VEGFR-2 在肿瘤血管生成中的作用及其研究进展

新生血管生成（angiogenesis）是指从预先存在的毛细血管以出芽方式形成新的血管的过程。人体的多种生理和病理过程都涉及了新生血管生成包括胚胎发育、月经周期、伤口愈合、肿瘤、风湿性关节炎和糖尿病视网膜病变等。而在新生血管生成的过程中,血管内皮生长因子受体-2（Vascular endothelial growth factor receptor-2,VEGFR-2）起着及其关键的作用。本文就VEGFR-2的结构、功能、在信号转导中的作用及可能的应用前景作一介绍。对VEGFR-2的深入了解,有助于我们设计包括新生血管生成在内的生理和病理过程的干预策略。     

Inhibition of angiogenesis and tumour growth by VEGF121-toxin conjugate: differential effect on proliferating endothelial cells

Vascular endothelial growth factor (VEGF) plays an important role in tumour angiogenesis. VEGF binds to tyrosine kinase receptors, which are expressed almost exclusively on tumour endothelium. Therefore, VEGF can be used to target toxin molecules to tumour vessels for anti-angiogenic therapy. However, recent evidence suggests that VEGF can also bind in an isoform-specific fashion to a newly identified neuropilin-1 (NP-1) receptor. NP-1 is widely expressed in normal tissue and presents a potential target for unwanted toxicity. As a consequence, we investigated whether the VEGF121 isoform, which lacks the NP-1 binding domain, could be used to target toxin polypeptides to tumour vasculature. Treatment of endothelial cells with a VEGF121-diphtheria toxin (DT385) conjugate selectively inhibited proliferating endothelial cells, whereas confluent cultures were completely resistant to the construct. In addition, VEGF121-DT385 conjugate treatment completely prevented tumour cell induced angiogenesis in vivo. Most importantly, the conjugate inhibited tumour growth in athymic mice and induced tumour-specific vascular damage. There was also no apparent toxicity associated with the treatment. Our results suggest that proliferating endothelial cells are highly sensitive to VEGF121-toxin conjugates and that the binding to NP-1 receptors is not necessary for efficient inhibition of tumour growth.     

Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor-induced tyrosine phosphorylation of KDR/Flk-1

Previous studies revealed that gambogic acid (GA), the major active ingredient of gamboge, a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia, possessed significant anticancer activity both in vitro and in vivo. In this study, we explored the high antiangiogenic activities of GA for the first time. GA inhibits the VEGF-stimulated proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) as well as microvessel sprouting from rat aortic rings in vitro. Moreover, GA inhibits vessel growth in matrigel plugs and CAM in vivo and transplanted tumor in mice. The results also indicated that GA decreases VEGF production of cultured tumor cells and inhibits VEGF-induced tyrosine phosphorylation of KDR/Flk-1. This inhibition of receptor phosphorylation is correlated with a significant decrease in VEGF-triggered phosphorylated forms of ERK, AKT and p38. Taken together, these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor.     

前列腺癌细胞株VEGF及其受体KDR,bFGF及其受体FGFR2的表达及意义

目的:探讨人前列腺癌细胞株血管内皮细胞生长因子(VEGF)及其受体(KDR),碱性成纤维细胞生长因子(bFGF)及其受体(FGFR2)的表达,进一步阐明前列腺癌细胞中VEGF和bFGF的自分泌机制。方法:以小鼠成纤维细胞系L929作为对照,选取三种前列腺癌细胞株(PC3、LNcap和DU145),采用免疫组化染色、RT-PCR及Westernblot,检测VEGF及其受体KDR,bFGF及其受体FGFR2的表达。结果:三种前列腺癌细胞株(PC3、LNcap和DU145)中均有VEGF、KDR及bFGF、FGFR2的表达,但表达水平略有差别。结论:在前列腺癌的血管形成中可能存在VEGF和bFGF的自分泌机制。     

Dual targeting of vascular endothelial growth factor and bone morphogenetic protein‐9/10 impairs tumor growth through inhibition of angiogenesis

