Prognostic value of plasma vascular endothelial growth factor in patients with colorectal cancer

BACKGROUND: Vascular endothelial growth factor (VEGF) is thought to be the most powerful angiogenic factor in many malignancies while and several reports have determined serum VEGF to be a prognostic indicator for various malignancies. However, serum VEGF may not be suitable for the measurement of circulating VEGF levels, given that clot formation during the process of collecting sample induces platelet activation and the subsequent release of many cytokines. MATERIALS AND METHODS: Blood samples were obtained prior to surgery from 33 patients with colorectal cancer, and additional samples were obtained 6 months post-operatively from 15 of the 33 patients. Plasma levels of VEGF were assessed using the quantitative sandwich-enzyme immunoassay technique. We investigated the relationships between plasma levels of pre-operative VEGF, prognosis and clinicopathological factors in patients with colorectal cancer. In addition, the relationship between pre-operative and post-operative plasma levels of VEGF obtained at 6 months was assessed. RESULTS: Although not significant, a trend was observed for high plasma levels of VEGF to occur with more advanced colorectal cancer. Plasma levels of VEGF were only significantly increased in patients who had recurrence and a worsening of colorectal cancer. In blood samples obtained from 15 patients both prior to surgery and 6 months post-operatively, post-operative mean plasma VEGF tended to decrease relative to the pre-operative level. CONCLUSION: These results suggest that high plasma levels of VEGF may be observed in more advanced colorectal cancer patients, especially in patients who develop recurrence or a worsening of their condition. Thus, such patients may require additional immunochemotherapy after surgery.     

Serum and plasma vascular endothelial growth factor levels in testicular cancer patients.

I read with interest Aigner and colleagues’ article [1]published recently in Annals of Oncology. Although the authorsshould be congratulated for their results on the study of pleiotrophinand fibroblast growth factor, I would like to report some methodologicalissues concerning     

大肠癌患者血清血管内皮生长因子和内皮抑素的水平及意义

 目的 探讨大肠癌患者血清血管内皮生长因子（sVEGF）和血清内皮抑素（s内皮抑素）的水平。方法 应用酶联免疫吸附试验检测32例大肠癌患者和28例对照组的sVEGF、s内皮抑素水平，分析二者的相关性及与临床病理学因素的关系。结果 大肠癌患者sVEGF和s内皮抑素水平呈正相关关系（P＜0.01）；大肠癌患者sVEGF和s内皮抑素水平均显著高于对照组（P＜0.01）；sVEGF、s内皮抑素与患者的性别、年龄、肿瘤部位、肿瘤分化程度和肿瘤直径大小无关，与淋巴结转移和Dukes分期相关。结论 大肠癌患者的sVEGF和s内皮抑素水平明显升高，二者可能共同调控肿瘤新生血管生成。     

Pre-operative serum vascular endothelial growth factor can select patients for adjuvant treatment after curative resection in colorectal cancer

We aim to determine the clinical usefulness of pre-operative serum vascular endothelial growth factor (VEGF) as a predictor of outcome in patients undergoing curative resection for colorectal cancer. Serum VEGF was assayed by quantitative ELISA in 81 patients prior to curative resection for node-negative (n = 53) and node-positive (n = 28) disease. Median follow-up for patients without cancer death was 27 months (range 21-37). Pre-operative serum VEGF was significantly higher in patients who went on to develop metastases than those who did not (median, 713 pg ml-1 vs. 314 pg ml-1, P < 0.0001). Using multivariate Cox regression analysis, pre-operative serum VEGF was the most important prognostic factor independent of nodal status and adjuvant chemotherapy, and was superior to nodal status in predicting outcome (P < 0.00001). At 575 pg ml-1, pre-operative serum VEGF was 64% sensitive and 89% specific in predicting the development of metastases in curative resections, with a positive predictive value of 73% and a negative predictive value of 85%. Pre-operative serum VEGF is a powerful predictor of outcome following curative surgery for colorectal cancer. These data support the measurement of pre-operative serum VEGF as a method for selecting patients who require adjuvant therapy.     

