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 and osteopontin in tumor biology

Tumor growth and metastasis are angiogenesis-dependent and tumor angiogenesis is a result of complex interplay of positive and negative regulators. Vascular endothelial growth factor (VEGF) occupies a particular place among the positive regulators of angiogenesis due to its potency and specificity for endothelial cells. VEGF upregulates several molecules such as growth factors, adhesion molecules, proteases, and protease receptors and it actually induces microvascular hyperpermeability, resulting in activation of thrombin from prothrombin. Osteopontin (OPN) is a secreted arginine-glycine-asparic acid (RGD)-containing phosphoprotein and it contains a predicted thrombin cleavage site. OPN binds to several integrins and CD44 variants. OPN has diverse functions such as cell adhesion, chemoattraction, and immunomodulation, and it induces endothelial cell migration and upregulates endothelial cell migration induced by VEGF. OPN expression is upregulated in human carcinomas. This review documents the functional roles of VEGF and OPN in angiogenesis and their clinical significance in tumor biology.     

Vascular endothelial growth factor in ovarian cancer

Tumor growth requires nutrients and oxygen. Both nutrients and oxygen are provided via the vasculature. Thus, when a tumor increases in volume, new blood vessels must form and invade the expanding tumor. This process, called angiogenesis, has theoretical significance in the context of ovarian cancer for two reasons. First, the process of angiogenesis and vessel regression occurs in a tightly controlled way as part of normal ovarian function. This suggests that at least some ovarian cells are primed to produce the paracrine stimulus needed for new blood vessel growth and that, on tranformation, this capability is present early in tumor development. Second, the characteristically large size of ovarian tumors indicates that angiogenesis is mandatory to sustain the tumor. In this article, we review the experimental and clinical correlative data that support the hypothesis that ovarian cancers are highly angiogenic. Because a critical component of angiogenesis is the paracrine and autocrine production of vascular endothelial cell growth factor, there is substantial focus on this topic.     

Vascular endothelial growth factor in esophageal cancer

Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis of many solid malignancies. The influence of angiogenesis and VEGF expression on progression and recurrence of esophageal cancer has been investigated over the last years. This article reviews the prognostic significance of VEGF expression, microvessel density (MVD), and lymphangiogenic factors in squamous cell carcinoma (SCC), Barrett's dysplasia, and adenocarcinoma (AC) of the esophagus, their predictive value for treatment response to chemo-radiotherapy and new anti-angiogenic treatment strategies.     

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 and breast cancer risk

Vascular endothelial growth factor (VEGF) is a key factor in angiogenesis and is important to carcinogenesis. Previous studies relating circulating levels of VEGF to breast cancer have been limited by small numbers of participants and lack of adjustment for confounders. We studied the association between serum VEGF and breast cancer in an unmatched case–control study of 407 pre- and postmenopausal women (n = 203 cases, n = 204 controls). Logistic regression was used to model the breast cancer risk as a function of natural log transformed VEGF levels adjusted for age, Gail score, education, physical activity, history of breastfeeding, serum testosterone, and hormone therapy (HT) use. The majority of the population was postmenopausal (67.6%) and the average age was 56 years; age and menopausal status were similar among cases and controls. Geometric mean VEGF levels were non-significantly higher in cases (321.4 pg/ml) than controls (291.4 pg/ml; p = 0.21). In a multivariable model, the odds of breast cancer was 37% higher for women with VEGF levels ≥314.2 pg/ml compared to those with levels below 314.2 pg/ml, albeit not significantly (p = 0.16). There was no interaction between VEGF and menopausal status (p = 0.52). In this case–control study, VEGF was not significantly associated with breast cancer risk in pre- and postmenopausal women.     