Clinical development of anti‐angiogenic agents has been a major landmark in cancer therapy for several types of cancers. Signals mediated by both vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)‐9 and 10 have been implicated in tumor angiogenesis. However, previous studies have shown that targeting the individual signals was not sufficiently effective in retarding tumor growth in certain preclinical and clinical conditions. In the present study, we developed a novel decoy chimeric receptor that traps both VEGF and BMP‐9/10. Single targeting of either VEGF or BMP‐9/10 signals significantly reduced the formation of tumor vessels in a mouse xenograft model of human pancreatic cancer; however, it did not show significant therapeutic effects on tumor growth. In contrast, dual targeting of the angiogenic signals resulted in more significant inhibition of tumor angiogenesis, leading to delay of tumor growth. Our findings suggest that simultaneous blockade of VEGF and BMP‐9/10 signals is a promising therapeutic strategy for the cancers that are resistant to anti‐VEGF and BMP‐9/10 therapies.     

Expression of vascular endothelial growth factor and its receptor KDR (kinase domain-containing receptor)/Flk-1 (fetal liver kinase-1) as prognostic factors in human colorectal cancer

Background. To clarify the clinical significance of the expression of vascular endothelial growth factor (VEGF) and its receptor, kinase domain-containing receptor (KDR) in colorectal cancer, we evaluated the relationship between the expression of VEGF and KDR, and the microvessel counts and clinicopathological factors in colorectal cancer. Methods. A total of 259 specimens from sequential colorectal cancer patients who had undergone surgery were examined by the avidin-biotin peroxidase complex method, using anti-human VEGF, anti-human KDR, and anti-human von Willebrand factor antibodies. Results. The incidence of VEGF expression in the tumor cells of the patients with liver metastasis was significantly higher than that in the tumor cells of the patients without liver metastasis (67% vs 44%). The microvessel count at the tumor invasive edge in the patients whose tumor cells were positive for VEGF was significantly higher than that in the patients whose tumor cells were negative for VEGF (33.0 ± 7.8 vs 28.0 ± 7.9); the significant difference in microvessel counts was greater when there was a combination of VEGF and KDR expression. The overall survival rate of patients positive for VEGF was significantly (P = 0.0276) lower than that of those who were negative for VEGF. Although there was no significant difference (P = 0.0743) in the survival rates after potentially curative resection according to VEGF expression, the survival rate of the patients positive for both VEGF in tumor cells and KDR in endothelial cells was significantly (P = 0.0026) lower than that in the patients who were negative for VEGF and/or KDR. In addition, multivariate analysis revealed that the expression of both VEGF and KDR was an independent prognostic factor even after potentially curative resection. Conclusion. VEGF may be implicated in the definition of the malignant phenotype of colorectal cancer via tumor angiogenesis. VEGF and its receptor KDR expression in tumorous tissues could be useful prognostic factors in colorectal cancer. Received: September 18, 2000 / Accepted: August 27, 2001     

Significance of vascular endothelial growth factor (VEGF)/soluble VEGF receptor-1 relationship in breast cancer

Angiogenesis, the formation of new blood vessels, is controlled by a balance between positive and negative endothelial regulatory factors. Soluble vascular endothelial growth factor receptor-1 (sVEGFR1), a naturally occurring soluble form of VEGFR1, is a negative counterpart of the vascular endothelial growth factor (VEGF) signaling pathway, which has been characterized as one of the most important endothelial regulators in human tumor angiogenesis. In our study, we examined the expression of sVEGFR1 in 110 primary breast carcinomas, and assessed its clinical significance. Ninety-four of 110 tumors showed > or = 0.1 ng/mg protein of sVEGFR1 (range:0. 1-6.9 ng/mg protein; median: 1.03 ng/mg protein) as determined by a specific enzyme-linked immunosorbent assay (ELISA). Immunoblot analysis confirmed the presence of sVEGFR1 in breast tumor tissues. The levels of sVEGFR1 were correlated significantly with the levels of VEGF. There was no significant correlation between the levels of sVEGFR1 and any clinico-pathological factors including age, menopause, nodal involvement and hormone receptor status. A univariate prognosis analysis showed that the intratumoral VEGF status, as determined by ELISA, was a significant prognostic indicator, but sVEGFR1 status was not. In the combined analysis, however, the ratio of sVEGFR1 and VEGF levels provided more statistically significant prognostic value than VEGF status alone. Tumors in which the sVEGFR1 levels exceeded VEGF levels 10-fold had a markedly favorable prognosis. Multivariate analysis also demonstrated that the ratio of sVEGFR1 and VEGF was an independent prognostic indicator after nodal status. In conclusion, sVEGFR1, an intrinsic inhibitor of VEGF, frequently co-expressed with VEGF in primary breast cancer tissues. The intratumoral balance between sVEGFR1 and VEGF levels might be crucial for the progression of breast cancer.     