Correlation of plasma level and immunohistochemical expression of vascular endothelial growth factor in patients with advanced colorectal cancer

BACKGROUND: Vascular endothelial growth factor (VEGF) is thought to be the most potent angiogenic factor and may contribute to the progression of various cancers. In colorectal cancer, the immunohistochemical expression of VEGF is reported to be an independent prognostic factor, and elevated plasma levels of VEGF are reported to be a prognostic marker. The purpose of this study is to evaluate whether plasma levels of VEGF correlate with its immunohistochemical expression and with microvessel density (MVD) in patients with colorectal cancer. MATERIALS AND METHODS: Thirty-one patients with advanced colorectal cancer, who underwent surgery between February 1998 and April 2000, were included in this study. We measured the preoperative plasma levels of VEGF using the ELISA kit and immunostained the resected specimens for VEGF and CD34, as a marker of MVD. We then investigated the correlation among plasma levels of VEGF, expression of VEGF and MVD, and between these three factors and several clinical features. RESULTS: The plasma levels of VEGF were significantly associated with liver metastasis, the immunohistochemical expression of VEGF was significantly associated with lymph node metastasis and TNM stage, while MVD was significantly associated with lymph node metastasis, depth of invasion and TNM stage. Among the 3 parameters for angiogenesis studied, the plasma levels of VEGF significantly correlated with its immunohistochemical expression, and immunohistochemical expression of VEGF significantly correlated with MVD. There was no significant correlation between plasma levels of VEGF and MVD. CONCLUSION: Measuring plasma levels of VEGF is a good predictor of the immunohistochemical expression of VEGF in patients with advanced colorectal cancer, and may be a better indicator for tumor VEGF levels, since plasma levels can be measured much more quickly than expression levels.     

乳腺癌患者血管内皮生长因子水平与外周血各成分的相关性

目的寻求血管内皮生长因子（VEGF）的最佳检测方法并探讨VEGF水平与血小板、白细胞数量之间的关系。方法采集42例乳腺癌患者（乳腺癌组）及20例健康志愿者（对照组）外周静脉血,用VEGF单克隆抗体ELISA法分别测定血清、血浆、P—APRVEGF水平,经酶标仪半定量,同时血细胞分析仪计数血小板、白细胞数量。结果血清VEGF水平与血小板数量呈正相关（r=0．424,P=0．063）,血清VEGF水平与白细胞数量呈正相关（r=0．443,P=0．050）。P—APR中的VEGF含量在局限性乳腺癌组与对照组间的差异有统计学意义（P=0．007）。结论外周血VEGF水平与血小板、白细胞呈线性相关,血小板、白细胞在外周血中可分泌VEGF;相对血清、血浆,P—APR是外周血中VEGF检测的最佳成分。     

Inhibition of vascular endothelial growth factor by octreotide in colorectal cancer patients

Vascular endothelial growth factor (VEGF) seems to be essential for angiogenesis and for the growth of colorectal cancer, thus its inhibition can arrest tumor growth and decrease metastatic potential. Octreotide has been shown to inhibit growth of colorectal tumors in vitro and in vivo. Part of the antiproliferative activity of octreotide could be related to its antiangiogenic properties. Effects of octreotide on VEGF expression were evaluated in 35 patients with operable colorectal cancer receiving octreotide for 2 weeks before surgery. Tissue VEGF expression and serum VEGF concentrations were determined before and after treatment with octreotide. There was a statistically significant reduction in the tissue VEGF expression both considering the percentage of VEGF positive cells (P = 0.006) and the intensity of VEGF staining (P = 0.003). A similar significant reduction was observed in serum values of VEGF (P = 0.03). The present study indicates that octreotide inhibits expression of VEGF in colorectal cancer patients, and, furthermore, that serum VEGF expression correlates with tissue VEGF, representing a safe method to monitor the activity of antiangiogenic agents.     

