血管内皮细胞生长因子及其受体与肿瘤血管形成

血管内皮细胞生长因子（ＶＥＧＦ）调控血管生长特异性高，作用强，许多肿瘤细胞均有表达；仅有极少正常组织，在特定的条件下，才量表达；也只有血管内皮细胞表达细胞表达ＶＥＧＦ特异性受体，因此，可通过干预ＶＥＧＦ及其受体，抑制肿瘤血管形成，达到预防和治疗肿瘤转移和复发的目的。     

乳腺癌血管生成图像分析定量研究

目的探讨乳腺癌肿瘤血管生成与淋巴结转移的生物学行为关系。方法在９２例原发性乳腺浸润性导管癌术后病例的石蜡包埋肿瘤组织标本中,应用免疫组化方法检测血管内皮生长因子（ＶＥＧＦ）表达程度和新生血管数目,并采用目镜网格测微尺和图像分析系统分别对二者进行定量观察。结果ＶＥＧＦ表达程度与肿瘤新生血管数目之间具有极为显著的正相关关系（Ｐ＜０００１）,新生血管数目随着ＶＥＧＦ表达程度的增高而增加。乳腺癌的淋巴结转移与ＶＥＧＦ表达程度、新生血管数目密切相关,淋巴结转移组的ＶＥＧＦ表达程度及新生血管数目明显高于淋巴结无转移组（Ｐ＜０００５～０００１）。结论ＶＥＧＦ在原发性乳腺癌的血管生成中起着重要作用,肿瘤的血管生成促进肿瘤的淋巴结转移。     

胰腺癌组织中VEGF的表达与血管计数的关系

目的　研究血管内皮生长因子（ＶＥＧＦ）在胰腺癌组织血管形成中的作用。方法采用免疫组织化学 ＡＢＣ法研究了３３的胰腺癌标本中 ＶＥＧＦ的表达及分布,并研究了ＶＥＧＦ的表达强度与肿瘤血管计数的关系。结果（１）２２例（６６．７％）强表达ＶＥＧＦ, ８例（２４．２％）表达呈中等强度,３例（９．１％）呈弱阳性。ＶＥＧＦ在癌细胞呈胞浆内染色,肿瘤间质血管内皮细胞及瘤周正常组织中也可见 ＶＥＧＦ着色。（２）ＶＥＧＦ中等强度以上染色的病例中７例（２３．３％）血管计数不足 ２０个,弱阳性的标本中 １例计数达 １５个。（３）ＶＥＧＦ表达强度与肿瘤血管计数存在显著相关性（Ｐ＜０．０５）。结论ＶＥＧＦ在胰腺病组织血管形成过程中起重要作用,可以作为肿瘤血管抑制治疗的靶因子。     

ＥＧＦＲ和ＶＥＧＦ在大肠癌组织中的表达及临床意义

目的：通过免疫组化检测表皮生长因子受体（ＥＧＦＲ）、血管内皮生长因子（ＶＥＧＦ）在大肠癌（ＣＲＣ）和大肠正常组织中的表达,探讨其与临床病理特征的相关性。方法：应用免疫组化ＥｎＶｉｓｉｏｎ法检测５８例大肠癌组织（其中２０例患者年龄＜４０岁）和癌旁正常组织２８例中的ＥＧＦＲ和ＶＥＧＦ的表达水平,并结合临床资料进行统计学分析。结果：大肠癌组织中的ＥＧＦＲ和ＶＥＧＦ阳性表达率分别为４３.１０％和４８.２７％;癌旁正常组织ＥＧＦＲ和ＶＥＧＦ阳性表达率分别为７.１４％和１０.７１％,大肠癌组织中ＥＧＦＲ和ＶＥＧＦ表达率均明显高于癌旁正常组织（Ｐ＜０.０１）。ＥＧＦＲ和ＶＥＧＦ的表达与大肠癌的ＴＮＭ分期以及有无淋巴结转移有关（Ｐ＜０.０５）。ＥＧＦＲ和ＶＥＧＦ阳性表达率在年龄＜４０岁的大肠癌组明显高于其在年龄≥４０岁的大肠癌组（Ｐ＜０.０５）;在年龄＜４０岁的大肠癌组中,两者共阳性表达伴淋巴结转移率高（Ｐ＜０.０１）。结论：ＥＧＦＲ和ＶＥＧＲ在大肠癌组织中高表达,与大肠癌临床分期及淋巴结转移密切相关,可作为临床判断转移及预后等生物学行为的重要参考指标。年龄＜４０岁的早发性大肠癌具有更高的ＥＧＦＲ和ＶＥＧＦ阳性率及共表达率,提示其侵袭性更强、预后更差。     

