SIRT2在膀胱尿路上皮癌中的表达及意义

目的:研究SIRT2在人膀胱尿路上皮癌中的表达及临床意义,探讨其在肿瘤发生发展中的作用.方法:收集人正常膀胱移行上皮组织标本16例,膀胱尿路上皮癌标本36例.按照病理分级、临床分期分组,用免疫组织化学法(SP法)检测SIRT2蛋白的表达,分析其与膀胱尿路上皮癌的病理分级、临床分期的关系.结果:正常膀胱移行上皮组织中SIRT2阳性表达率为87.50％;膀胱尿路上皮癌组织中SIRT2阳性表达率为55.56％,膀胱尿路上皮癌组织中的SIRT2表达水平明显低于正常膀胱移行上皮组织(P=0.04).SIRT2蛋白在膀胱尿路上皮癌中低级别组与高级别组阳性表达率分别为75.0％和40.0％,差异有统计学意义(P=0.04),同时SIRT2在非肌层浸润(T1)与肌层浸润(T2-4)间阳性表达率分别为78.6％及40.9％,差异有统计学意义(P=0.03).结论:SIRT2蛋白在膀胱尿路上皮癌组织中的表达明显低于正常膀胱移行上皮组织,且与膀胱尿路上皮癌的病理分级、临床分期呈负相关,提示SIRT2蛋白表达下调在膀胱尿路上皮癌发生、发展中起重要作用.     

荧光原位杂交和免疫组织化学方法检测乳腺癌组织中人类表皮生长因子受体2基因状态差异及其特征分析

目的比较荧光原位杂交(fluorescence in situ hybridization,FISH)和免疫组织化学(immunohistochemistry,IHC)检测乳腺癌组织中人类表皮生长因子受体2(human epidermal growth factor receptor 2,HER-2)基因状态差异,分析其相关特征。方法回顾性收集51例中山大学附属第三医院2007年10月至2008年9月间乳腺浸润性导管癌组织标本和相关信息,分别采用IHC和FISH法检测HER-2蛋白表达情况和基因扩增状态,比较两种方法的结果差异,用Fisher精确概率检验分析这种差异的相关因素。结果在51例标本中,FISH检测乳腺癌组织中HER-2基因阴性32例(62.75%,32/51),阳性19例(37.25%,19/51);IHC检测乳腺癌组织中HER-2为(-)和(+)者的FISH检测均为阴性(21例);12例IHC检测HER-2为(++),其中3例FISH检测为阳性,其余9例FISH检测为阴性;18例IHC检测HER-2为(+++)者仍有2例FISH检测结果阴性。月经状态和雌激素受体(ER)表达与IHC检测HER-2阳性病例的FISH阳性结果具有显著联系(P值分别为0.023和0.007),即在IHC检测HER-2阳性[(++)和(+++)]的病例中,绝经前女性较绝经期女性以及ER阴性者较阳性者更可能为FISHHER-2阳性(有HER-2基因扩增)。结论本研究的结果有助于提高IHC判断HER-2基因扩增的准确性。     

表皮生长因子受体在卵巢癌中的表达

目的：为研究表皮生长因子受体（ＥＧＦＲ）与卵巢癌发生发展的关系。方法：采用ＡＢＣ免疫组化、原位杂交方法研究了ＥＧＦＲ在６０例卵巢肿瘤（包括３８例卵巢癌，１０例良性卵巢肿瘤，１２例交界性卵巢肿瘤）及１２例正常卵巢组织中的表达。结果：ＥＧＦＲ在卵巢癌、良性卵巢肿瘤、交界性肿瘤及正常卵巢组织四组中的免疫组化检出率分别为７６．３２％、４０％、６６．６７％和４１．６７％，除交界性肿瘤组外，后三组与卵巢癌组相比差异显著（Ｐ＜０．０５）。原位杂交结果显示ＥＧＦＲｍＲＮＡ在各组中的表达率分别为６５．７９％、２０．００％、３３．３３％和２５．００％，后三者与卵巢癌组间有显著差异（Ｐ＜０．０５）。结论：ＥＧＦＲ在卵巢癌中有较高水平的表达，表明ＥＧＦＲ在卵巢癌的发生发展中起着重要的作用。     