Pyrazolo-pyrimidine-derived c-Src inhibitor reduces angiogenesis and survival of squamous carcinoma cells by suppressing vascular endothelial growth factor production and signaling

Src tyrosine kinase family cooperates with activated growth factor receptors to regulate growth, invasion and metastasis. The authors examined the influence of a novel c-Src inhibitor, 1l, derived from 4-amino-substituted-pyrazolo-pyrimidines, on tumor angiogenesis and on the angiogenic output of squamous carcinoma cells, A431 and SCC-4. The effect of 1l was assessed on growth and microvessel density in A431 tumors and its effect compared with the established c-Src inhibitor PP-1. The effects of c-Src inhibition were investigated on vascular endothelial growth factor (VEGF) expression and activity in tumor cells grown in vivo and in vitro, as well as on VEGF mediated signaling and on endothelial cell functions. Nanomolar concentrations of 1l decreased tumor volume promoted by A431 implanted in nude mice, without affecting in vitro cell tumor survival. This effect was related to 1l inhibition of VEGF production, and secondary to an effect on tumor microvessel density. The rabbit cornea assay confirmed that 1l markedly decreased neovessel growth induced by VEGF. In cultured endothelial cells, 1l inhibited the VEGF-induced phosphorylation on tyr416 of c-Src, resulting in a reduced cell proliferation and invasion. Consistently, 1l dowregulated endothelial nitric oxide synthase, MAPK-extracellular receptor kinase 1-2 (ERK1-2) activity and matrix metalloproteinases (MMP-2/MMP-9), while the tissue inhibitors of metalloproteinases (TIMP2/TIMP-1) were upregulated. These results demonstrate that nM concentrations of c-Src kinase inhibitors (1l and PP-1), by reducing the production of VEGF released by tumor cell and its endothelial cell responses, have a highly selective antiangiogenesis effect, which might be useful in combination therapies.     

Somatostatin inhibits the production of vascular endothelial growth factor in human glioma cells

In various cell types, the neuro- and endocrine peptide somatostatin induces inhibitory and anti-secretory effects. Since somatostatin receptors, especially of the subtype sst2A, are constantly over-expressed in gliomas, we investigated the influence of somatostatin and the receptor subtype-selective peptide/non-peptide agonists octreotide and L-054,522 on the secretion of the most important angiogenesis factor produced by gliomas, vascular endothelial growth factor (VEGF). Cultivated cells from solid human gliomas of different stages and glioma cell lines secreted variable amounts of VEGF, which could be lowered to 25% to 80% by co-incubation with somatostatin or sst2-selective agonists (octreotide and L-054,522). These effects were dose-dependent at nanomolar concentrations. Stimulation with different growth factors (EGF, bFGF) or hypoxia considerably increased VEGF production over basal levels. Growth factor-induced VEGF synthesis could be suppressed to <50% by co-incubation with somatostatin or an sst2-selective agonist; this was less pronounced in hypoxia-induced VEGF synthesis. The effects were detected at the protein and mRNA levels. These experiments indicate a potent anti-secretory action of somatostatin or sst2 agonists on human glioma cells that may be useful for inhibiting angiogenesis in these tumors.     