VEGF、Ang-2在肿瘤生长及转移中作用的研究进展

血管内皮生长因子 Ａ（ｖａｓｃｕｌａｒｅｎｄｏｔｈｅｌｉａｌｇｒｏｗｔｈｆａｃｔｏｒＡ,ＶＥＧＦＡ）在肿瘤组织中高表达,不仅在肿瘤血管 生成中起着重要作用,还能直接或间接参与肿瘤免疫反应;血管生成素 ２（ａｎｇｉｏｐｏｉｅｔｉｎ ２,Ａｎｇ ２）在肿瘤血管内皮细胞 （ｅｎｄｏｔｈｅｌｉａｌｃｅｌｌｓ,ＥＣｓ）中高表达,导致血管结构异常和功能性减弱,肿瘤血管呈现紊乱、渗漏。目前,有关 ＶＥＧＦＡ与 Ａｎｇ ２抑制剂的研究在动物实验及临床试验中已取得一定进展。本文就 ＶＥＧＦＡ、Ａｎｇ ２在肿瘤生长及转移中的作用 及 ＶＥＧＦＡ、Ａｎｇ ２抑制剂研究的进展作一综述。     

血管内皮生长因子在大肠癌中的表达及预后价值

目的：研究血管内皮生长因子（ＶＥＧＦ）在朋肠癌中的表达及其与临床病理特征的关系。方法：采用免疫组织化学方法检测８０例大肠癌手术标本肿瘤组织内的血管内皮生长因子（ＶＥＧＦ）和微血管计数（ＭＶＤ）。结果：ＶＥＧＦ表达阳性率为６１．２％,ＶＥＧＦＤ表达阳性的肿瘤组织其ＭＶＤ明显高于阴性者（Ｐ＜０．０５）。ＶＥＧＦ表达与肿瘤的浸润性生长、浆膜浸润、淋巴结转移和肝转移有明显相关性（Ｐ＜０．０５）。此外,ＶＥ     

肝门部胆管癌组织中VEGF和血管生成相关性的研究

目的：探讨肝门部胆管癌组织中血管内皮细胞生长因子（ＶＥＧＦ）和血管生成的相关性。方法：应用逆转录多聚酶链反应（ＲＴ－ＰＣＲ）和免疫组化技术对２６例肝门部胆管癌、癌周组织及１２例正常组织中ＶＥＧＦｍＲＮＡ和蛋白及微血管密度（ＭＶＤ）进行了检测。结果：２６例肝门部胆管癌组织中ＶＥＧＦｍＲＮＡ阳性表达率为７６．９％（２０／２６）;癌周组织阳性表达率为２８．９％（７／２６）;正常组织表达率为８．３％（１／１２）,三者差异有显著性（Ｐ＜０．０１）。ＶＥＧＦｍＲＮＡ阳性表达与ＶＥＧＦ蛋白表达具有一致性;ＶＥＧＦｍＲＮＡ阳性者ＭＶＤ值显著高于阴性者（Ｐ＜０．０１）;ＶＥＧＦｍＲＮＡ表达和ＭＶＤ与肝门部胆管癌的分化程度、浸润转移密切相关（Ｐ＜０．０５）;而与发生部位、病理类型、肿瘤大小、临床分型无关（Ｐ＞０．０５）。结论：ＶＥＧＦ在肝门部胆管癌发生和浸润转移过程中发挥重要作用,肿瘤血管生成与肝门部胆管癌浸润转移密切相关。     