Vascular endothelial growth factor and bevacitumab in breast cancer

Cancer development requires neovascularization. The level of angiogenic activity in breast cancer has been shown to be a determinant of disease progression and survival. Vascular endothelial growth factor (VEGF) is a one of the most essential pro-angiogenic growth factors expressed by most cancer-cell types and certain tumor stromal cells. Blocking the action of VEGF appears to be a promising anti-angiogenic approach to treat multiple types of solid tumors including breast cancer, and clinical trials using agents which target VEGF were launched beginning in the late 1990s. The effort reached fruition in 2005 with the first report of a large, prospective randomized trial of anti-VEGF therapy in patients with metastatic breast cancer (MBC), which demonstrated the benefit of adding the monoclonal antibody bevacizumab to the chemotherapeutic agent paclitaxel. The success of this trial provided proof of principle that inhibition of angiogenesis has the potential to enhance the effectiveness of treatment of this disease. Adjuvant therapy trials are in development with bevacizumab and numerous other anti-VEGF agents are now being tested in patients with breast cancer in various settings. Nevertheless, since bevacizumab monotherapy has minimal activity, a question for future therapeutic development of these agents in breast cancer relates to the interaction between anti-angiogenic strategies and cytotoxic therapies. Further research is still needed for complete understanding of the exact role of VEGF and angiogenesis in health and disease, to take best advantage and avoid the adverse effects of anti-angiogenic therapy.     

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

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 and psychosocial factors in colorectal cancer

BACKGROUND: Vascular endothelial growth factor (VEGF) and psychosocial factors have both been shown to have independent prognostic value in colorectal cancer. Recently, an association between VEGF and psychosocial factors has been reported in patients with ovarian cancer. METHODS: A consecutive series of eligible patients undergoing elective resection for colorectal cancer were invited to participate. Standardized measures of various aspects of quality of life (QoL) were administered 5-12 days before surgery, and again 6-8 weeks after the operation, blood samples were obtained at the same times. Solid phase ELISA was used for VEGF-A analysis using serum samples. Correlations and multiple regression analysis were used to examine the relationship between VEGF and psychosocial factors. RESULTS: One hundred and four patients with colorectal cancer were recruited. Seventy (67%) were male and the mean age was 67.6 years.A significant positive correlation was found between preoperative VEGF level and preoperative depression (r=0.227, p=0.03). Preoperative VEGF was negatively correlated with preoperative cancer-related concerns (r=-0.273, p=0.009) and positive affectivity (r=-0.219, p=0.05). Linear regression using TNM stage as a covariate showed that cancer-related concerns were an independent predictor of preoperative VEGF levels (p=0.02).Preoperative cancer-related concerns and global QoL were negatively correlated with postoperative VEGF (r=-0.381, p=0.001, r=-0.264, p=0.005), whereas preoperative depression correlated positively with postoperative VEGF (r=0.333, p=0.003). Linear regression analysis showed that preoperative HADS depression (p=0.005) and cancer-related concerns (p=0.002) were independent predictors of postoperative VEGF levels. Postoperative VEGF was significantly correlated with postoperative anxiety (r=0.249, p=0.02), depression (r=0.289, p=0.01), and functional well-being (r=-0.242, p=0.03). Linear regression analysis showed that postoperative anxiety (p=0.048), depression (p=0.013) and functional well-being (p=0.046) independently predicted postoperative VEGF-A levels. CONCLUSION: Various psychosocial factors, particularly cancer-related concerns and depression, appear to be related to preoperative and postoperative VEGF level in patients with newly diagnosed colorectal cancer. However, the clinical significance of these findings needs to be addressed in longitudinal follow-up studies of recurrence and survival. Future prognostic studies involving VEGF and related cytokines should assess psychosocial variables at various time points and include these in a multivariate analysis of outcomes.     

Vascular endothelial growth factor and p53 expressions in liver and abdominal metastases from colon cancer.

OBJECTIVE: To determine the relationship between p53 overexpression and vascular endothelial growth factor (VEGF) upregulation in liver and abdominal metastases from colon cancer. The analysis in the two metastatic sites was carried out to evaluate the potential role of microenvironment in the molecular regulation of VEGF. METHODS: Bioptic specimens of liver and abdominal metastases from colon carcinomas were examined by immunohistochemistry for p53 and VEGF expressions. Consecutive cases with assessable tumor tissue were selected. RESULTS: The study population consisted of 24 cases having liver metastases and 34 cases having abdominal metastases. Abdominal metastases showed a higher number of VEGF-positive cases and a higher intensity of VEGF immunoreactivity than liver metastases did (p = 0.01). The combined analysis of p53 and VEGF showed a strong association between the two markers in the 24 liver metastases; 9 cases were VEGF positive/p53 positive and 15 cases were VEGF negative/p53 negative. This relationship was not found in the 34 abdominal metastases, which showed concordance between the two markers in 9 VEGF-positive/p53-positive cases only. CONCLUSIONS: Microenvironment factors like hypoxia may have a predominant role in inducing VEGF expression and they can override the molecular control of p53 on VEGF.     