成人急性白血病患者细胞血管内皮生长因子及其受体FLT-1、KDR的表达

目的　探讨成人急性白血病 (AL )患者细胞血管内皮生长因子 (VEGF)及其受体 FL T- 1(fm s- like tyro-sine kinase)、KDR(kinase- dom ain insert containing receptor)的表达。方法　采用 RT- PCR方法检测骨髓单个核细胞 (BM MNCs) VEGF及其受体 FL T- 1、KDR m RNA的表达水平。结果　 (1)初发未治患者、骨髓缓解患者 (BMR)和正常对照者 BM MNCs VEGF m RNA阳性表达例数的差异无显著性 (P>0 .0 5 ) ,而 BM MNCs VEGF/β- actin相对表达量 ,在初发未治组显著高于 BMR组和正常对照组 (P值均 <0 .0 1) ,后两组之间的差异无显著性 (P>0 .0 5 ) ;AML组高于 AL L患者 (P<0 .0 5 )。 (2 )初发未治患者 BM MNCs FL T- 1、KDR m RNA阳性表达例数较 BMR及正常对照者高 (P值均 <0 .0 5 ) ,后两组之间的差异无显著性 (P>0 .0 5 ) ;AML组 BM MNCs KDR m RNA阳性表达例数高于 AL L组 (P<0 .0 5 ) ;应用 FL T- 1/β- actin、KDR/β- actin相对表达量分析与上述结果一致。 (3) BM MNCsVEGF的相对表达量与其受体 FL T- 1和 KDR的相对表达量呈相关性 (P值均 <0 .0 5 )。结论　 AL细胞 VEGF、FL T- 1和 KDR m RNA呈过表达 ;VEGF和 KDR m RNA表达强度 ,在 AML明显高于 AL L。应用半定量方法更能反映患者细胞 VEGF m RNA表达     

Inhibition of renal cell carcinoma angiogenesis and growth by antisense oligonucleotides targeting vascular endothelial growth factor

Angiogenesis is critical for growth and metastatic spread of solid tumours. It is tightly controlled by specific regulatory factors. Vascular endothelial growth factor has been implicated as the key factor in tumour angiogenesis. In the present studies we evaluated the effects of blocking vascular endothelial growth factor production by antisense phosphorothioate oligodeoxynucleotides on the growth and angiogenic activity of a pre-clinical model of renal cell carcinoma (Caki-1). In vitro studies showed that treating Caki-1 cells with antisense phosphorothioate oligodeoxynucleotides directed against vascular endothelial growth factor mRNA led to a reduction in expressed vascular endothelial growth factor levels sufficient to impair the proliferation and migration of co-cultured endothelial cells. The observed effects were antisense sequence specific, dose dependent, and could be achieved at a low, non-toxic concentration of phosphorothioate oligodeoxynucleotides. When vascular endothelial growth factor antisense treated Caki-1 cells were injected into nude mice and evaluated for their angiogenic potential, the number of vessels initiated were approximately half that induced by untreated Caki-1 cells. To test the anti-tumour efficacy of vascular endothelial growth factor antisense, phosphorothioate oligodeoxynucleotides were administrated to nude mice bearing macroscopic Caki-1 xenografts. The results showed that the systemic administration of two doses of vascular endothelial growth factor antisense phosphorothioate oligodeoxynucleotides given 1 and 4 days after the tumours reached a size of approximately 200 mm(3) significantly increased the time for tumours to grow to 1000 mm(3).     

VEGF及其受体KDR在非小细胞肺癌中的表达及与肿瘤血管形成关系

目的：探讨血管内皮生长因子（VEGF）及其受体（KDR）的表达与非小细胞肺癌（NSCLC）血管形成的关系。方法：分别应用免疫组织化学S-P法和原位分子杂交法检测62例NSCLC组织和16例肺的良性瘤样病变组织中的VEGF和KDR mRNA的表达，并对血管进行染色、计数。结果：62例肺癌组织中46例有VEGF的表达（占74．29％），阳性表达位于肿瘤细胞胞膜及胞质；KDR mRNA在49例中有阳性表达（占79．03％），阳性表达位于肿瘤血管内皮细胞、肿瘤细胞胞膜及胞质。VEGF和KDR mRNA的表达与有无淋巴结转移和临床病理分期密切相关；VEGF和KDR mRNA阳性表达组微血管密度明显高于阴性表达组，P〈0．01。结论：VEGF和KDR的表达与NSCLC的发生、发展和转移可能密切相关，可作为评估NSCLC患者预后的一项指标。     