胃癌组织中Ａｎｇ ２和ＶＥＧＦ的表达与血管生成的关系

目的：研究胃癌组织中血管生成素-２（Ａｎｇ-２）和血管内皮生长因子（ＶＥＧＦ）的表达与临床病理学特征和肿瘤血管生成的关系。方法：应用免疫组织化学方法检测５５例胃癌组织以及１２例胃癌癌旁组织和正常胃组织中Ａｎｇ-２、ＶＥＧＦ表达及微血管密度（ＭＶＤ）。结果：Ａｎｇ-２、ＶＥＧＦ表达及ＭＶＤ在胃癌组织中均显著高于癌旁组织及正常胃组织（Ｐ＜０.０５）;胃癌组织Ａｎｇ-２、ＶＥＧＦ表达与浸润深度、淋巴结转移、病理分期、肿瘤分化程度密切相关（Ｐ＜０.０５）;Ａｎｇ-２与ＶＥＧＦ表达呈正相关性（Ｐ＜０.０５）。结论：Ａｎｇ-２、ＶＥＧＦ在胃癌组织中高表达,两者在胃癌的肿瘤血管生成和进展中起重要作用。     

血管内皮生长因子在食管癌中的表达和临床意义

目的探讨食管癌血管内皮生长因子（ＶＥＧＦ）、血管生成与食管癌临床病理特点的关系。方法采用免疫组织化学技术,检测５０例食管癌组织ＶＥＧＦ蛋白表达和微血管密度（ＭＶＤ）。分析ＶＥＧＦ和ＭＶＤ的关系及其与食管癌组织学分型、浸润度、生长方式、淋巴结转移和预后的关系。结果ＶＥＧＦ阳性者ＭＶＤ值显著高于阴性者,ＶＥＧＦ及ＭＶＤ与食管癌浸润深度、淋巴结转移密切相关,与组织学分型、生长方式也有明显相关性。结论ＶＥ     

血管内皮生长因子在卵巢上皮性癌中的表达

目的 探讨血管内皮生长因子（ｖｅｓｃｕｌａｒ ｅｎｄｏｔｈｅｌｉａｌ ｇｒｏｗｔｈ ｆａｃｔｏｒ,ＶＥＧＦ）在血管生成及其在卵巢癌发展中的作用。方法 用免疫组织化学方法检测ＶＥＧＦ在７９例人卵巢上皮性癌组织中的表达,并标记肿瘤内血管,分析ＶＥＧＦ与瘤内微血管密度（ｍｉｃｒｏｖｅｓｓｅｌ ｄｅｎｓｉｔｙ,ＭＶＤ）及其与组织学分类、临床分期、腹水、淋巴结转移、预后的关系。结果 在７９例卵巢上皮性癌中５     

Lewis y抗原促进卵巢癌细胞RMG—I血管内皮生长因子受体的表达

目的：探讨α1,2-岩藻糖转移酶（α1,2-fucosyltransferase,α1,2-FT）基因转染对卵巢癌细胞系RMG—I血管内皮生长因子受体（VEGFR）的影响。方法：利用已经建立的α1,2-岩藻糖转移酶及LewisY稳定高表达的RMG—I—H细胞系、裸鼠移植瘤模型,采用逆转录-聚合酶链式反应（RT—PCR）测定基因转染前后细胞中VEGFRmRNA的变化,采用免疫组织化学法测定基因转染前后细胞及裸鼠移植瘤组织中VEGFR蛋白的变化。结果：基因转染后细胞中KDRmRNA表达明显增高（P〈0．01）,细胞、裸鼠移植瘤组织中KI）R蛋白表达也明显增高,差异有统计学意义（P〈0．01）。结论：LewisY抗原可能通过VEGF的自分泌和旁分泌途径引起KDR受体数目增多,从而促进肿瘤血管生成,介导卵巢癌的生长、侵袭、转移和耐药等生物学行为。     

AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts

The growth of solid tumors is dependent on the continued stimulation of endothelial cell proliferation and migration resulting in angiogenesis. The angiogenic process is controlled by a variety of factors of which the vascular endothelial growth factor (VEGF) pathway and its receptors play a pivotal role. Small-molecule inhibitors of VEGF receptors (VEGFR) have been shown to inhibit angiogenesis and tumor growth in preclinical models and in clinical trials. A novel nicotinamide, AMG 706, was identified as a potent, orally bioavailable inhibitor of the VEGFR1/Flt1, VEGFR2/kinase domain receptor/Flk-1, VEGFR3/Flt4, platelet-derived growth factor receptor, and Kit receptors in preclinical models. AMG 706 inhibited human endothelial cell proliferation induced by VEGF, but not by basic fibroblast growth factor in vitro, as well as vascular permeability induced by VEGF in mice. Oral administration of AMG 706 potently inhibited VEGF-induced angiogenesis in the rat corneal model and induced regression of established A431 xenografts. AMG 706 was well tolerated and had no significant effects on body weight or on the general health of the animals. Histologic analysis of tumor xenografts from AMG 706-treated animals revealed an increase in endothelial apoptosis and a reduction in blood vessel area that preceded an increase in tumor cell apoptosis. In summary, AMG 706 is an orally bioavailable, well-tolerated multikinase inhibitor that is presently under clinical investigation for the treatment of human malignancies.     

Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice

Vascular endothelial growth factor (VEGF) is a multifunctional angiogenic growth factor that is a primary stimulant of the development and maintenance of a vascular network in embryogenesis and the vascularization of solid tumors. At the present time there are two well-characterized receptors for VEGF that are selectively expressed on endothelium. VEGF receptor 2 [VEGFR2 (KDR/Flk-1)] mediates endothelial cell mitogenesis and permeability increases, whereas the role of VEGF receptor 1 [VEGFR1 (Flt-1)] has not been clearly defined. In the present study, a monoclonal antibody, 2C3, is shown to block the interaction of VEGF with VEGFR2 but not with VEGFR1 through ELISA, receptor binding assays, and receptor activation assays. 2C3 blocks the VEGF-induced vascular permeability increase in guinea pig skin. 2C3 has potent antitumor activity, inhibiting the growth of newly injected and established human tumor xenografts in mice. These findings demonstrate the usefulness of 2C3 in dissecting the pathways that are activated by VEGF in cells that express both VEGFR1 and VEGFR2, as well as highlighting the dominant role of VEGFR2 in mediating VEGF-induced vascular permeability increase and tumor angiogenesis.     

Angiogenesis and radiation response modulation after vascular endothelial growth factor receptor-2 (VEGFR2) blockade

The formation of new blood vessels (angiogenesis) represents a critical factor in the malignant growth of solid tumors and metastases. Vascular endothelial cell growth factor (VEGF) and its receptor VEGFR2 represent central molecular targets for antiangiogenic intervention, because of their integral involvement in endothelial cell proliferation and migration. In the current study, we investigated in vitro and in vivo effects of receptor blockade on various aspects of the angiogenic process using monoclonal antibodies against VEGFR2 (cp1C11, which is human specific, and DC101, which is mouse specific). Molecular blockade of VEGFR2 inhibited several critical steps involved in angiogenesis. VEGFR2 blockade in endothelial cells attenuated cellular proliferation, reduced cellular migration, and disrupted cellular differentiation and resultant formation of capillary-like networks. Further, VEGFR2 blockade significantly reduced the growth response of human squamous cell carcinoma xenografts in athymic mice. The growth-inhibitory effect of VEGFR2 blockade in tumor xenografts seems to reflect antiangiogenic influence as demonstrated by vascular growth inhibition in an in vivo angiogenesis assay incorporating tumor-bearing Matrigel plugs. Further, administration of VEGFR2-blocking antibodies in endothelial cell cultures, and in mouse xenograft models, increased their response to ionizing radiation, indicating an interactive cytotoxic effect of VEGFR2 blockade with radiation. These data suggest that molecular inhibition of VEGFR2 alone, and in combination with radiation, can enhance tumor response through molecular targeting of tumor vasculature.     

