Clinical importance of serum vascular endothelial and basic fibroblast growth factors in children with acute lymphoblastic leukemia.

The aim of this study is to evaluate, for the first time serum levels of vascular endothelial growth factor (s-VEGF), and basic fibroblast growth factor (s-b FGF) in children with acute lymphoblastic leukemia (ALL), and its relation to clinical manifestations of the disease. Although VEGF and b FGF have been suggested to be reliable prognostic indicators and important tools for treatment approach in malignant haematopoietic and solid tumours, experience in childhood ALL has been limited to only one study on angiogenesis and urine b FGF. All 31 ALL patients included in the present study at the time of diagnosis and in remission, and all 10 control children had detectable serum levels of VEGF and b FGF. The median level of s-VEGF at the time of diagnosis was significantly lower than in the control group and at the time of remission (respectively p = 0.005, p = 0.0001). Twenty six of 31 patients had an increasing trend of s-VEGF levels in remission reaching control values compared with the levels obtained at diagnosis. S-b FGF median levels at the time of diagnosis were the same as those of the control group, significantly lower than the median s-b FGF values in remission (p = 0.001). In patients with lower platelet counts (< 50 x 10(9)/L) growth factors (VEGF and b FGF) were lower than in patients with higher platelet counts (p = 0.0009 and p = 0.002 respectively). In patients with hepatosplenomegaly (longitudinal size > 3 cm) b FGF levels were higher than patients without hepatosplenomegaly (P = 0.003). We concluded that the increment in both s-VEGF and s-b FGF in patients in remission may be related to the renewal of normal haematopoiesis. The increase in s-VEGF values in 26 out of 31 patients in remission compared to normal control values, may also suggest that there is clinical significance in ALL patients.     

Expression of vascular endothelial growth factor and basic fibroblast growth factor in small adenocarcinomas.

The expression of two angiogenetic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), in small adenocarcinomas (相似文献   

Serum basic fibroblast growth factor and vascular endothelial growth factor and tumour growth kinetics in advanced colorectal cancer

BACKGROUND:: The development of new microvessels in the surrounding stromais a prerequisite for tumour progression. Basic fibroblast growthfactor (bFGF) and vascular endothelial growth factor (VEGF)are angiogenic factors expressed in a broad range of human tumours.We have measured the concentrations of both cytokines in theserum of patients with advanced colorectal cancer. We questionedwhether these levels are related to the number of tumour sites,the volume of liver and/or lung involvement and the growth kinetics. PATIENTS AND METHODS:: 44 untreated colorectal adenocarcinoma patients who had developedmetastatic and/or recurrent disease were evaluated. Serum levelsof bFGF and VEGF were repeatedly measured using ELISA. The extentof target organ involvement and the kinetics of tumour volumegrowth were determined on consecutive computer tomography (CT)images. RESULTS:: Patients with a tumour volume doubling time of less than 6 monthsshowed a higher bFGF and VEGF serum level than others, independentof the number of sites involved and the extent of the metastaticdisease. CONCLUSIONS:: The data suggest a predictive value of serum bFGF and VEGF levelsfor the progression of disease in patients with untreated metastaticcolorectal cancer. The results corroborate the importance ofangiogenesis in the process of tumour growth. The serum levelsmight prove a useful tool in the quantitication of angiogenesisand might be of valuable information in the decision processof initiating palliative chemotherapy. It will be of considerableimportance to investigate whether the serum bFGF and VEGF levelshave a predictive value on the probability of response to cytotoxictherapy. angiogenesis, colorectal carcinoma, tumour growth, serum bFGF, esrum VEGF     

Quantitative analysis of basic fibroblast growth factor and vascular endothelial growth factor in human colorectal cancer.