荧光原位杂交在膀胱尿路上皮癌中的应用

目的探讨3,7,17号染色体及9p21(p16基因)组合探针在监测膀胱尿路上皮癌术后复发及诊断膀胱尿路上皮癌的应用价值。方法利用荧光原位杂交（FISH）检测膀胱尿路上皮癌患者的尿脱落细胞及组织切片中3,7,17号染色体及9p21组合的畸变情况。结果FISH监测膀胱尿路上皮癌术后复发的敏感度为87.50%;术前FISH阳性的患者术后更易复发;FISH诊断膀胱尿路上皮癌的阳性率为78.85％。结论利用FISH检测尿脱落细胞中3,7,17号染色体及9p21组合的畸变能有效辅助监测膀胱尿路上皮癌术后复发;并可能在一定程度上预测术后复发;同时利用FISH检测组织切片中3,7,17号染色体及9p21组合的畸变也能有效辅助膀胱尿路上皮癌的诊断。     

乳腺浸润性导管癌中p53和表皮生长因子受体的表达及其意义

目的探讨p53和表皮生长因子受体(Epidermal growth factor receptor,EGFR)在乳腺浸润性导管癌中的表达及其临床病理意义。方法采用免疫组化SP法检测30例正常乳腺组织、160例浸润性乳腺癌组织中p53和EGFR的表达。结果乳腺浸润性导管癌中p53、EGFR的阳性表达与正常乳腺组织间差异有显著统计学意义(P<0.01)。p53、EGFR的阳性表达与浸润性乳腺导管癌的病理分级、临床分期及淋巴结转移有关(P<0.05),而与患者的年龄、肿块的大小无关。结论 p53和EGFR在乳腺浸润性导管癌的发生、发展过程中发挥了一定的作用,两者联合检测有助于预测患者的预后,并为临床进行靶向治疗提供依据。     

尿路上皮癌mdm-2、p53蛋白及性激素受体免疫组化研究

目的　探讨ｍ ｄ ｍ２ 、ｐ５３ 基因蛋白及雄激素受体（ ＡＲ） 、雌激素受体（ＥＲ） 在尿路上皮癌中的表达及意义以及 ｍ ｄ ｍ２蛋白与ＡＲ 、ＥＲ 和ｐ５３ 蛋白表达的相互关系。方法　采用免疫组化技术检测６０ 例尿路上皮癌石蜡标本。结果　ｍ ｄ ｍ２ 蛋白阳性率为５５ ．０ ％ ,与肿瘤分级、分期密切相关,高分化癌、浅表性癌阳性表达显著高于低分化及浸润性癌。ｐ５３ 蛋白阳性率为５３ ．３ ％ ,在低分化及浸润性癌组织阳性率明显高于高分化及浅表性癌（ Ｐ＜ ０ ．０５） 。ＡＲ 、ＥＲ 阳性率分别为５１ ．７ ％ 及４８ ．３ ％ ,与肿瘤分级呈正相关表达（ Ｐ＜ ０ ．０５） ,与临床分期无关。男、女两性间仅ＡＲ 表达有显著差异（ Ｐ＜ ０ ．０５） 。ｍ ｄ ｍ ２ 与ＡＲ 及ＥＲ 表达呈正相关（γ值分别为０ ．４０１８ 、０ ．２２４９） ,与ｐ５３ 表达呈负相关（γ＝ － ０ ．４９８９） 。结论　提示ｍ ｄ ｍ２ ,ｐ５３ 、ＡＲ 及ＥＲ 均与肿瘤组织病理学有关,对尿路上皮癌的发生发展均有各自的作用。联合检测癌相关基因蛋白及性激素受体可了解尿路上皮癌多方面的生物学信息,为临床提供更有价值的预后判断指标。     

尿路上皮癌mdm—2,p53蛋白及性激素受体免疫化研究

目的 探讨ｍｄｍ－２、ｐ５３基因蛋白及雄激素受体（ＡＲ）、雌激素受体（ＥＲ）在尿路上皮癌中的表达及意义以及ｍｄｍ－２蛋白与ＡＲ、ＥＲ和ｐ５３蛋白表达的相互关系。方法 采用免疫组化技术检测６０例睡上皮癌石蜡标本。结果 ｍｄｍ－２蛋白阳性率为５５．０％,与肿瘤分级、分期密切相关,高分化癌、浅表性癌阳性表达显著高于低分化及浸润性癌。ｐ５３蛋白阳性率为５３．３％,在低分化及浸润性癌组织阳性率明显高于高分化     