Tumor-derived vascular endothelial growth factor (VEGF)-a facilitates tumor metastasis through the VEGF-VEGFR1 signaling pathway

Vascular endothelial growth factor (VEGF) and its receptors are involved in carcinogenesis, invasion and tumor angiogenesis, but the underlying mechanism by which VEGF promotes tumor metastasis is poorly understood. In this study, we show that in cancer patients high expression of VEGF is correlated with metastasis, and anti-VEGF treatment (bevacizumab) has clinical effects on tumor metastasis. Two human lung carcinoma cell lines (A549 and SPCA1 cells) with distinct VEGF expression were injected intravenously through the lateral tail vein of SCID mice and a murine model was developed. We investigated the association between the expression of VEGF and tumor metastasis by microvessel density, immunohistochemistry and whole mount staining. At sacrifice, in the high VEGF expression A549 cell line group, the induced tumor was distinctively larger in size and multiple metastatic lesions were found in lung tissues. Two specific neutralizing anti-mouse VEGFR1 and VEGFR2 antibodies were administered to the tumor-bearing mice; anti-VEGFR1, but not anti-VEGFR2 treatment produced inhibitive effects on VEGF-induced tumor metastasis. These findings demonstrate that the VEGF-VEGFR1 signaling pathway is crucial for tumor metastasis and the blockade of VEGF-VEGFR1-induced metastasis may provide a novel approach for the prevention and treatment of tumor metastasis.     

A receptor for vascular endothelial growth factor that stimulates endothelial apoptosis.

Vascular endothelial growth factor (VEGF) is a dimeric angiogenic factor that is overexpressed by many tumors and stimulates tumor angiogenesis. VEGF initiates signaling by dimerizing the receptors VEGFR-1 and VEGFR-2. The Fas receptor stimulates apoptosis, and artificial dimerization of the Fas cytoplasmic domain has been shown to induce apoptosis. We constructed a chimeric receptor (VEGFR2Fas) combining the extracellular and transmembrane domains of VEGFR-2 with the cytoplasmic domain of Fas receptor. When VEGFR2Fas was stably expressed in endothelial cells in vitro, treatment with VEGF rapidly induced cell death with features characteristic of Fas-mediated apoptosis. These findings demonstrate that VEGFR2Fas functions as a VEGF-triggered death receptor and raise the possibility that introduction of VEGFR2Fas into tumor endothelium or tumor cells in vivo may convert tumor-derived VEGF from an angiogenic factor into an antiangiogenesis agent.     

Anti-flt1 peptide, a vascular endothelial growth factor receptor 1-specific hexapeptide, inhibits tumor growth and metastasis.

PURPOSE: The purpose of this study was to develop antagonists specific for the vascular endothelial growth factor receptor 1 (VEGFR1) and to investigate the effects of the antagonists on the VEGF-induced endothelial cell functions and tumor progression. EXPERIMENTAL DESIGN: Hexapeptides that inhibit binding of VEGFR1 and VEGF were identified through screening of synthetic peptide library. A selected peptide, anti-Flt1, was investigated for binding specificity with various receptors and ligand peptides. Effects of the peptide on proliferation, cell migration, and fibrin gel-based angiogenesis of endothelial cells were also investigated. The activity of anti-Flt1, in vivo, was evaluated for inhibition of tumor growth and metastasis in VEGF-secreting cancer cell-implanted mice by s.c. injections of the peptide. RESULTS: Here, we report on a short peptide that binds to VEGFR1 and prevents binding of VEGF. A hexapeptide, anti-Flt1 (Gly-Asn-Gln-Trp-Phe-Ile or GNQWFI), was identified from peptide libraries. The anti-Flt1 peptide shows specificity toward binding to VEGFR1 and it inhibits binding of VEGF, placental growth factor (PlGF), and VEGF/PlGF heterodimer to VEGFR1. This peptide does not inhibit the proliferation of endothelial cells induced by VEGF and VEGF/PlGF heterodimer but it effectively blocks VEGF-induced migration of endothelial cells and their capacity to form capillary-like structures on fibrin gel-based in vitro angiogenesis system. Furthermore, growth and metastasis of VEGF-secreting tumor cells were also significantly inhibited by s.c. injections of anti-Flt1 peptide in nude mice. Accordingly, VEGF-induced migration and capillary formation are mediated through VEGFR1, and these processes may play an important role in the growth and metastasis of VEGF-secreting tumors. CONCLUSIONS: We show that a peptide (anti-Flt1) specific for VEGFR1 inhibits growth and metastasis of tumor that secretes VEGF. The effects on endothelial cell functions, in vitro, indicate that the anticancer activity of anti-Flt1 peptide with reduced blood vessel density could also be due to the blocking of VEGFR1-mediated endothelial cell migration and tube formation. Although the effects of anti-Flt1 peptide still remain to be further characterized, the receptor 1-specific peptide antagonist, anti-Flt1, has potential as a therapeutic agent for various angiogenesis-related diseases, especially cancer.     

