检测腹水中血管内皮生长因子对晚期卵巢癌维持治疗的临床意义

目的 评价检测腹水中血管内生长因子水平、腹腔灌注顺铂联合沙利度胺在晚期卵巢癌维持治疗中的临床意义。方法 回顾性分析不能耐受联合或强烈化疗、腹水检测血管内皮生长因子(VEGF)阳性的晚期卵巢癌患者69例的临床资料。腹腔灌注顺铂(DDP)联合沙利度胺(实验组)患者36例,单纯腹腔灌注顺铂患者(对照组)33例,具体方法如下:腹腔灌注顺铂40~60 mg/m²,1次/周,连续应用两次,4周为一周期,同时口服沙利度胺,治疗2个周期评价临床疗效、免疫功能及不良反应。结果 实验组有效率为72.2%,对照组有效率为46.9%,两组差异具有统计学意义。实验组、对照组治疗前与治疗2个周期后腹水VEGF水平相比,差异均具有统计学意义;实验组VEGF的下降幅度高于对照组VEGF的下降幅度。实验组、对照组治疗前与治疗2个周期后T淋巴细胞亚群百分率相比,差异均无统计学意义。实验组Ⅲ~Ⅳ级恶心呕吐发生率低于对照组,两组差异具有统计学意义;而实验组其它Ⅲ-Ⅳ级不良反应(如中性粒细胞减少、血红蛋白减少、疲倦)发生率与对照组相比,两组差异无统计学意义。结论 检测腹水中VEGF水平可提高恶性腹水的诊断率,腹腔灌注化疗药物联合沙利度胺治疗晚期卵巢癌恶性腹水有效率高,降低腹水中VEGF水平,提高生活质量,减轻不良反应,患者耐受性和依从性好。     

Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer

Background  

Most bladder cancer patients experience lymphatic metastasis in the course of disease progression, yet the relationship between lymphangiogenesis and lymphatic metastasis is not well known. The aim of this study is to elucidate underlying mechanisms of how expanded lymphatic vessels and tumor microenvironment interacts each other and to find effective therapeutic options to inhibit lymphatic metastasis.     

Tumor-secreted vascular endothelial growth factor-C is necessary for prostate cancer lymphangiogenesis, but lymphangiogenesis is unnecessary for lymph node metastasis

Dissemination to draining lymph nodes is a frequent first step in prostate cancer metastasis. Although tumors metastasize to lymph nodes via the lymphatics, the importance of lymphangiogenesis in mediating the process remains controversial. Here, we inhibit intratumoral lymphangiogenesis in s.c. and surgical orthotopic implantation mouse models of human prostate cancer using several strategies. Stable expression of small interfering RNAs (siRNA) targeted against human vascular endothelial growth factor-C (VEGF-C) in PC-3 cells reduced intratumoral lymphatics by 99% in s.c. tumors, indicating that tumor-secreted VEGF-C is necessary for lymphangiogenesis. Expression of siRNAs against human VEGF-A somewhat reduced tumor lymphangiogenesis. Secretion of a soluble VEGF receptor-3/Flt4 fusion protein by PC-3 cells reduced intratumoral lymphatics by 100% in s.c. tumors. Combination of soluble Flt4 and VEGF-C siRNA yielded >92% reduction of intratumoral lymphatics in orthotopic prostate tumors. However, metastasis to lymph nodes was not significantly affected regardless of intratumoral lymphatic vessel density. The abundance of marginal lymphatics at the tumor-stromal interface was unchanged in orthotopic tumors whose intratumoral lymphatics were inhibited, suggesting that these marginal vessels could be sufficient for lymph node metastasis. Hematogenous metastasis (blood tumor burden, lung metastasis) correlated with degree of lymph node invasion. We also analyzed the lymphatics in spontaneous transgenic adenocarcinomas of the mouse prostate which metastasize to lymph nodes. Progression from well-differentiated prostate intraepithelial neoplasia to metastatic, undifferentiated adenocarcinoma was accompanied by loss of lymphatics. These results suggest that tumor-secreted VEGF-C and, to a lesser extent, VEGF-A, are important for inducing prostate cancer intratumoral lymphangiogenesis but are unnecessary for lymph node metastasis.     

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

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

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.     