Prognostic value of vascular endothelial growth factor expression in colorectal cancer patients

Solid tumours require neovascularisation for growth and metastasis. Vascular endothelial growth factor (VEGF) has been shown to be an important regulator of tumour angiogenesis. To examine the relevance of VEGF in the neoplastic transformation of human colon, we analysed protein expression in a total 30 polyps and 145 colorectal carcinomas by immunohistochemistry. All adenoma specimens, regardless of histological differentiation, and normal colonic mucosa did not express VEGF. Amongst 90 patients with non-metastatic colorectal cancer, VEGF expression was observed in 43 (48%) cases, whilst 29 of the 55 patients (53%) with metastases expressed the angiogenic factor. Both the proportion and intensity of VEGF expression were positively associated with the progression of colon carcinogenesis. Tumours with the highest VEGF expression tended to correlate with patients' survival, although VEGF expression did not emerge as an independent risk factor in a multivariate analysis. After exclusion of the patients with distant metastases, both univariate and multivariate analysis did not indicate any prognostic value for the tissues with the highest VEGF expression. Our results suggest that VEGF may play a role in the progression of colon cancer, although evaluation of this angiogenic phenotype did not provide additional prognostic information compared with that obtained from Dukes' staging of the tumours.     

Prognostic significance of vascular endothelial growth factor gene polymorphisms in patients with colorectal cancer

Background

Angiogenesis plays an important role in tumor development, progression, and metastasis. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis. However, the contribution of common VEGF polymorphisms to colorectal cancer (CRC) prognosis remains unclear.

Methods

We have genotyped four polymorphisms of VEGF (?2578C>A, ?1154G>A, ?634G>C, and 936C>T) in 350 CRC cases from the Korean population. The genotyping of VEGF polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism assay.

Results

Although not every VEGF polymorphism was significantly correlated with patient prognosis in overall 350 CRC patients, we found that the VEGF ?2578CA genotype was associated with a significantly poor prognosis for rectal cancers compared to the CC genotype (HR = 2.156; 95 % CI 1.090–4.267; P = 0.028). In addition, we found that the ?2578A/?1154G/?634G/+936C haplotype was significantly associated with a decreased overall survival (OS) rate in all 350 CRC patients (HR = 2.530; 95 % CI 1.340–4.780; P = 0.004). In combination analysis, we found that the combined VEGF ?2578CA+AA/?1154GG genotype was associated with a poor OS rate in all 350 CRC patients (HR = 2.068; 95 % CI 1.159–3.693; P = 0.015).

Conclusions

The VEGF gene polymorphisms investigated in this study were not found to be independent prognostic markers in Korean CRC populations. However, our results suggest that the VEGF ?2578C>A variant may be a potential genetic marker for rectal cancer prognosis. Further large population studies are warranted to define whether the ?2578C>A polymorphism is a prognostic marker of rectal cancer.     

Prediagnostic plasma vascular endothelial growth factor levels and risk of prostate cancer.

Vascular endothelial growth factor (VEGF) plays important roles in endothelial cell proliferation, vascular permeability, and angiogenesis that may be critical to prostatic carcinogenesis and progression. Plasma VEGF levels were significantly greater in patients with metastatic prostate cancer compared with those with localized disease or healthy controls, and plasma VEGF level at prostate cancer diagnosis was an independent prognostic marker for survival in patients with hormone refractory prostate cancer. We therefore examined the association between prediagnostic plasma VEGF levels and risk of prostate cancer and disease phenotype. Using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, we conducted a nested case-control study among 504 men diagnosed with prostate cancer during 13 years of follow-up and 520 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multivariate logistic regression. Prediagnostic plasma VEGF levels were similar among cases and controls. Plasma VEGF concentration was not associated with subsequent risk of prostate cancer (third versus first tertile OR, 1.09; 95% CI, 0.80-1.49; P(trend) = 0.65). Furthermore, no association was observed among men with advanced (stage C or D) prostate cancer or among those who died of prostate cancer. Our results indicate that prediagnostic circulating VEGF levels are not associated with prostate cancer development and have limited value in predicting future risk of prostate 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     

Preclinical data targeting vascular endothelial growth factor in colorectal cancer

