The Role of Anti–Epidermal Growth Factor Receptor and Anti–Vascular Endothelial Growth Factor Therapies in the Treatment of Non–Small-Cell Lung Cancer

Standard first-line therapy for non–small-cell lung cancer (NSCLC) with platinum-based agents, given in combination with cytotoxic compounds, has reached a relative plateau in its therapeutic efficacy. Novel molecular targeted agents acting on specific pathways have emerged as effective agents for treating NSCLC; some have already produced positive results in phase III trials. Notably, inhibition of the vascular endothelial growth factor (VEGF) pathway with an anti-VEGF antibody, bevacizumab, and targeting the epidermal growth factor receptor (EGFR) pathway with a small-molecule EGFR tyrosine kinase inhibitor erlotinib or a monoclonal antibody (cetuximab) have demonstrated prolonged survival in patients with advanced disease in both the first- and second-line settings. The heterogeneity of signaling processes leading to tumor cell survival and proliferation supports the targeting of multiple signaling pathways as an effective anticancer treatment strategy. Consequently, rational combinations of molecular targeted agents might offer superior clinical efficacy and an alternative treatment option to patients refractory to, or unable to tolerate, standard chemotherapy. The challenge lies in determining which molecular entities should be pursued and the best approach to combine them. This review discusses the potential clinical utility of combining bevacizumab and erlotinib to inhibit both angiogenesis and EGFR signaling as a valid nonchemotherapeutic approach for the treatment of NSCLC. Other combinations of novel therapies that block EGFR and angiogenic pathways, as well as complementary signaling pathways, with unique modes of action and low toxicity profiles could offer an increased repertoire of individualized treatment options for patients with advanced NSCLC.     

宫颈癌组织中Endoglin和VEGF表达与血管生成和癌细胞增殖及侵袭转移的关系

目的：探讨Endoglin和血管内皮生长因子（VEGF）在宫颈癌组织中的表达及意义。方法：采用免疫组织化学SP法检测75例宫颈癌（ICC）、18例宫颈上皮内瘤变（CIN）和15例正常宫颈上皮（NCE）组织中Endoglin和VEGF的表达情况,并检测其中微血管密度（MVD）（CD34标记）和Ki-67表达。结果：从NCE到CIN再到ICC,Endoglin和VEGF的阳性率显著升高,P〈0.05。Endoglin和VEGF在ICC组织中表达均与MVD显著正相关,P=0.000。Endoglin在ICC组织中表达与间质浸润深度和Ki-67表达有关,P〈0.05。ICC突破深肌层间质浸润和Ki-67高度表达者,其Endoglin阳性率分别显著高于未突破深肌层间质浸润和Ki-67表达在中度以内者,P〈0.05。VEGF在ICC组织中表达与盆腔淋巴结转移、脉管浸润、组织学分级及Ki-67表达有关,P〈0,05。ICC伴有盆腔淋巴结转移、脉管浸润、组织学分级为Ⅲ级及Ki-67高度表达者,其VEGF阳性率分别显著高于无盆腔淋巴结转移、无脉管浸润、组织学分级在Ⅱ级以内及Ki-67表达在中度以内者,P〈0.05。Endoglin在ICC组织中表达与VEGF显著正相关,P=0.021。宫颈癌Endoglin和VEGF均阳性表达者,其Ki-67高度表达率及MVD均显著高于两者均阴性表达者,P〈0.05。结论：宫颈癌组织Endoglin和VEGF均过度表达,其血管生成显著增加,癌细胞增殖活跃,更易发生侵袭转移。     

VEGF及其受体Flt和KDR水平变化与胶质瘤关系及临床意义

 目的 探讨胶质瘤患者血清血管内皮生长因子（VEGF）及其受体Flt-1和KDR水平变化，为评价胶质瘤治疗效果，判断预后寻找一种科学的生物学标志物。方法 收集治疗前后胶质瘤患者、脑转移癌患者和健康对照者血清，进行VEGF，Flt-1和KDR水平的检测，SPSS11.5统计软件包对数据进行t检验和相关分析。结果 （1）治疗前脑胶质瘤和脑转移瘤患者血清VEGF水平明显高于健康对照组； 脑胶质瘤患者组和脑转移瘤患者组血清Flt-1水平明显高于健康对照组；脑胶质瘤患者组血清KDR水平明显高于健康对照组； 治疗后缓解的胶质瘤患者组VEGF和Flt-1水平明显低于治疗前。差异均有统计学意义。（2） VEGF与Flt-1和KDR有显著的相关性。结论 胶质瘤患者血清中VEGF及其受体的检测，可作为胶质瘤辅助诊断、治疗效果监测和预后判断的重要生物学指标。     

Vascular endothelial growth factor (VEGF) expression is a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix

The aim of the study was to evaluate VEGF expression in tumour biopsies as a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix. A retrospective study was carried out on 100 patients. Pre-treatment tumour VEGF expression was examined immunohistochemically in formalin-fixed, paraffin-embedded biopsies using a widely available commercial antibody. A semi-quantitative analysis was made using a scoring system of 0, 1, 2, and 3, for increasing intensity of staining. High VEGF expression was associated with a poor prognosis. A univariate log rank analysis found a significant relationship with overall survival (P = 0.0008) and metastasis-free survival (P = 0.0062), but not local control (P = 0.23). There was no correlation between VEGF expression and disease stage, tumour differentiation, patient age, or tumour radiosensitivity (SF2). In a Cox multivariate analysis of survival VEGF expression was the most significant independent prognostic factor (P = 0.001). After allowing for VEGF only SF2 was a significant prognostic factor (P = 0.003). In conclusion, immunohistochemical analysis of VEGF expression is a highly significant and independent prognostic indicator of overall and metastasis-free survival for patients treated with radiotherapy for advanced carcinoma of the cervix. It is also a rapid and easy method that could be used in the clinical setting, to identify patients at high risk of failure with conventional radiotherapy who may benefit from novel approaches or chemoradiotherapy.     

Correlation between vascular endothelial growth factor-C expression and invasion phenotype in cervical carcinomas

The correlation between vascular endothelial growth factor (VEGF)-C gene expression and in vitro invasive activity and matrix metalloproteinase (MMP)-2 or 9 gene expression and proteolytic activity in 11 cervical carcinoma cell lines, was investigated. Immunohistochemical expression of VEGF-C in 52 cervical carcinoma tissues was also correlated with tumor aggressiveness with respect to clinicopathologic features, tumor vascularity, MMP-2 expression and patient outcome. Expression of VEGF-C mRNA differed remarkably among the cell lines and there was a statistical correlation between VEGF-C gene expression and the number of invaded tumor cells (p = 0.0009) and MMP-2 gene expression and activity (p < 0.05). Anti-VEGF-C antibody inhibited the invasive and proteolytic activity of tumor cells in a concentration-dependent manner. VEGF-C or MMP-2 expression in clinical tissue samples was well correlated with depth of myometrial invasion, endometrial invasion, pelvic lymphnode metastasis and tumor vascularity (p < 0.05) and there was a close relation between VEGF-C and MMP-2 expression (p < 0.0001) in cervical carcinomas. Overall survival rates for 14 patients with strong VEGF-C staining tumors were lower than those for 38 patients with weak VEGF-C staining tumors (p = 0.0132) and VEGF-C tissue status emerged as an independent prognostic parameter (p = 0.0232). These results suggest that VEGF-C expression is closely related to invasion phenotype and affects the patient's survival in cervical carcinomas.     

血管内皮生长因子和新生血管在非小细胞肺癌中的表达及其意义

目的研究血管内皮生长因子（vascular endothelial growth factor, VEGF）和新生血管在不同分期非小细胞肺癌（non-small cell lung cancer,NSCLC）中的表达及其相互关系. 方法共收集79例原发性NSCLC手术标本和12例尸检正常肺组织,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. 结果非小细胞肺癌中VEGF和新生血管的表达水平与正常肺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和新生血管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）.结论 VEGF的表达水平与新生血管的表达成正相关.     

FAK和VEGF在胃癌中的表达及其相互关系

目的检测粘着斑激酶(FAK)和血管内皮生长因子(VEGF)在胃癌中的表达及其与侵袭和转移的关系,并探讨二者的相关性.方法采用免疫组织化学sABC法,观察86例胃癌及30例非胃癌组织中FAK和VEGF的表达情况.结果FAK和VEGF在胃癌中的阳性率分别为80%和59%.在非胃癌组织中的阳性表达率分别为10%和13%.FAK和VEGF在侵及浆膜层胃癌病例中的表达明显高于未侵及浆膜层者,二者之间有显著差异性(P＜0.05);有淋巴结转移组与无淋巴结转移组比较有明显差异(P＜0.05),FAK与VEGF阳性表达呈正相关(P＜0.01).结论FAK、VEGF在胃癌的侵袭和转移中起重要作用,二者在胃癌中表达升高可以作预测胃癌侵袭和转移的指标.     

The constitutive level of vascular endothelial growth factor (VEGF) is more important than hypoxia-induced VEGF up-regulation in the angiogenesis of human melanoma xenografts

Angiogenesis of tumours might develop as a result of environmental conditions, such as hypoxia, and/or as a result of genetic alterations specific for tumour cells. The relative contributions of these mechanisms were investigated by comparing the in vivo expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) to the hypoxic fraction, the angiogenic potential and the vascular density of four human melanoma lines (A-07, D-12, R-18, U-25) grown intradermally in Balb/c nu/nu mice. VEGF expression, bFGF expression and expression of pimonidazole, a marker of hypoxic cells, were investigated by immunohistochemistry. An association between high VEGF and bFGF expression and high angiogenic potential was detected, suggesting an important role for VEGF/bFGF in the angiogenesis of melanomas. High VEGF/bFGF expression was also related to low hypoxic fraction and high vascular density. Thus, the constitutive, genetically determined level of VEGF was probably more important than hypoxia-induced upregulation in the angiogenesis of the melanoma xenografts.     