The role of vascular endothelial growth factor in pathological angiogenesis

Summary Vascular endothelial growth factor (VEGF) is a diffusible endothelial cell-specific mitogen and angiogenic factor that can also increase vascular permeability. By alternative splicing of mRNA, VEGF may exist as one of four different isoforms that have similar biological activities but differ markedly in targeting and bioavailability. The VEGF receptors are specifically expressed in the cell surface of vascular endothelial cells. Recent studies point to VEGF as a major regulator of physiological angiogenesis, such as developmental and reproductive angiogenesis. Furthermore, VEGF appears to be a crucial mediator of blood vessel growth associated with tumors and proliferative retinopathies. The VEGF mRNA is up-regulated in the majority of human tumors and the VEGF protein is increased in the aqueous and vitreous humors of patients with proliferative retinopathies. Anti-VEGF antibodies have the ability to suppress the growth of a variety of tumor cell lines in nude mice and also can inhibit angiogenesis in animal models of intraocular neovascularization. Therefore, strategies aimed at antagonizing VEGF may form the basis for an effective treatment of tumors and retinopathies. Furthermore, VEGF-induced angiogenesis is sufficient to achieve a therapeutic endpoint in models of coronary or limb ischemia.     

Tamoxifen inhibits endothelial cell proliferation and attenuates VEGF-mediated angiogenesis and migration in vivo

INTRODUCTION: Angiogenesis is fundamental to tumour growth and vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic cytokines known. We have previously demonstrated that tamoxifen reduces serum VEGF in certain cancer patients. We hypothesized that tamoxifen may attenuate the angiogenetic response to VEGF. METHODS: Human dermal microvessel endothelial primary cell cultures (HMEC) were incubated with tamoxifen (1.25-5.0 microg) or vehicle. Cell proliferation was quantified using 5-bromo-2'-deoxyuridine (BrdU) labelling endothelial cell proliferation assay. The effect of oral tamoxifen (20 mg/day) on VEGF-mediated angiogenesis in vivo was assessed using a Matrigel angiogenesis assay in the Sprague-Dawley rat. RESULTS: Tamoxifen (5.0 microg/ml) significantly reduced HMEC proliferation over 24 h when compared with cells treated with vehicle alone. Oral administration of tamoxifen in the rat (20 mg/day) significantly reduced endothelial cell proliferation and migration in response to VEGF. CONCLUSION: Tamoxifen (5.0 microg/ml) reduces proliferation of a VEGF-dependent endothelial cell line in vitro. In vivo, orally administered tamoxifen reduces VEGF-mediated angiogenesis in the rat. These findings indicate that tamoxifen may directly inhibit the effect of VEGF on the endothelial cell, in addition to its previously described effect of reducing serum VEGF levels. This data supports a role for tamoxifen in modulation of the VEGF-dependent angiogenic response to surgical trauma, particularly as an adjuvant therapy for VEGF-dependent tumours.     

Neuropilin-1与肿瘤血管新生和生长转移

神经纤毛蛋白-1（Neuropilin-1）最早是作为轴突导向分子collapsin／semaphorin的受体被发现，在神经发育过程中引导轴突选择正确途径以成功到达靶区，与此同时又可作为血管内皮生长因子受体-2（VEGFR-2）的共受体表达于血管内皮细胞，在血管新生中发挥作用。近来的研究表明NRP-1可通过依赖于VEGF和独立于VEGF的方式参与调节肿瘤血管新生，在肿瘤生长转移中发挥作用。     

VEGF及其受体KDR在非小细胞肺癌中的表达及与肿瘤血管形成关系

目的:探讨血管内皮生长因子(VEGF)及其受体(KDR)的表达与非小细胞肺癌(NSCLC)血管形成的关系。方法:分别应用免疫组织化学S-P法和原位分子杂交法检测62例NSCLC组织和16例肺的良性瘤样病变组织中的VEGF和KDRmRNA的表达,并对血管进行染色、计数。结果:62例肺癌组织中46例有VEGF的表达(占74·29%),阳性表达位于肿瘤细胞胞膜及胞质;KDR mRNA在49例中有阳性表达(占79·03%),阳性表达位于肿瘤血管内皮细胞、肿瘤细胞胞膜及胞质。VEGF和KDR mRNA的表达与有无淋巴结转移和临床病理分期密切相关;VEGF和KDR mRNA阳性表达组微血管密度明显高于阴性表达组,P<0·01。结论:VEGF和KDR的表达与NSCLC的发生、发展和转移可能密切相关,可作为评估NSCLC患者预后的一项指标。     

Tenascin-C regulates angiogenesis in tumor through the regulation of vascular endothelial growth factor expression