肌层浸润性膀胱尿路上皮癌的治疗进展

膀胱癌是全球常见的癌症,90%以上的膀胱癌为尿路上皮癌（urothelial carcinoma,UC）。UC的治疗与其进展阶段密切相关,肿瘤一旦出现肌层浸润,5年生存率不足40%,且有很高的复发或进展风险,即使接受了根治性手术,仍有50%的患者术后复发,大多数复发时远处转移形成转移性膀胱癌。目前,肌层浸润性膀胱癌（muscle-invasive bladder cancer,MIBC）的治疗标准是在新辅助化疗后行根治性膀胱切除术,但术后患者生活质量欠佳。保留膀胱的综合治疗因其良好的肿瘤反应率和无病生存期而越来越受欢迎。全身化疗仍是局部晚期或转移性膀胱癌的治疗标准,新型药物免疫检查点抑制剂的批准为化疗进展后的晚期患者提供了治疗新方案。此外,FDA 授予了Enfortumab Vedotin和Erdafitinib两种药物突破性疗法认定。本文将就各种疗法在肌层浸润性膀胱尿路上皮癌治疗中的地位及应用进展进行综述。     

ADNP在膀胱尿路上皮癌组织中的表达及其临床意义

目的：探讨神经依赖性活性保护蛋白（ADNP）在膀胱尿路上皮癌中的表达情况及其临床意义。方法：收集中南大学湘雅医学院附属肿瘤医院2019 年6 月1 日至2019 年7 月15 日手术切除的膀胱癌及其配对的癌旁组织标本各28 例,采用qPCR检测20 例膀胱癌组织和癌旁组织的ADNP mRNA表达水平,WB检测其余8 对标本的ADNP蛋白表达水平。同时,回顾性分析我院2005 年1 月1 日至2007 年12 月31 日收治的膀胱尿路上皮癌患者221 例的临床病理资料,免疫组化染色方法检相应患者手术切除的石蜡标本中ADNP的表达情况,并收集同期因其他膀胱疾病而手术患者的非肿瘤膀胱组织切片用作对照。卡方检验分析ADNP表达与不同临床病理因素之间的相关性,Kaplan-Meier 法进行生存分析,Cox 比例风险回归模型对患者预后影响因素进行单因素及多因素分析。结果：膀胱尿路上皮癌组织中ADNP的转录和翻译水平均高于非肿瘤组织（均P<0.05）,且ADNP的表达量与膀胱癌的组织学分级、临床分期及患者存活状态有着相关性(P<0.05）。纳入的221 例患者随访中失访32 例,ADNP高表达较低表达的膀胱患者有着不良的预后（5 年OS：49.5% vs 78.6%,P<0.01;5 年PFS：40.0% vs 72.2% ,P<0.01;10 年OS：26.6% vs 58.6% ,P<0.01;10 年PFS：25.3% vs 47.9%,P<0.01）。Cox 单因素回归模型显示,ADNP表达量与膀胱癌的预后密切相关（P<0.05）;同时Cox 多因素回归也表明ADNP表达量（95% CI：1.300~2.905,P=0.001）是影响膀胱癌预后的独立危险因素。结论：ADNP在膀胱癌组织中的表达水平比非肿瘤的膀胱组织有显著的升高,组织学分级及临床分期与ADNP的表达水平有相关性,ADNP低表达的膀胱癌患者预后相对较好,ADNP有望成为膀胱癌的特异性治疗候选靶点。     

表皮生长因子受体在肺癌组织中的表达

目的　探讨肺癌组织中表皮生长因子受体 (EGFR)的表达水平及其临床意义。方法　采用免疫组化ABC法检测 3 9例肺良性疾病、95例原发性肺癌及癌旁肺组织中EGFR的表达水平。结果　非小细胞肺癌 (NSCLC)组织EGFR表达阳性率为 87.9% ( 80 / 91) ,肺良性病变肺组织为 10 .3 % ( 4/3 9) ,4例小细胞肺癌 (SCLC)无EGFR表达。在NSCLC中 ,距癌组织 3cm以内癌旁肺组织EGFR阳性率为6 3 .7% ( 5 8/ 91) ,6cm以远正常肺组织为 12 .1% ( 11/ 91)。结论　肺癌组织EGFR表达水平显著高于良性疾病肺组织 ,检测EGFR表达有助于肺部良恶性疾患的鉴别诊断。     

Expression of epidermal growth factor receptor and transforming growth factor alpha in human larynx carcinoma.