Tumour growth is angiogenesis dependent. Some authors suggest a prognostic role of microvessel count in colorectal cancer. We tested the role of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the switch to the angiogenic phenotype in 35 patients with colorectal cancer at different stages of disease. We evaluated the two angiogenic factors, by enzyme-linked immunosorbent assay (ELISA), in tumour, peritumoral mucosa, pathological mesenteric and peripheral blood. We used ten endoscopic intestinal biopsies and ten peripheral blood samples from healthy subjects as control. bFGF was significantly lower in tumour tissues and in peritumoral mucosas than in healthy mucosas, whereas VEGF was up-regulated in tumours but not in peritumoral mucosa. Both angiogenic factors were greatly increased in mesenteric blood. VEGF tumour and serum levels were significantly correlated with the stage of disease. bFGF tumour and serum concentration were not correlated with the stage of disease. The high levels of bFGF in mesenteric blood suggest that this growth factor might be abnormally released from tumour tissue and peritumoral mucosa and could function as an early effector in the switch to the angiogenic phenotype. In contrast, VEGF, whose levels show a significant correlation with the stage of disease, could act in a following step, supporting tumour progression.     

Prognostic correlation of basic fibroblast growth factor and vascular endothelial growth factor in 1307 primary breast cancers

This study was designed to investigate the possible relationship between the protein expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) with p53 status, breast cancer prognostic factors, metastatic site, and survival after adjuvant therapy. Basic fibroblast growth factor and VEGF expression were determined by enzyme-linked immunosorbent assays in cytosol specimens obtained from 1307 patients with T1-3 primary breast cancer (789 node-negative, 518 node-positive) diagnosed between 1990 and 1997. The median follow-up time was 70 months. Increased bFGF expression was more frequently found in tumors with low VEGF expression (r = -0.286; P = 0.095). Increased bFGF was associated with smaller tumors (P < 0.001), absence of axillary metastasis (P = 0.003), low S-phase fraction (P < 0.001), and longer recurrence-free survival (RFS; P = 0.0038) and overall survival (OS; P = 0.0316). Vascular endothelial growth factor was a prognostic factor for RFS (P < 0.0001) and OS (P < 0.0001) in univariate and multivariate analyses (RFS: 95% CI, 1.1-1.7; P = 0.036; OS: 95% CI, 1.2-2.2; P = 0.002), whereas bFGF expression was not correlated with RFS or OS. Increased VEGF content was correlated with shorter survival after adjuvant endocrine therapy (RFS, P = 0.0004; OS, P = 0.0009). Patients with estrogen receptor-negative disease were excluded from the analysis. Basic fibroblast growth factor was not a prognostic factor after adjuvant systemic therapy, nor was it related to metastatic site. Expression of VEGF is an independent prognostic factor for patients with primary breast cancer. High bFGF expression was related to good prognostic features and longer survival times, but did not add prognostic information in multivariate analysis. The results might implicate that different angiogenic pathways exist in human breast cancer.     

肺癌患者血浆中血管内皮生长因子与碱性纤维母细胞生长因子表达

目的　研究血管内皮生长因子 (VEGF)与碱性纤维母细胞生长因子 (bFGF)在肺癌患者血浆中表达水平。方法　采用定量免疫酶标 (ELISA)方法 ,检测 92例肺癌患者及肺部良性疾病血浆中VEGF与bFGF的含量。结果　 84例肺癌与 7例肺部良性疾病血浆中VEGF含量分别为 2 0 1.5± 183.0pg/ml,10 2 .5± 6 2 .5pg/ml,两者差异有显著性 (P <0 .0 5 ) ;其中 4 4例腺癌和 7例小细胞癌的VEGF含量分别为 2 0 2 .3± 177.0pg/ml、381.4± 314 .3pg/ml,与其肺部良性疾病比较 ,差异均有显著性 (分别为P <0 .0 5、P <0 .0 0 1)。在 5 6例肺癌与 4例肺部良性疾病血浆中bFGF含量分别为 4 5 .4± 2 3.9pg/ml,5 0 .4± 2 7.2pg/ml,两者差异无显著性。结论　在肺癌患者血浆中VEGF的含量明显高于肺部良性疾病的含量 ,其中腺癌和小细胞肺癌差异有显著性。而肺癌与肺部良性疾病无明显差异     

Survivin promotes glioma angiogenesis through vascular endothelial growth factor and basic fibroblast growth factor in vitro and in vivo