Preoperative serum vascular endothelial growth factor levels: significance in ovarian cancer.

PURPOSE: To assess the clinical relevance of serum vascular endothelial growth factor (VEGF) levels in distinguishing patients with ovarian cancer from those with benign adnexal masses. Experimental Design: Preoperative serum VEGF levels were assessed in 101 women with invasive epithelial ovarian cancer, 16 with low malignant potential (LMP) ovarian tumors, and 34 women with benign ovarian tumors. VEGF levels were determined using an ELISA (R&D Systems, Minneapolis, MN). RESULTS: Ovarian cancer patients had a mean preoperative VEGF level of 549 pg/ml (median 379 pg/ml), which was significantly higher than those with benign adnexal masses (mean 228 pg/ml, median 155 pg/ml; P < 0.001) and LMP tumors (mean 200 pg/ml, median 129 pg/ml; P < 0.001). There were no significant differences in VEGF levels between individuals with benign masses and LMP tumors. The ability of VEGF to differentiate malignancy from benign masses at a cutoff VEGF level of 246 pg/ml gave a sensitivity of 74%, a specificity of 71%, a positive predictive value of 88%, and a negative predictive value of 48%. VEGF levels were also significantly higher in patients with stage I ovarian cancer compared with those with benign disease or LMP tumors. Among patients with ovarian cancer, there were no significant differences in VEGF levels based on age, stage, grade, or level of cytoreduction. The presence of ascites was associated with a significantly higher VEGF level (mean 667 pg/ml, median 445 pg/ml versus mean 317 pg/ml, median 293 pg/ml; P < 0.001). Various preoperative VEGF levels were assessed as a predictor of survival, and a VEGF level >380 pg/ml was associated with a hazard ratio of 2.13 (P = 0.009) by univariate analysis. In multivariate analysis of age, stage, cytoreduction, preoperative CA-125, grade, ascites, and VEGF levels above 380 pg/ml, only VEGF levels >380 pg/ml (hazard ratio 2.33; P = 0.02) and advanced stage (hazard ratio 9.03; P = 0.004) were significant. CONCLUSIONS: Preoperative VEGF levels may be useful in differentiating benign adnexal masses from malignancy. Preoperative VEGF levels >380 pg/ml are an independent risk factor for death because of disease.     

Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review

The introduction of molecularly targeted anticancer therapies has brought the promise of longer survival times for select patients with cancers previously considered untreatable. However, it has also brought new toxicities that require understanding and management, sometimes for long periods of time. Vascular endothelial growth factor inhibitors are associated with a broad range of adverse effects, with vascular toxicity being particularly serious. This review focuses on the current understanding of the pathophysiology and mechanisms of macrovascular toxicities (hypertension, hemorrhage, and thromboembolism), their incidence and severity, the current clinical management, and implications in the advanced cancer setting. Movement of these agents into the early disease setting will alter the impact of these toxicities. Search Strategy and Selection Criteria. Information for this review was collected by searching PubMed/Medline and American Society of Clinical Oncology abstract databases. The medical subject heading terms used included toxicity, hypertension, thromboembolism, hemorrhage, intestinal perforation, risk factors, pharmacokinetics, and metabolism, combined with free text search terms including, but not limited to, VEGF inhibitor*, bevacizumab, sunitinib, and sorafenib. Articles published in English before March 2010 were included, in addition to information from case reports and pharmaceutical agent package inserts.     

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     

Expression of Vascular Endothelial Growth Factor-C and Vascular Endothelial Growth Factor Receptor-3 in Ovarian Epithelial Tumors

