生长因子（ＶＥＧＦ）是一种序列高度保守、高度特异性的促血管内皮细胞生长因子,广泛分布于人和动物体内的大脑、肾脏、肝脏、脾脏、胰腺和骨骼等组织中,对内皮细胞具有强烈的促有丝分裂作用,刺激血管内皮细胞增殖和血管通透性增加,促进新生血管形成。ＶＥＧＦ通过与血管内皮细胞表面受体（ＶＥＧＦＲ）特异性结合发挥生物学效应。抑制ＶＥＧＦ及ＶＥＧＦＲ的活性可以减缓或阻滞骨肉瘤侵袭和转移。研究表明,ＶＥＧＦ及ＶＥＧＦＲ对肿瘤血管及淋巴管的生成及肿瘤侵袭和转移起重要作用。本文对ＶＥＧＦ及ＶＥＧＦＲ与骨肉瘤血管与淋巴管生成及其侵袭与转移的关系作一综述。     

Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells

PURPOSE: The resistance to selective EGFR inhibitors involves the activation of alternative signaling pathways, and Akt activation and VEGF induction have been described in EGFR inhibitor-resistant tumors. Combined inhibition of EGFR and other signaling proteins has become a successful therapeutic approach, stimulating the search for further determinants of resistance as basis for novel therapeutic strategies. EXPERIMENTAL DESIGN: We established human cancer cell lines with various degrees of EGFR expression and sensitivity to EGFR inhibitors and analyzed signal transducers under the control of EGFR-dependent and EGFR-independent pathways. RESULTS: Multitargeted inhibitor vandetanib (ZD6474) inhibited the growth and the phosphorylation of Akt and its effector p70S6 kinase in both wild-type and EGFR inhibitor-resistant human colon, prostate, and breast cancer cells. We found that the resistant cell lines exhibit, as common feature, VEGFR-1/Flt-1 overexpression, increased secretion of VEGF and placental growth factor, and augmented migration capabilities and that vandetanib is able to antagonize them. Accordingly, a new kinase assay revealed that in addition to VEGF receptor (VEGFR)-2, RET, and EGFR, vandetanib efficiently inhibits also VEGFR-1. The contribution of VEGFR-1 to the resistant phenotype was further supported by the demonstration that VEGFR-1 silencing in resistant cells restored sensitivity to anti-EGFR drugs and impaired migration capabilities, whereas exogenous VEGFR-1 overexpression in wild-type cells conferred resistance to these agents. CONCLUSIONS: This study shows that VEGFR-1 contributes to anti-EGFR drug resistance in different human cancer cells. Moreover, vandetanib inhibits VEGFR-1 activation, cell proliferation, and migration, suggesting its potential utility in patients resistant to EGFR inhibitors.     

Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer

High microvessel density, an indirect measure of angiogenesis, has been shown to correlate with increased tumour size, lymph node involvement and poor prognosis in non-small-cell lung cancer (NSCLC). Tumour cell vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) expression correlate with angiogenesis and a poor outcome in this disease. In a retrospective study VEGF and PD-ECGF expression and microvessel density were evaluated immunohistochemically in surgically resected specimens (T1-3, N0-2) from 223 patients with operable NSCLC using the VG1, P-GF.44C and JC70 monoclonal antibodies respectively. High VEGF immunoreactivity was seen in 104 (46.6%) and PD-ECGF in 72 (32.3%) cases and both were associated with high vascular grade tumours (P= 0.009 and P= 0.05 respectively). Linear regression analysis revealed a weak positive correlation between VEGF and PD-ECGF expression in cancer cells (r= 0.21; P = 0.002). Co-expression of VEGF and PD-ECGF was not associated with a higher microvessel density than VEGF or PD-ECGF only expressing tumours. Furthermore a proportion of high vascular grade tumours expressed neither growth factor. Univariate analysis revealed tumour size, nodal status, microvessel density and VEGF and PD-ECGF expression as significant prognostic factors. Tumour size (P < 0.02) and microvessel density (P < 0.04) remained significant on multivariate analysis. In conclusion, VEGF and PD-ECGF are important angiogenic growth factors and have prognostic significance in NSCLC. Furthermore the study underlines the prognostic significance of microvessel density in operable NSCLC.     

Vascular endothelial growth factor and its receptors in multiple myeloma.

Multiple myeloma (MM) progresses from an avascular to a vascular phase (active MM) accompanied by a significant increase in microvessel density in the bone marrow. This article summarizes the literature concerning the specific role played by vascular endothelial growth factor (VEGF) in this process. Recent applications of antiangiogenic agents that interfere with VEGF signaling and block MM progression are also described.     

Vascular endothelial growth factor and its relationship to inflammatory mediators.

Inflammation occurs in response to host injury or infection, as the result of an autoimmune disease, or in response to the development of a tumor. Although the immune system may be helpful in fighting the tumor, it may also fuel the tumorigenic process. In fact, recent data suggest a strong link between chronic inflammation, angiogenesis, and the development of cancer. For example, inflammation and scarring caused by recurring infections with Mycobacterium tuberculosis may be a cause for cancers of the lung. Inflammatory breast cancer exhibits increased angiogenesis and lymphangiogenesis and has a higher metastatic potential than noninflammatory breast cancer. Nonsteroidal anti-inflammatory drugs have been proposed as preventives for the development of colon carcinoma and ovarian cancer. Inhibition of nuclear factor-kappaB contributes to the proposed mechanism of action. Inflammatory cytokines, including interleukin-6, serve as autocrine and paracrine growth factors for several cancers, and high levels of these cytokines may correlate with a poor prognosis and increased production of angiogenic factors. The state of the art of our understanding of this critical interaction is reviewed.     

血管内皮生长因子在脑星形细胞瘤中的表达及其意义

目的　探讨血管内皮生长因子 (VEGF)在脑星形细胞瘤中的表达及其与肿瘤生长、预后和血管生成的关系。方法　应用免疫组化方法检测 82例脑星形细胞瘤瘤组织中VEGF表达、MVD ,并分析VEGF表达与血管生成、病理分级、临床预后等临床病理的关系。结果　VEGF表达与MVD呈正相关 (r=0 .6 3,P <0 .0 1)。星形细胞瘤病理级别越高 ,VEGF表达越强 (P <0 .0 5 ,0 .0 1)。瘤周水肿越重 ,VEGF表达也越强 (P <0 .0 5 ,0 .0 1)。VEGF表达与星形细胞瘤的大小、发生部位及男女性别无明显的相关关系 (P >0 .0 5 )。结论　星形细胞瘤的VEGF表达与其血管生成、预后及病理分级密切相关 ,可作为判断预后的独立指标。