血管内皮生长因子在子宫颈癌组织中的表达及意义

目的　探讨血管内皮生长因子 (VEGF ,VEGFmRNA)在子宫颈癌组织中的表达及意义。方法　采用免疫组织化学技术SP法及原位杂交方法检测 33例宫颈癌 ,其中鳞癌 2 0例 ,腺癌 13例及 10例正常宫颈组织中VEGF及VEGFmRNA的表达情况。结果　宫颈癌组织切片中VEGF及VEGFmRNA皆有活跃表达。正常宫颈组织中VEGFmRNA呈阴性表达 ,VEGF蛋白可见弱阳性表达 ,两组比较差异有显著性 (P <0 .0 5 ) ;宫颈癌组织切片中的VEGFmRNA的表达与宫颈癌病理类型比较差异有显著性 (P <0 .0 5 ) ;而与宫颈癌临床分期及病理分化程度比较差异无显著性 (P >0 .0 5 )。结论　VEGF及VEGFmRNA的阳性表达在子宫颈癌的发生 ,发展中可能有着重要的意义。VEGF的检测对判断宫颈癌的病理类型有一定的临床价值。     

肝门部胆管癌组织中VEGF和血管生成相关性的研究

目的：探讨肝门部胆管癌组织中血管内皮细胞生长因子（ＶＥＧＦ）和血管生成的相关性。方法：应用逆转录多聚酶链反应（ＲＴ－ＰＣＲ）和免疫组化技术对２６例肝门部胆管癌、癌周组织及１２例正常组织中ＶＥＧＦｍＲＮＡ和蛋白及微血管密度（ＭＶＤ）进行了检测。结果：２６例肝门部胆管癌组织中ＶＥＧＦｍＲＮＡ阳性表达率为７６．９％（２０／２６）;癌周组织阳性表达率为２８．９％（７／２６）;正常组织表达率为８．３％（１／１２）,三者差异有显著性（Ｐ＜０．０１）。ＶＥＧＦｍＲＮＡ阳性表达与ＶＥＧＦ蛋白表达具有一致性;ＶＥＧＦｍＲＮＡ阳性者ＭＶＤ值显著高于阴性者（Ｐ＜０．０１）;ＶＥＧＦｍＲＮＡ表达和ＭＶＤ与肝门部胆管癌的分化程度、浸润转移密切相关（Ｐ＜０．０５）;而与发生部位、病理类型、肿瘤大小、临床分型无关（Ｐ＞０．０５）。结论：ＶＥＧＦ在肝门部胆管癌发生和浸润转移过程中发挥重要作用,肿瘤血管生成与肝门部胆管癌浸润转移密切相关。     

Mutant epidermal growth factor receptor enhances induction of vascular endothelial growth factor by hypoxia and insulin-like growth factor-1 via a PI3 kinase dependent pathway

Over-expression of truncated epidermal growth factor receptor (EGFR) occurs in a variety of malignancies including glioblastoma multiforme, breast and lung cancer. The truncation deletes an extracellular domain and results in constitutive activation of the receptor. NIH3T3 cells were transfected with full length or truncated human EGFR and differences in growth rates in vivo and in vitro analysed. A growth advantage was seen for cells expressing mutant receptor compared to full length EGFR in vivo only. Administration of an anti-mutant EGFR antibody to mice transiently reduced the growth rates of mutant tumours, confirming that the mutant receptor itself was important in this enhanced tumorigenicity. This showed that stimuli present in vivo and not in vitro may be contributing to growth. We therefore analysed the regulation of the angiogenic factor vascular endothelial growth factor (VEGF). Although levels of secreted VEGF did not differ significantly between wild-type and mutant EGFR cell lines when grown in vitro under normoxic conditions, following exposure to 0.1% hypoxia levels of VEGF produced by mutant cells increased 3.5-6.6 fold compared to 2 or less for full length EGFR cells. The fold induction was influenced by experimental conditions, including cell confluence and percentage of fetal bovine serum, but was consistently higher for mutant cell lines. The increase in VEGF under hypoxic conditions was blocked by the addition of PI3 kinase inhibitors, indicating that the latter pathway is important in the hypoxic stress response. Basal levels were not affected. Addition of insulin-like growth factor-1 also increased levels of VEGF under normoxic conditions in the mutant cells and no further increase was seen when added to cells exposed to 0.1% oxygen, indicating that levels of VEGF were already maximally stimulated. These results show that the mutant EGFR interacts with other growth factors and hypoxia to regulate VEGF via a PI3 kinase pathway, and suggests a specific role for anti-mutant EGFR antibodies and PI3 kinase inhibitors as therapy of this specific tumour target.