Altered expression of growth factors and growth factor receptors is frequently described in human tumors and human tumor cell lines. This further supports the hypothesis that oncogenesis is due to the subversion of mitogen-responsive pathways. The aim of this study was to investigate the expression of epidermal growth factor receptor (EGFR) and transforming growth factor alpha (TGF alpha) in 13 larynx carcinomas and 2 carcinomas of the oral cavity. We found receptor overexpression in 7 out of 15 tumors at mRNA and/or protein level but low expression in the majority of the normal adjacent tissues. TGF alpha was expressed only in 1 case, but no tyrosine kinase activity of the receptor was detected by antiphosphotyrosine antibody.     

Overexpression of epidermal growth factor receptor in urothelium elicits urothelial hyperplasia and promotes bladder tumor growth

Although urothelium is constantly bathed in high concentrations of epidermal growth factor (EGF) and most urothelial carcinomas overexpress EGF receptor (EGFr), relatively little is known about the role of EGFr signaling pathway in urothelial growth and transformation. In the present study, we used the uroplakin II gene promoter to drive the urothelial overexpression of EGFr in transgenic mice. Three transgenic lines were established, all expressing a higher level of the EGFr mRNA and protein in the urothelium than the nontransgenic controls. The overexpressed EGFr was functionally active because it was autophosphorylated, and its downstream mitogen-activated protein kinases were highly activated. Phenotypically, the urinary bladders of all transgenic lines developed simple urothelial hyperplasia that was strongly positive for proliferative cell nuclear antigen and weakly positive for bromodeoxyuridine incorporation. When coexpressed with the activated Ha-ras oncogene in double transgenic mice, EGFr had no apparent tumor-enhancing effects over the urothelial hyperplastic phenotype induced by Ha-ras oncogene. However, when coexpressed with the SV40 large T antigen, EGFr accelerated tumor growth and converted the carcinoma in situ of the SV40T mice into high-grade bladder carcinomas, without triggering tumor invasion. Our studies indicate that urothelial overexpression of EGFr can induce urothelial proliferation but not frank carcinoma formation. Our results also suggest that, whereas EGFr and Ha-ras, both of which act in the same signal transduction cascade, stimulated urothelial hyperplasia, they were not synergistic in urothelial tumorigenesis, and EGFr overexpression can cooperate with p53 and pRB dysfunction (as occurring in SV40T transgenic mice) to promote bladder tumor growth.     

Expression of epidermal growth factor receptor in urinary bladder cancer metastases

Bladder cancers frequently exhibit an increased number of epidermal growth factor receptors (EGFR) in comparison to normal urothelium. The EGFR could potentially be a target for toxic conjugates. The aim of our study was to compare the expression of EGFR in metastases with concurrent or primary tumour in the urinary bladder using immunohistochemical techniques and a monoclonal antibody. Tumour material from 20 patients was investigated. The majority (13/20) of the metastases were homogeneously stained and showed a moderate to strong membranous staining for EGFR. The expression of EGFR in primary bladder tumours and metastases was similar. There was no indication that tumour tissue exposed to chemotherapy or radiation had a decreased number of EGFR. Targeting of the EGFR thus seems potentially applicable to metastatic disease. Int. J. Cancer 76:189–193, 1998.© 1998 Wiley-Liss, Inc.     