Survivin is involved in multiple signaling mechanisms in tumor maintenance, and accumulated studies elucidate that knockdown of survivin in endothelial cells could inhibit angiogenesis; however, the role of survivin in tumor cells to regulate tumor-derived angiogenesis remains largely unclear. In the present study 80 cases of brain glioma were chosen and protein expressions of survivin, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) in glioma cells were investigated by immunohistochemistry (IHC). Human umbilical vein endothelial cells (HUVEC) were cocultured with human glioma U251 wild-type cells, U251 cells survivin silenced, SHG44 wild-type cells, and SHG44 survivin-overexpressing cells, respectively. The proliferation and migration of HUVEC were evaluated by MTT assay and transwell chamber assay. The microvessels density (MVD) marked by CD31 expression in vascular endothelial cells in glioma xenografts in nude mice was detected by IHC. VEGF, bFGF, and PDGF in the aforementioned cells were detected by quantitive PCR (qPCR), Western blot, ELISA, and IHC in vitro and in vivo. The results showed that VEGF immunoreactivity score (IRS), bFGF IRS, and PDGF IRS were all positively correlated with survivin IRS in gliomas, respectively (P < 0.01). Survivin in human glioma cells could significantly promote the proliferation and migration of HUVEC and increase MVD, which could be contributed to survivin-dependent burst of VEGF and bFGF expression, followed by increase of tumor growth and proliferation. In summary, survivin, through upregulation of VEGF and bFGF, plays an essential role during glioma angiogenesis.     

血管内皮生长因子、碱性成纤维细胞生长因子在宫颈癌中的表达及其与微血管密度的关系

目的 探究血管内皮生长因子(VEGF)、碱性成纤维细胞生长因子(bFGF)在宫颈癌中的表达情况及其与微血管密度(MVD)的关系.方法 选取118例宫颈癌患者、71例宫颈上皮内瘤变患者和50例宫颈炎患者作为研究对象,分别纳入宫颈癌组、瘤变组和对照组.取所有患者的宫颈组织,采用免疫组化法检测组织中VEGF、bFGF的阳性表...     

Modulation of angiogenesis and tumorigenicity of human melanocytic cells by vascular endothelial growth factor and basic fibroblast growth factor

Human melanoma cells express two prominent angiogenic factors, e.g., vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF/fibroblast growth factor-2). In this study, we report on the relative contribution of these two factors to in vitro and in vivo growth of a tumorigenic melanoma cell line (WM164) and nontumorigenic, immortalized melanocytes (FM516SV). Overexpression of either cytokine significantly boosted tumorigenicity of WM164 cells in immunodeficient SCID mice. Attempting to overexpress bFGF antisense sequences produced no viable clones confirming earlier reports that autocrine bFGF is obligatory to melanoma cell survival and growth. By contrast, down-regulation of endogenous VEGF production did not affect growth of WM164 cells in vitro. In vivo expansion of WM164 cells expressing VEGF antisense was delayed but not abrogated. Forced expression of either bFGF or VEGF in immortalized but nontumorigenic melanocytes did not induce sustained tumor growth in vivo highlighting that neither of the two factors is sufficient for induction of tumorigenicity in this model system. Overexpression of either cytokine in WM164 cells led to the development of atypical large vessels but not to an increase in microvessel density. Taken together our results confirm an essential autocrine role of bFGF in human melanoma and indicate a beneficial but nonessential role of VEGF in the tumorigenic phenotype of human melanoma cells.     

EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND BASIC FIBROBLAST GROWTH FACTOR IN HUMAN NON-SMALL CELL LUNG CANCER AND THEIR CLINICAL SIGNIFICANCE

Solid tumors contain tumor cells and vascular systems[1]. The growth and metastasis of solid tumors beyond 1-2mm in diameter depends on neovascularization. So the study of neovascularization helps to explain the biologic behavior of tumor. Angiogenesis is a complicated process mediated by a variety of angiogenic factors, which include vascular endothelial growth factor(VEGF) and basic fibroblast growth factor(bFGF). VEGF is an endothelial cell-specific mitogen with a pivotal role and may a…     