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 (VEGF) in human breast cancer: Correlation with disease-free survival

Studies have shown that microvessel density influences breast-cancer prognosis. Since tumor angiogenesis is considered to be substantially affected by the excretion of vascular endothelial growth factor (VEGF) from tumor cells, we examined whether VEGF concentration is different in malignant and in non-malignant breast tissue. It was also of interest to discover whether intratumoral VEGF concentration influences disease-free survival (DFS) of breast-cancer patients. Analysis is based on 120 tissue specimens taken from breast fibromas (n = 23), normal epithelial breast tissue adjacent to fibromas (n = 8) and invasive breast cancer (n = 89). VEGF concentration was quantified by using an immunoassay. Microvessel density was determined by immunostaining for factor-VIII-related antigen. Median VEGF concentration is given in pg/mg protein (25%-quantile—75%-quantile) and it was 0 (0–1.8) in normal breast tissue, 9.8 (0.52–43.0) in fibromas and 130.4 (50.8–362.2) in invasive carcinomas. A univariate Cox model revealed that node status, tumor size, estrogen-receptor concentration, histological grading and microvessel density were prognostic factors for disease-free survival in breast cancer. We found a significant correlation between VEGF concentration and microvessel count, but VEGF concentration did not significantly influence disease-free survival. Although VEGF protein was found at a significantly higher concentration in malignant than in non-malignant tissue, determination of intratumoral VEGF protein by an enzyme immunoassay was not prognostically relevant in our patient population. Int. J. Cancer 74:455–458, 1997. © 1997 Wiley-Liss, Inc.     

VEGF基因多态性与肺痛遗传危险因素的关系

Objective:We investigated the potential association between vascular endothelial growth factor (VEGF) poly-morphisms and the risk of lung cancer. Methods:In the case-control study, we used PCR-RFLP technique to determine two VEGF genotypes-2578C/A and 936C/T in 171 lung cancer patients and 172 healthy controls for conformation, and construct-ed haplotypes of the two gene sites by PHASE1.0 software. Unconditional logistic regression model was used to analyze the statistical association of genontypes or haplotypes in the two groups adjusted by gender and age. Results:Compared with at least one -2578A allele, individuals with-2578CC genotype found associated with a significantly decreased risk of lung can-cer [P=0.001;adjusted odds ratio (OR), 0.391;95% confidence interval (95% CI), 0.226-0.686]. Analyses stratified by gender showed that the combined -2578 CA and AA genotype were also associated with a significantly decreased risk of lung cancer. (P=0.016;OR 0.303;95% CI=0.153-0.601 and P=0.018;OR=0.547;95% CI=0.331-0.903, respectively). The distribu-tion of the two haplotypes (936C/-2578C and 936C/-2578A) were significantly different between case-and -control groups (P = 0.016, OR=0.317, 95% CI=0.124-0.809 and P=0.018, OR=0.547, 95% CI=0.331-0.903). Analyses categorized by tumor histology showed that Haplotype C-C was associated with a significantly decreased risk of adenocarcinoma compared with the reference haplotypes. (P=0.004;OR=0.237;95% CI=0.090-0.627). Conclusion:These results suggest that the VEGF polymorphisms may be a critical factor for the risk of lung cancer.     

Vascular endothelial growth factor and insulin-like-growth factors in prostate cancer.

To study the levels of vascular endothelium growth factor (VEGF), insulin-like growth factor of type I and II (IGF-I and IGF-II), prostate-specific antigen (PSA) and their correlations in prostatic cancer (PC) and benign prostatic hyperplasia (BPH), we examined 38 PC patients (mean age 66.6 +/- 5.5 years) and 80 BPH patients (mean age 60.3 +/- 2.5 years). Serum concentrations of VEGF, IGF-I and IGF-II were measured using kits made by R&D (USA), PSA by Boehringer Mannheim (Germany). Sensitivity and specificity of the tests were analysed by plotting the curves. The serum VEGF concentration in PC patients was 518.9 +/- 60.7 pkg/ml, in BPH patients--267.9 +/- 99.9 pkg/ml (p < 0.001). The IGF-I and IGF-II it was 178 +/- 19 and 136 +/- 9 ng/ml (p < 0.05), 400 +/- 31 and 351 +/- 23 ng/ml (p < 0.05), respectively. The ratio of growth factor concentration to PSA concentration in the blood serum in BPH patients was higher than in PC patients (p < 0.01). Sensitivity and specificity of PSA (4 ng/ml) made up 85.7 and 57%, VEGF (151.5 pg/ml)--76.2 and 57.6%, IGF-I (157 ng/ml)--57.6 and 50%; IGF-II (392 ng/ml)--57.5 and 50%, respectively. Sensitivity and specificity VEGF/PSA was 85.7 and 70%; IGF-I/PSA--84.2 and 75%; IGF-II/PSA--84.2 and 79.6%, respectively. Thus, the ratio of concentrations of IGF-I, IGF-II and VEGF to PSA level in blood serum has high sensitivity and specificity for PC detection. Clinical implications of serum levels of VEGF, IGF-I and IGF-II for prediction of PC course and detection is to be elicited.     