The antitumor and antiangiogenic activity of vascular endothelial growth factor receptor inhibition is potentiated by ErbB1 blockade.

PURPOSE: Receptor tyrosine kinases of the ErbB family play important roles in the control of tumor growth. Vascular endothelial growth factor (VEGF) stimulates endothelial cell proliferation, enhances vascular permeability, and plays an important role in tumor vascularization. We evaluated the effects of selective VEGF receptor (VEGFR; PTK787/ZK222584) and ErbB (PKI166 and ZD1839) inhibitors on tumor growth and angiogenesis and asked whether additional therapeutic benefit was conferred by combination treatment. EXPERIMENTAL DESIGN: The antitumor activity of each inhibitor alone or in combination was assessed in human cancer models in immunocompromised mice. ErbB receptor expression and activation of downstream signaling pathway was evaluated in both tumor and endothelial cells. RESULTS: Both ErbB inhibitors significantly enhanced the antitumor activity of PTK787/ZK222584. In vitro, ErbB1 inhibition blocked VEGF release by tumor cells and proliferation of both tumor and endothelial cells. In an in vitro angiogenesis assay, epidermal growth factor (EGF) stimulated the release of VEGF by smooth muscle cells resulting in increased angiogenesis, a response blocked by administration of PTK787/ZK222584. Under basal condition, both ZD1839 and PTK787/ZK222584 blocked sprouting, likely via inhibition of an autocrine ErbB1 loop and VEGFR signaling, respectively, in endothelial cells. In conditions of limiting VEGF, EGF plays an important role in endothelial cell proliferation, survival, and sprouting. CONCLUSION: We have shown that activation of ErbB1 triggers a plethora of effects, including direct effects on tumor and endothelial cells and indirect effects mediated via induction of VEGF release. Simultaneous blockade of ErbB1 and VEGFR pathways results in a cooperative antitumor effect, indicating that this combination may represent a valid therapeutic strategy.     

Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis which drives endothelial cell survival, proliferation, and migration while increasing vascular permeability. Playing an important role in the physiology of normal ovaries, VEGF has also been implicated in the pathogenesis of ovarian cancer. Essentially by promoting tumor angiogenesis and enhancing vascular permeability, VEGF contributes to the development of peritoneal carcinomatosis associated with malignant ascites formation, the characteristic feature of advanced ovarian cancer at diagnosis. In both experimental and clinical studies, VEGF levels have been inversely correlated with survival. Moreover, VEGF inhibition has been shown to inhibit tumor growth and ascites production and to suppress tumor invasion and metastasis. These findings have laid the basis for the clinical evaluation of agents targeting VEGF signaling pathway in patients with ovarian cancer. In this review, we will focus on VEGF involvement in the pathophysiology of ovarian cancer and its contribution to the disease progression and dissemination.     

Enhanced expression of vascular endothelial growth factor in metastatic melanoma.

Tumour growth is dependent on angiogenesis. Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific cytokine. VEGF is angiogenic in vivo and it also acts as a vascular permeability factor. VEGF is overexpressed in many skin disorders characterized by angiogenesis and increased vascular permeability. We investigated VEGF expression in 22 primary cutaneous melanomas, 33 melanoma metastases and six naevocellular naevi using immunohistochemistry. VEGF accumulated on the vascular endothelia in the normal dermis, suggesting that a constitutive low level of VEGF expression may regulate skin vessel function under normal physiological conditions. No VEGF was detected in the cells of naevocellular naevi or normal dermis. In contrast, 32% of the primary and 91% of the metastatic melanomas contained melanoma cells staining for VEGF. Expression of VEGF was more frequent in metastases than in primary melanomas (P <0.0001). Tumour-infiltrating inflammatory cells expressed VEGF in all melanomas. A high number of VEGF-expressing inflammatory cells was associated with high VEGF expression in melanoma cells (P = 0.003). Our results suggest that VEGF is up-regulated during the course of melanoma progression and dissemination and that tumour-infiltrating cells expressing VEGF may contribute to the progression of melanoma.