Targeting epidermal growth factor receptor/human epidermal growth factor receptor 2 signalling pathway by a dual receptor tyrosine kinase inhibitor afatinib for radiosensitisation in murine bladder carcinoma

Given the promising control of bladder cancer achieved by combined chemotherapy/radiotherapy with selective transurethral resection, obstacles remain to the treatment of unresectable bladder cancer. The aim of this study was to determine whether targeting epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) can radiosensitise a murine bladder tumour (MBT-2) cell line. Cell survival, expression of signal proteins and cell cycle changes in MBT-2 cells treated in vitro and in vivo with afatinib, an irreversible EGFR/HER2 inhibitor, plus radiotherapy were investigated by colony formation assay, Western blot assay and flow cytometry, respectively. Ectopic xenografts were established by subcutaneous injection of MBT-2 cells in C3H/HeN mice. Mice were randomised into 4 groups to receive afatinib (10 mg/kg/day on day 1–7) and/or radiotherapy (15 Gy on day 4). Positron emission tomography (PET) on day 8 was used to evaluate the early treatment response. Afatinib (200–1000 nM) increased cell killing by radiation (0–10 Gy). Pre-treatment of irradiated cells with afatinib inhibited radiation-activated HER2 and EGFR phosphorylation. As compared to either treatment alone, the combination increased the level of the cleavage form of poly (ADP-ribose) polymerase, the expression of phospho-γH2AX and the percentage of cells in subG1 phase (indicating enhanced induction of apoptosis), and decreased tumour metabolism and inhibited tumour growth by 64%. Afatinib has therapeutic value as a radiosensitiser of murine bladder cancer cells. The synergism between afatinib and radiation likely enhances DNA damage, leading to increased cell apoptosis.     

Expression of mutant p53, c-erbB-2 and the epidermal growth factor receptor in transitional cell carcinoma of the human urinary bladder.

Expression of the p53, the epidermal growth factor receptor (EGFr; c-erbB-1) and c-erbB-2 proteins was studied in 82 patients with primary transitional cell carcinoma of the bladder using an immuno-histochemical method. Strong or moderate staining was found in 18% of tumours for p53 with weaker staining in a further 36% giving a total of 54% of tumours stained for p53. Strong staining was found in 15% of tumours for c-erbB-2 and in 31% for the EGFr. Tumours invading the bladder muscle were significantly more likely to be strongly stained positively for p53 and/or EGFr compared with superficial tumours: only 15% of invasive tumours were stained negatively for both p53 and EGFr. No statistical association was found between p53 and EGFr expression. Weakly positive associations were found between the expression of c-erbB-2 and p53 and between muscle invasive tumours and increased expression of c-erbB-2. Alterations in the expression of p53, c-erbB-1 and c-erbB-2 were found frequently in human transitional cell carcinoma of the urinary bladder and may be of clinical use in defining patient sub-groups of differing prognosis.     

Expression of epidermal growth factor receptor in different salivary adenoid cystic carcinoma cell lines

Objective： To investigate the expression of epidermal growth factor receptor, a receptor tyrosine protein kinase, in the subcellular fractions of human salivary adenoid cystic carcinoma cell lines SACC-83 and SACC-LM. Methods： Low metastatic and high metastatic cells of the adenoid cystic carcinoma, SACC-83 and SACC-LM, were cultured. Their subcellular fractions were extracted. The expression of epidermal growth factor receptor was detected with Western blot method, and the results of protein expression were quantitatively analyzed by FluorChem V2.0 software. Results： The results of Western blot analysis indicated that, EGFR expression on the membrane of SACC-83 cells was significantly higher than that of SACC-LM cells, but its expression in cytoplasm was significantly less in the former than the later （P〈0.01）. In SACC-83 cell line, EGFR was over-expressed in membrane （P〈0.01）, but in SACC-LM cell line, EGFR was over-expressed in cytoplasm （P〈0.01）. Conclusion： The results suggest that the obtaining of metastasis ability is related to the high expression of EGFR protein in cytoplasm, so the molecular targeting therapy to EGFR may be an ideal treatment for the invasion and metastasis of salivary adenoid cystic carcinoma.     