Vascular endothelial growth factor expression in human neuroblastoma: up-regulation by hypoxia

Enhanced angiogenesis apparently contributes to the poor clinical outcome of human neuroblastoma, but the mechanisms have remained unclear. We report here that cultured human neuroblastoma cells express a bioactive endothelial cell growth factor indistinguishable from the angiogenesis stimulator vascular endothelial growth factor (VEGF). VEGF is present in neuroblastoma but not vascular endothelial cells, whereas the corresponding VEGF receptors (Flt-1 and Flk-1/KDR) are expressed in endothelial but not neuroblastoma cells. Exposure of neuroblastoma cells to hypoxia induces a marked increase in bioactive VEGF. VEGF is also present in human neuroblastoma specimens, with substantial amounts in apparently hypoxic neuroblastoma cells, eventually accumulating in tumor microvessels. Our results indicate that VEGF (i) is present in human neuroblastomas, (ii) is up-regulated by tumor hypoxia and (iii) may stimulate neuroblastoma angiogenesis by paracrine mechanisms, thereby contributing to the progression of human neuroblastomas. We suggest that inhibition of VEGF activity may represent a novel approach for the therapy of human neuroblastoma.     

beta-Catenin regulates vascular endothelial growth factor expression in colon cancer

To evaluate whether beta-catenin signaling has a role in the regulation of angiogenesis in colon cancer, a series of angiogenesis-related gene promoters was analyzed for beta-catenin/TCF binding sites. Strikingly, the gene promoter of human vascular endothelial growth factor (VEGF, or VEGF-A) contains seven consensus binding sites for beta-catenin/TCF. Analysis of laser capture microdissected human colon cancer tissue indicated a direct correlation between up-regulation of VEGF-A expression and adenomatous polyposis coli (APC) mutational status (activation of beta-catenin signaling) in primary tumors. In metastases, this correlation was not observed. Analysis by immunohistochemistry of intestinal polyps in mice heterozygous for the multiple intestinal neoplasia gene (Min/+) at 5 months revealed an increase and redistribution of VEGF-A in proximity to those cells expressing nuclear beta-catenin with a corresponding increase in vessel density. Transfection of normal colon epithelial cells with activated beta-catenin up-regulated levels of VEGF-A mRNA and protein by 250-300%. When colon cancer cells with elevated beta-catenin levels were treated with beta-catenin antisense oligodeoxynucleotides, VEGF-A expression was reduced by more than 50%. Taken together, our observations indicate a close link between beta-catenin signaling and the regulation of VEGF-A expression in colon cancer.     

Vascular endothelial growth factors and receptors in colorectal cancer: implications for anti-angiogenic therapy

There are conflicting associations between growth factor expression and clinicopathological variables in colorectal cancer. This study aimed to define the expression of members of the VEGF family and the receptor, VEGFR2, in primary and metastatic sites of colorectal cancer and their relationship to metastatic potential. Thirty colorectal cancers, 12 lymph node metastases and 9 liver metastases were immunostained for VEGF-A, VEGF-C, VEGF-D and VEGFR2. VEGFR2 was expressed by endothelial cells and by the malignant epithelium. VEGF-C and VEGFR2 were co-expressed in the same territory and correlated throughout the primary tumour and in metastatic lymph nodes, but not in liver metastases. Their expression at the invasive tumour edge correlated with expression in metastatic nodes. The benefit of anti-VEGF antibodies might be increased by directing additional therapies against VEGF-C or against the kinase receptors to target redundancy in the system. A component of the therapeutic benefit might be due to a direct anti-tumour effect as well as an anti-angiogenic effect.     

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