Vascular endothelial growth factor (VEGF) is the driving force behind angiogenesis in most solid malignancies. This also holds true for colorectal cancer (CRC), where increased levels of VEGF in primary cancers are associated with increased microvessel density and poor prognosis. These findings have led to preclinical studies evaluating the efficacy of anti-VEGF therapy in inhibiting the growth of CRC in ectopic and orthotopic locations. In preclinical models, numerous approaches to inhibit VEGF activity led to decreased tumor growth and angiogenesis. These studies led to clinical trials in which, unfortunately, single-agent anti-VEGF therapy was relatively ineffective for patients with metastatic CRC. However, combinations of anti-VEGF therapies with chemotherapy have clearly demonstrated clinical benefit. Understanding the mechanisms of the role of VEGF in CRC angiogenesis and the effect of anti-VEGF therapy on the tumor vasculature will allow oncologists to optimize therapeutic regimens targeting VEGF and its receptors.     

Impact of surgery and chemotherapy on von Willebrand factor and vascular endothelial growth factor levels in colorectal cancer

The online version of the original article can be found at     

Impact of surgery and chemotherapy on von Willebrand factor and vascular endothelial growth factor levels in colorectal cancer

Introduction von Willebrand factor (vWf) is thought to mediate binding of tumour cells to platelets and to favour their systemic spreading capacity. Platelets involved in tumour angiogenesis are capable of releasing vascular endothelial growth factor (VEGF). Hence, levels of vWf and VEGF may correlate with cancer stage. The objectives are determine the impact of surgery and chemotherapy on vWf and VEGF in colorectal cancer (CRC) patients. Material and methods Twenty healthy volunteers (group 1), 14 patients with locally advanced CRC (group 2) and 12 patients with metastatic CRC (group 3) were enrolled. Blood samples were taken at recruitment in group 1, and before and after surgery and chemotherapy in groups 2 and 3, respectively. Blood levels of vWf, VEGF, platelet count, C-reactive protein (CRP), ceruloplasmin and carcinoembrionary antigen (CEA) were measured. Results At baseline, group 3 showed higher concentrations of vWf than the other groups (p<0.05). In group 2, vWf became elevated 40% post-surgery (p=0.016), independently of changes in CRP or ceruloplasmin. In group 3, chemotherapy caused a 42% reduction in VEGF (p=0.015). Conclusions There was a strong correlation between higher vWf levels and more advanced CRC stage at diagnosis. These levels were elevated post-surgery in patients with locally advanced CRC. Chemotherapy significantly decreased VEGF in metastatic CRC patients before CEA showed any significant change.     

Correlation between serum vascular endothelial growth factor and endostatin levels in patients with breast cancer

Serum vascular endothelial growth factor (VEGF) and endostatin levels were detected in 59 patients with breast cancer before surgery and at 3 weeks after surgery. Pre-operatively, their levels were significantly elevated and correlated with each other. Post-operatively, VEGF level decreased significantly and endostatin remained at a high level. Patients with both normalized VEGF and elevated endostatin following surgery had a lower risk of relapse than patients whose VEGF failed to normalize. Univariate and multivariate analyses showed a correlation between elevated VEGF level and short free-relapse survival. These findings suggest a new angiogenesis balance is formed in the patients after surgery and such a resultant balance may be beneficial for the prognosis of breast cancer, which deserves more extensive study.     

Surgery for gastric cancer increases plasma levels of vascular endothelial growth factor and von Willebrand factor

Background: Angiogenesis and hemostatic activation are important factors in tumor progression and metastasis. Because surgical intervention induces tissue hypoxia and hemostatic activation, we analyzed the effect of gastric surgery on the plasma concentrations of vascular endothelial growth factor (VEGF), soluble P-selectin (sP-selectin), and von Willebrand factor (vWf). Methods: Plasma VEGF, sP-selectin, and vWf concentrations were measured in 14 patients with gastric cancer before operation and on postoperative day 1 (POD 1). Correlations between disease stage and the effect of surgical intervention were analyzed. Results: The plasma concentrations of these three factors did not correlate with the disease stage. Plasma levels of sP-selectin did not change after operation (before surgery, 87.6 ± 34.1 ng/ml; on POD 1, 101.1 ± 48.1 ng/ml; P = 0.123). Plasma VEGF and vWf concentrations were significantly elevated on POD 1 (VEGF, 33.3 ± 20.5 pg/ml before surgery and 61.9 ± 35.6 pg/ml on POD 1; P = 0.0013; vWf, 164 ± 31.1% before surgery and 211.1 ± 66.1% on POD 1; P = 0.027). Conclusion: Because VEGF and vWf are involved in angiogenesis, tumor-platelet adhesion, and tumor-endothelial cell adhesion, surgical intervention could influence tumor growth and metastasis. Received: February 1, 2002 / Accepted: April 9, 2002 Offprint requests to: M. Ikeda     

Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer

Placenta growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A) are angiogenic growth factors interacting competitively with the same receptors. VEGF-A is essential in both normal and pathologic conditions, but the functions of PlGF seem to be restricted to pathologic conditions such as ischemic heart disease, arthritis and tumor growth. Angiogenesis is a complex process with several growth factors involved. Because PlGF modulates VEGF-A responses, we investigated their mutual relationship and impact on breast cancer prognosis. Quantitative PlGF and VEGF-A levels were measured in 229 tumor tissue specimen from primarily operated patients with unilateral breast cancer. Non-malignant breast tissue was also dissected near the tumor and quantitative measurements were available for 211 patients. PlGF and VEGF-A protein levels in homogenized tissue lysates were analyzed using the Luminex system. We found significantly higher median levels of PlGF and VEGF-A in tumor tissue compared to non-malignant tissue (PlGF: 69.8 vs. 31.4 pg/mg, p < 0.001 and VEGF-A: 1148.2 vs. 163.5 pg/mg, p < 0.001). PlGF and VEGF-A were correlated in both malignant tissue (r = 0.41, p < 0.001) and in non-malignant tissue (r = 0.69, p < 0.001). The proportion of node positive patients was higher with high PlGF expression (61.4%) than with low PlGF expression (45.6%) in tumor tissue, p = 0.024. High levels of PlGF and VEGF-A in tumor tissue were associated with significant shorter recurrence-free survival (RFS) in both univariate analysis (PlGF: p = 0.023; VEGF-A: p = 0.047) and in multivariate analysis (PlGF: p = 0.026; VEGF-A: p = 0.036). Neither PlGF nor VEGF-A expression in non-malignant tissue were predictors for RFS. In conclusion, our results support the mutual relationship between PlGF and VEGF-A and encourage further investigations as prognostic markers in breast cancer patients.     

Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific mitogen and permeability factor. Malignant human tumors have been shown to produce VEGF. Elevated levels of VEGF have been detected in sera of cancer patients, but its origin is unsettled. We analyzed VEGF concentrations in serum, plasma, whole blood, and peripheral blood mononuclear cells (PBMNCs) and platelets in 56 cancer patients and 52 healthy controls using ELISA. The VEGF concentrations in the lysed whole blood samples [blood VEGF (B-VEGF)] were higher in cancer patients than in healthy controls (median, 464 versus 298 pg/ml; P<0.0001). The highest B-VEGF values were found in disseminated cancer. In cancer patients, a high B-VEGF concentration was associated with a high peripheral blood leukocyte count (P = 0.0012) and platelet count (P = 0.019). In healthy individuals, a high B-VEGF was associated with a high leukocyte count (P = 0.0001) but not with the platelet count (P>0.1). The cancer patients regularly had higher B-VEGF concentrations than healthy individuals with comparable leukocyte or platelet counts. The VEGF content of isolated PBMNCs and platelets was severalfold higher in cancer patients than in healthy controls (median, 10.6 versus 0.9 pg per 10(6) PBMNCs, and median, 1.6 versus 0.5 pg per 10(6) platelets; P<0.0001 and P = 0.0008, respectively). Serum VEGF and B-VEGF correlated strongly (P<0.0001). Very little or no VEGF was found in the plasma. The results indicate that VEGF in the bloodstream is transported by blood cells, including leukocytes and platelets. The blood cells of cancer patients contain greatly elevated amounts of this major angiogenic growth factor, and this reservoir of VEGF may have a role in tumor angiogenesis and metastasis formation. VEGF in serum samples originates from blood cells, and the use of VEGF of whole blood or of isolated blood cells may improve the clinical value of VEGF measurements.