急性淋巴细胞白血病患者血清ＶＥＧＦ及Ｓｕｒｖｉｖｉｎ的测定及其临床意义

目的：检测血清血管内皮细胞生长因子（ＶＥＧＦ）和凋亡存活蛋白（Ｓｕｒｖｉｖｉｎ）在急性淋巴细胞白血病（ＡＬＬ）患者中的含量变化并探讨其临床意义。方法：应用双抗体夹心酶联免疫吸附法检测５３例ＡＬＬ患者血清ＶＥＧＦ及Ｓｕｒｖｉｖｉｎ在化疗前后含量的变化。结果：与正常成人对照组相比,初治组在化疗前血清ＶＥＧＦ、Ｓｕｒｖｉｖｉｎ含量明显增高,差异均有统计学意义（Ｐ＜０.０１）。未缓解组化疗前血清ＶＥＧＦ及Ｓｕｒｖｉｖｉｎ的含量与完全缓解组化疗前和对照组相比明显升高,差异均有统计学意义（Ｐ＜０.０１）,化疗后血清ＶＥＧＦ和Ｓｕｒｖｉｖｉｎ的含量无明显下降,但均明显高于完全缓解组化疗后（Ｐ＜０.０１）。ＡＬＬ初治患者化疗前血清ＶＥＧＦ与Ｓｕｒｖｉｖｉｎ含量呈正相关（ｒ＝０.５０,Ｐ＜０.０１）。结论：ＶＥＧＦ及Ｓｕｒｖｉｖｉｎ在ＡＬＬ的发病中具有重要作用,可作为了解病情、观察疗效和判断预后的指标之一。     

Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients.

The concentration of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) was determined in the serum of 90 untreated and 42 treated metastatic cancer patients, including patients with colorectal, breast, ovarian and renal carcinomas, with an enzyme-linked immunosorbent assay (ELISA). Levels higher than the 95th percentile of the concentrations of a control group, i.e. 7.5 pg ml(-1) for bFGF and 500 pg ml(-1) for VEGF, were identified as ''elevated''. One measurement during follow-up was included into the analysis per patient. For 19 treated patients, consecutive serum samples were analysed. Fifty-seven per cent of all untreated patients had elevated serum levels of one or both angiogenic factors. The fraction of patients with elevated serum levels of bFGF and/or VEGF was similar in the different tumour types. Agreement of bFGF levels and VEGF levels, classified in relation to their respective cut-off values, was present in 67% of all patients. Fifty-eight per cent of the patients with progressive disease during treatment compared with 15% of the patients showing response to treatment (chi-squared test P < 0.05) had elevated bFGF and/or VEGF serum levels. When consecutive serum samples were analysed, two-thirds of the patients showing progressive disease had increasing serum levels of the angiogenic factors compared with less than one-tenth of the patients showing response (chi-squared test P < 0.05). The lack of association between the serum bFGF and VEGF levels and the tumour type may suggest an aspecific host reaction responsible for solid tumour-related angiogenesis. The main determinants of the serum bFGF and VEGF concentration are the progression kinetics of the metastatic carcinomas.     

Levels of vascular endothelial growth factor,hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis

Angiogenesis is a possible target in the treatment of human gliomas. To evaluate the role of 3 growth factors, vascular endothelial growth factor (VEGF), hepatocyte growth factor/scatter factor (HGF/SF) and basic fibroblast growth factor (bFGF), in the angiogenic cascade, we determined their levels in extracts of 71 gliomas by enzyme‐linked immunosorbent assay (ELISA). The levels of bFGF were only marginally different between gliomas of World Health Organization (WHO) grade II (low grade) and grades III and IV (high grade). In contrast, the mean concentrations of VEGF were 11‐fold higher in high‐grade tumors and those of HGF/SF 7‐fold, respectively. Both were highly significantly correlated with microvessel density (p < 0.001) as determined by immunostaining for factor VIII‐related antigen. In addition, VEGF and HGF/SF appeared to be independent predictive parameters for glioma microvessel density as determined by multiple regression analysis. We measured the capacity of all 3 factors to induce endothelial tube formation in a collagen gel. In this assay, bFGF was found to be an essential cofactor with which VEGF as well as HGF/SF were able to synergize independently. According to the concentrations of angiogenic factors, extracts from high‐grade tumors were significantly more potent in the tube formation assay than the low‐grade extracts (p = 0.02). Adding neutralizing antibodies to bFGF, VEGF and HGF/SF together with the extracts, tube formation was inhibited by up to 98%, 62% and 54%, respectively. Our findings suggest that bFGF is an essential cofactor for angiogenesis in gliomas, but in itself is insufficient as it is present already in the sparsely vascularized low‐grade tumors. Upon induction of angiogenesis in high‐grade tumors, bFGF may synergize with rising levels of not only VEGF but possibly also with HGF/SF, which appears here to be an independent angiogenic factor. Int. J. Cancer (Pred. Oncol.) 84:10–18, 1999. © 1999 Wiley‐Liss, Inc.     