In order to verify whether tenascin-C (TN-C) is involved in angiogenesis as an extracellular signal molecule during tumorigenesis, cancerous cell transplantation experiments and coculture experiments were carried out, focusing on the regulation of vascular endothelial growth factor (VEGF). The A375 human melanoma cells introduced the GFP gene (A375-GFP), implanted subcutaneously into BALB/cA nude (WT) and TN-C knockout BALB/cA nude (TNKO) congenic mice. Furthermore, coculture experiments between A375-GFP and embryonic mesenchyme, which was prepared from both genotypes, were carried out to investigate the molecular mechanism in the cell-cell interactions. Both the content of TN-C and that of VEGF in the tumor and the conditioned medium were analyzed by the sandwich ELISA method. Seven days after transplantation of the A375-GFP, capillary nets became far more abundant in the tumors grown in WT mice than those in TNKO mice. Interestingly, VEGF and TN-C expressions showed antithetical expression patterns between the tumors in WT mice and those in TNKO mice. This peculiar phenomenon seems to be caused by a time lag prior to the onset of the mesenchymal regulation for the TN-C expression of A375-GFP. The coculture experiments revealed that WT mesenchyme had a much stronger effect than TNKO mesenchyme on both TN-C and VEGF expression. However, the defects of TNKO mesenchyme were restored in all cases by additional TN-C. These results clearly indicated that the expressions of both TN-C and VEGF depend on the surrounding mesenchyme, and that the function of mesenchyme is regulated by its own mesenchymal TN-C. In conclusion, the present data suggest that the matrix microenvironment organized by the host mesenchyme is very important for angiogenesis in tumor development.     

Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy

Biological evidence suggests that interference with the function of the angiogenic growth factor receptor VEGFR2 (flk1/KDR) is a particularly promising strategy to inhibit tumor-induced angiogenesis. Proof of concept was established by developing a monoclonal rat anti-mouse VEGFR2 antibody (DC101) and showing that it potently blocked the binding of VEGF to its receptor, inhibited VEGF-induced signaling, and strongly blocked tumor growth in mice through an anti-angiogenic mechanism. Since DC101 does not cross-react with the human VEGFR2 KDR, anti-KDR monoclonal antibodies were generated by standard hybridoma technology and by using phage display library. High affinity antibodies (K_d = 4.9 × 10¹⁰–¹⁰ – 1.1 × 10^{10 9} M) were found with both approaches. The anti-KDR antibodies compete on an equimolar basis with VEGF for binding to KDR and inhibit with similar potency the VEGF-induced signaling and mitogenesis in human endothelial cells. Although these antibodies cannot be tested for in vivo efficacy in standard murine tumor models because of lack of species cross-reactivity, the similarity of their in vitro properties with those of DC101 suggests that they may be effective in blocking KDR function in vivo.     

Human chondrosarcoma secretes vascular endothelial growth factor to induce tumor angiogenesis and stores basic fibroblast growth factor for regulation of its own growth.

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are well-known factors that induce neovascularization in many tumors. The molecular mechanisms that regulate tumor angiogenesis in human chondrosarcoma are not clear. We assessed in this work the angiogenic activities of a human chondrosarcoma cell line (OUMS-27) in vivo and determined the efficacies of angiogenic factors derived from OUMS-27 cells on human umbilical vein endothelial cells (HUVECs) in vitro. Tumor xenografts induced an increase in the formation of neovessels, but the distributions of Ki-67 antigen, VEGF and bFGF were unaffected. We also demonstrated that OUMS-27 cells secreted VEGF(165) into the culture medium and that it was the maximal angiogenic factor to stimulate endothelial proliferation and migration in chondrosarcoma. Anti-VEGF antibodies induced an approximately 70% inhibition of these responses of HUVECs, but did not have any effect on OUMS-27 cells. Anti-bFGF antibodies suppressed not only the activities of HUVECs but also the growth of tumor cells in vitro. We indicate that angiogenesis is principally elicited by VEGF(165) and that tumorigenesis is mainly regulated by bFGF stored in the extracellular matrix of OUMS-27 cells. The present study may offer the availability of combination therapies for inhibition of VEGF and bFGF action on vascular endothelial cells and chondrosarcoma cells, respectively.