Objective： To explore the role of vascular endothelial growth factor-C （VEGF-C） in the process of angiogenesis, lymphangiogenesis and lymphatic metastasis in epithelial ovarian tumors. Methods： In situ hybridization and immunohistochemical staining for VEGF-C were performed in 30 epithelial ovarian carcinomas, 9 borderline tumors and 26 benign tumors. Endothelial cells were immunostained with anti-VEGFR-3 pAb and anti-CD31 mAb, and VEGFR-3 positive vessels and microvessel density （MVD） were assessed by image analysis. Results： VEGF-C mRNA and protein expression were detected in cytoplasm of carcinoma cells. VEGF-C mRNA and protein expression in ovarian epithelial carcinomas were significantly higher than those in borderline tumors and benign tumors （P〈0.05 or P〈0.01）. In ovarian epithelial carcinomas, VEGF-C protein expression, VEGFR-3 positive vessels and MVD were significantly higher in the cases of clinical stage Ⅲ-Ⅳ and with lymph node metastasis than those of clinical stage Ⅰ-Ⅱ and without lymph node metastasis respectively （P〈0.05 or P〈0.01）. VEGFR-3 positive vessels and MVD were significantly higher in VEGF-C protein positive tumors than negative tumors （P〈0.05）. VEGFR-3 positive vessels was significantly correlated with MVD（P〈0.01）. Conclusion： VEGF-C might play a role in lymphatic metastasis via lymphangiogenesis and angiogenesis in epithelial ovarian tumors, and VBEGF-C could be used as a biologic marker of metastasis in ovarian epithelial tumors.     

血管内皮生长因子在卵巢上皮性癌中的表达

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

Akt3 controls vascular endothelial growth factor secretion and angiogenesis in ovarian cancer cells

The PI3 kinase/Akt pathway is commonly deregulated in human cancers, functioning in such processes as proliferation, glucose metabolism, survival and motility. We have previously described a novel function for one of the Akt isoforms (Akt3) in primary endothelial cells: the control of VEGF-induced mitochondrial biogenesis. We sought to determine if Akt3 played a similar role in carcinoma cells. Because the PI3 kinase/Akt pathway has been strongly implicated as a key regulator in ovarian carcinoma, we tested the role of Akt3 in this tumor type. Silencing of Akt3 by shRNA did not cause an overt reduction in mitochondrial gene expression in a series of PTEN positive ovarian cancer cells. Rather, we find that blockade of Akt3, results in smaller, less vascularized tumors in a xenograft mouse model that is correlated with a reduction in VEGF expression. We find that blockade of Akt3, but not Akt1, results in a reduction in VEGF secretion and retention of VEGF protein in the endoplasmic reticulum (ER). The reduction in secretion under conditions of Akt3 blockade is, at least in part, due to the down regulation of the resident golgi protein and reported tumor cell marker, RCAS1. Conversely, over-expression of Akt3 results in an increase in RCAS1 expression and in VEGF secretion. Silencing of RCAS1 using siRNA inhibits VEGF secretion. These findings suggest an important role for Akt3 in the regulation of RCAS1 and VEGF secretion in ovarian cancer cells.     

VEGF和CD44表达与乳腺癌分期的相关性研究

目的：研究血管内皮生长因子（vascular endothelial growth factor,VEGF）和CD44在不同分期乳腺癌中的表达及其相互关系。方法：共收集79例手术标本和12例正常乳腺组织,用免疫组织化学法（S-P法）检测,用免疫组化图象分析系统进行结果处理。结果：乳腺癌中VEGF和CD44的表达水平与正常乳腺组织相比差异具有显著性（P〈0.05）;Ⅰ期与Ⅱ期及Ⅲ期之间相比,VEGF和CD44的表达水平差异同样具有显著性,并且随分期越晚表达越强（P〈0.05）;不同细胞类型之间的差异无显著性（P〉0.05）,而与肿瘤的浸润深度、淋巴结转移、远处器官转移以及肿瘤的TNM分期密切相关（P〈0.05）。结论：VEGF与CD44的表达水平与乳癌分期成正相关,在排除创伤和炎症的前提下,可能提示肿瘤的活跃生长以及潜在转移。     

VEGF和CD44表达与乳腺癌分期的相关性研究

目的:研究血管内皮生长因子(vascular endothelial growth factor,VEGF)和CD44在不同分期乳腺癌中的表达及其相互关系。方法:共收集79例手术标本和12例正常乳腺组织,用免疫组织化学法(S-P法)检测,用免疫组化图象分析系统进行结果处理。结果:乳腺癌中VEGF和CD44的表达水平与正常乳腺组织相比差异具有显著性(P<0.05);Ⅰ期与Ⅱ期及Ⅲ期之间相比,VEGF和CD44的表达水平差异同样具有显著性,并且随分期越晚表达越强(P<0.05);不同细胞类型之间的差异无显著性(P>0.05),而与肿瘤的浸润深度、淋巴结转移、远处器官转移以及肿瘤的TNM分期密切相关(P<0.05)。结论:VEGF与CD44的表达水平与乳癌分期成正相关,在排除创伤和炎症的前提下,可能提示肿瘤的活跃生长以及潜在转移。     