Hypoxia-induced angiogenesis of cultured human salivary gland carcinoma cells enhances vascular endothelial growth factor production and basic fibroblast growth factor release

The angiogenic activity of two human salivary gland tumor cell lines, ACCS from adenoid cystic carcinoma and IT-2 from mucoepidermoid carcinoma, was examined by stimulating tube formation by bovine capillary endothelial cells (BCE). ACCS and IT-2 were cultured in 20 or 3% oxygen, representing normoxic and hypoxic conditions, respectively, and conditioned medium (CM) was obtained from each culture. The BCE tubes stimulated by hypoxic CM were 1.59 (ACCS) and 1.42 (IT-2) times longer than those stimulated by normoxic CM. The tube-forming activity of CM was inhibited by preincubation with either anti-vascular endothelial growth factor (VEGF) IgG or anti-basic fibroblast growth factor (bFGF) IgG, suggesting that both VEGF and bFGF with angiogenic activity were present in the CM. This was confirmed by ELISA, which also demonstrated increased concentrations of both proteins in the hypoxic CM. Northern blot analysis showed an increased VEGF mRNA level in both carcinoma cells with hypoxia, while hypoxia did not affect the bFGF mRNA level in either cell line. The results suggest that both VEGF and bFGF are major angiogenesis factors in salivary gland tumors, and hypoxia-induced angiogenesis results from upregulation of VEGF and increased release of bFGF.     

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.     

Vascular endothelial growth factor and basic fibroblast growth factor in primary lung carcinomas and the incidence of metastases

Paraffin-embedded tumor sections from 166 patients with squamous cell lung carcinomas (n=114) and lung adenocarcinomas (n=52) were analyzed for the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) by immunohistochemistry. The results were compared with the incidence of metastatic spread. Sixty-five tumors were characterized as VEGF-negative and 101 tumors as VEGF-positive. Fifty-eight tumors were bFGF-negative and 108 tumors classified as bFGF-positive. Tumors with expression of VEGF or bFGF showed an increase in the formation of metastases. Combining the VEGF and bFGF expressions improved the prognostic value. Corresponding results were obtained when the analysis was restricted to squamous cell lung carcinomas or adenocarcinomas of the lung. These data provide evidence that VEGF and bFGF may be relevant factors associated with the metastatic potential of primary lung carcinomas.     

脑膜瘤组织中bFGF及FGFR-1蛋白表达的研究

目的　探讨碱性成纤维生长因子 (basicfibroblastgrowthfactor ,bFGF)及成纤维生长因子受体 1(fibroblastgrowthfactorreceptor 1,FGFR 1)在脑膜瘤中的表达及其与脑膜瘤组织病理学和复发的关系。方法　用免疫组化技术检测bFGF、FGFR 1在不同类型的脑膜瘤组织中的蛋白表达 ,用组织病理学判断脑膜瘤的良恶性。结果　脑膜瘤细胞有不同程度的bFGF及FGFR 1表达 ,其表达阳性率与肿瘤的良恶性和复发有关。结论　bFGF和FGFR具有促进脑膜瘤细胞的增殖和生长的作用。脑膜瘤表达bFGF、FGFR的阳性率可作为鉴别肿瘤良恶性的有用指标 ,并对脑膜瘤的预后和术后复发起提示作用。     

Relationship between vessel density and expression of vascular endothelial growth factor and basic fibroblast growth factor in small cell lung cancer in vivo and in vitro.

In 21 human small cell lung cancer (SCLC) cell lines, we determined the expression of mRNA and secreted protein levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The VEGF expression was highly variable between cell lines, with a > 100-fold variation, under identical in vitro conditions. The bFGF expression in cell lines was generally very low. Nine of the cell lines were further analyzed during growth as solid tumor xenografts in nude mice (in vivo). A more uniform VEGF protein expression was present in vivo. Compared with the variable in vitro expression, VEGF was relatively up-regulated in the tumor lines CPH 54A and CPH 54B and down-regulated in GLC 3. One line, DMS 79, had a high VEGF expression in vivo as well as in vitro. The vessel density was determined by Chalkley point counting on CD31 immunostained cryosections of tumors of each of the nine SCLC lines. We found a strong positive correlation between vessel density and tissue VEGF protein expression (r(s) = 0.75; P = 0.02) and a comparatively strong negative correlation (r(s) = -0.80; P = 0.01) between vessel density and tissue bFGF expression. No significant correlation was present between vessel density and in vitro VEGF expression. We conclude that VEGF and bFGF expression is dependent on microenvironmental conditions, as well as cell line-specific factors, and that a strong positive correlation exists between in vivo VEGF expression and vessel density, whereas high tissue levels of bFGF are not correlated with higher vessel densities in SCLC xenografts.     

Overexpression of basic fibroblast growth factor and autocrine stimulation in acute myeloid leukemia

Basic fibroblast growth factor (bFGF) is known to play a critical role in tumorigenesis of solid tumors. The importance of bFGF in hematological malignancies such as acute myeloid leukemia (AML) remains to be elucidated. Therefore, we determined bFGF protein expression by immunohistochemical analyses in bone marrow biopsies of patients with newly diagnosed, untreated AML. The expression of bFGF was significantly increased in AML patients [n = 81; median, 3.0 (interquartile range, 1.8-3.9) arbitrary units (AU)] as compared with controls [n = 18; 1.9 (1.5-2.3) AU]. The degree of bFGF expression did not correlate with microvessel density. bFGF/FGF receptor mRNA and bFGF protein were detected in different AML cell lines. To study autocrine growth stimulation of AML blasts, the AML cell lines HL-60, M-07e, and KG-1 were incubated with bFGF. A significant dose-dependent increase in proliferation and colony formation was observed. These effects were abrogated by the addition of a polyclonal anti-bFGF antibody. In conclusion, increased expression of bFGF in the bone marrow of AML patients seems to play an important role in the pathophysiology of AML by promoting autocrine growth stimulation of leukemic blasts.     

Vascular endothelial growth factor, interleukin 8, platelet-derived endothelial cell growth factor, and basic fibroblast growth factor promote angiogenesis and metastasis in human melanoma xenografts

Angiogenesis is a significant prognostic factor in melanoma, but the angiogenic factors controlling the neovascularization are not well defined. The purpose of this study was to investigate whether the angiogenesis and metastasis of melanoma are promoted by vascular endothelial growth factor (VEGF), interleukin 8 (IL-8), platelet-derived endothelial cell growth factor (PD-ECGF), and/or basic fibroblast growth factor (bFGF). Cells from human melanoma lines (A-07, D-12, R-18, and U-25) transplanted to BALB/c nu/nu mice were used as tumor models. Expression of angiogenic factors was studied by ELISA, Western blotting, and immunohistochemistry. Angiogenesis was assessed by using an intradermal angiogenesis assay. Lung colonization and spontaneous lung metastasis were determined after i.v. and intradermal inoculation of tumor cells, respectively. The specific roles of VEGF, IL-8, PD-ECGF, and bFGF in tumor angiogenesis, lung colonization, and spontaneous metastasis were assessed in mice treated with neutralizing antibody. The melanoma lines expressed multiple angiogenic factors, and each line showed a unique expression pattern. Multiple angiogenic factors promoted angiogenesis in the most angiogenic melanoma lines, whereas angiogenesis in the least angiogenic melanoma lines was possibly promoted solely by VEGF. Tumor growth, lung colonization, and spontaneous metastasis were controlled by the rate of angiogenesis and hence by the angiogenic factors promoting the angiogenesis. Lung colonization and spontaneous metastasis in A-07 were inhibited by treatment with neutralizing antibody against VEGF, IL-8, PD-ECGF, or bFGF. Each of these angiogenic factors may promote metastasis in melanoma, because inhibition of one of them could not be compensated for by the others. Our observations suggest that efficient antiangiogenic treatment of melanoma may require identification and blocking of common functional features of several angiogenic factors.