宫颈癌组织血管内皮生长因子测定的临床意义

目的 :探讨血管内皮生长因子 (vascularen dothelialgrowthfactor ,VEGF)在宫颈癌诊断、治疗以及转移中的临床意义。方法 :酶联免疫吸附分析法(enzyme linkedimmunosorbentassay ,ELISA)测定 2 0例宫颈上皮内瘤样变患者和 60例宫颈癌患者组织中的VEGF含量。结果 :VEGF含量在宫颈上皮内瘤样变、宫颈癌组织中分别为 5 5 6pg/mg、410 2pg/mg ,差异有统计学意义 ,P <0 0 1。肿 瘤≥ 4cm者为 960 0 pg/mg ,淋巴结转移者为 780 5 pg/mg ,而肿瘤 <4cm者 ,淋巴结未转移者分别为 180 5 pg/mg、2 3 0 0pg/mg。差异有统计学意义 ,P <0 0 5。而在临床分期、病理分型、病理分级间差异无统计学意义。结论 :组织VEGF含量检测对宫颈癌的诊断有一定的临床价值 ,其含量变化可监测宫颈癌的转移。     

New therapeutic directions for advanced pancreatic cancer: targeting the epidermal growth factor and vascular endothelial growth factor pathways

In advanced pancreatic cancer, single-agent gemcitabine became the standard therapy approximately 10 years ago. Subsequently, combinations of gemcitabine with fluorouracil, cisplatin, irinotecan, oxaliplatin, or pemetrexed produced no clear survival benefit. Among the newer approaches, targeting human epidermal growth factor receptor (HER-1/EGFR) shows promise. The U.S. Food and Drug Administration recently approved erlotinib (a HER-1/EGFR tyrosine kinase inhibitor) combined with gemcitabine for the first-line treatment of advanced pancreatic cancer. This combination showed a statistically significant survival benefit over gemcitabine alone in locally advanced or metastatic disease (the median overall survival time was 6.24 months versus 5.91 months; hazard ratio, 0.82; p = .038); however, the clinical significance of this survival difference has been questioned. Additionally, a large phase III trial where the addition of cetuximab (an anti-HER-1/EGFR monoclonal antibody [mAb]) to gemcitabine failed to result in a longer overall survival time than with gemcitabine alone has been reported. Targeting vascular endothelial growth factor (VEGF) with bevacizumab (a recombinant, humanized IgG1 mAb that binds to VEGF) in combination with gemcitabine was investigated in a phase II trial, with promising outcomes that were unfortunately not supported by a subsequent phase III study. While the future treatment of pancreatic cancer may be influenced by the potential of certain biomarkers to predict better response to molecular-targeted therapies, allowing individualization of patient therapy, there are currently no clear candidates, and this remains an interesting area for further investigation.     

Isolation and purification of vascular endothelial growth factor (VEGF) from ascitic fluid of ovarian cancer patients

Vascular Endothelial Growth Factor (VEGF) or Vascular Permeability Factor (VPF) is an angiogenic cytokine expressed by many human and animal tumors. Because of the importance of VEGF in animal tumors, we purified VEGF/VPF from ascitic fluid of ovarian cancer patients with heparin sepharose column. The purified protein gave protein bands of 37 and 26 kD, respectively in 12% SDS PAGE. The specificity of the purified protein was determined with dot blot, trans-immunoblot and ELISA using polyclonal goat anti-VEGF antibody (Santa Cruz Biotechnology). The vasodilatatory effect of the purified protein was confirmed by a vascular permeability assay on mouse. A polyclonal mouse antibody was raised against the purified protein, which recognized the same protein by ELISA, transimmunoblot and dot-blot analysis. It has been also found that the raised polyclonal antibody in mouse- and the commercial VEGF polyclonal antibody (Santa Cruz Biotechnology) both inhibited in vitrocell proliferation of human MCF-7 cell line. This study shows for the first time an effort to purify VEGF from human source.(Pathology Oncology Research Vol 10, No 2, 104–108)