High incidence of amplification of the epidermal growth factor receptor gene in human squamous carcinoma cell lines

Southern blot-hybridization analysis of DNAs from human tumors demonstrated amplification of the epidermal growth factor (EGF) receptor gene in 10 of 12 squamous cell carcinoma cell lines tested and in none of 18 tumor cell lines of nonsquamous cell carcinomas. The degree of amplification in the squamous cells varied from 2- to 50-fold relative to the epidermal keratinocyte. Hybridization analysis of the RNA showed that the amplification of the EGF receptor gene is accompanied with an increase of the 5.6 kilobases of EGF receptor mRNA. Scatchard plot analysis and sodium dodecyl sulfate-polyacrylamide gel analysis of the EGF receptor revealed that the synthesis of the EGF receptor is also greater in the cells with amplified EGF receptor gene. In contrast, Southern blot analysis of DNAs of primary tumors showed that incidence of amplification of the EGF receptor gene in squamous cells (1 of 6) was almost as frequent as in nonsquamous cells (1 of 4). These results show that amplification of the EGF receptor gene is commonly found in various tumors. In addition, our data suggest that primary squamous cell carcinomas with amplified EGF receptor gene may readily adapt to growth in tissue culture.     

Association between epidermal growth factor receptor amplification and ADP-ribosylation factor 1 methylation in human glioblastoma

Purpose

Glioblastoma (GB) is the most frequent and most malignant primary brain tumor in adults. Previously, it has been found that both genetic and epigenetic factors may play critical roles in its etiology and prognosis. In addition, it has been found that the epidermal growth factor receptor gene (EGFR) is frequently over-expressed and amplified in primary GBs. Here, we assessed the promoter methylation status of 10 genes relevant to GB and explored associations between these findings and the EGFR gene amplification status.

Methods

Tumor samples were obtained from 36 patients with primary GBs. In addition, 6 control specimens were included from patients who were operated for diseases other than brain tumors. The amplification status of the EGFR gene, and its deletion mutant EGFRvIII, were evaluated using FISH and MLPA, respectively. The IDH1/2 gene mutation status was verified using Sanger sequencing. A commercial DNA methylation kit was used to assess the promoter methylation status of 10 pre-selected genes. Metabolic profiles were measured using HR-MAS NMR spectroscopy. The EGFR and ARF1 mRNA expression levels were quantified using qRT-PCR.

Results

Of the 10 genes analyzed, we found that only ARF1 promoter hypermethylation was significantly associated with EGFR gene amplification. ARF1 is a GTPase that is involved in vesicle trafficking and the Golgi apparatus. Subsequent tumor metabolism measurements revealed a positive association between EGFR amplification and different membrane precursors and methyl-donor metabolites. Finally, we found that EGFR gene amplifications were associated with distinct tumor infiltration patterns, thus representing a putative novel functional association between EGFR gene amplification and ARF1 gene promoter methylation in GB.

Conclusions

The results reported here provide a basis for a new hypotheses connecting EGFR gene amplification in GB cells with ARF1 gene promoter methylation, vesicle trafficking, membrane turnover and tumor metabolism. The mechanism(s) underlying these connections and their functional consequences remain to be established.

     

Expression and regulation of the novel vascular endothelial growth factor receptor neuropilin-1 by epidermal growth factor in human pancreatic carcinoma

BACKGROUND: It was recently shown that neuropilin-1 (NRP-1), which was described originally as a receptor for the semaphorins/collapsins (ligands involved in neuronal guidance), is a coreceptor for vascular endothelial growth factor (VEGF) and increases the affinity of specific isoforms of VEGF to its receptor, VEGF-R2. METHODS: The authors investigated the expression and regulation of NRP-1 in human pancreatic adenocarcinoma specimens and cell lines. RESULTS: Immunohistochemical analysis revealed that NRP-1 was expressed in 12 of 12 human pancreatic adenocarcinoma specimens but was absent in nonmalignant pancreatic tissue. Northern blot analysis revealed NRP-1 mRNA expression in 8 of 11 human pancreatic adenocarcinoma cell lines. NRP-1 mRNA expression was increased by epidermal growth factor (EGF) but not by tumor necrosis factor alpha in several of the human pancreatic adenocarcinoma cell lines studied. Treating human Panc-48 adenocarcinoma cells with EGF activated Akt and Erk but not P-38. Blockade of the phosphatidylinositol-3 kinase (PI-3K)/Akt, mitogen-activated protein kinase (MAPK)/Erk, or P-38 pathways abrogated EGF-induced NRP-1 expression. Finally, EGF receptor blockade in vivo led to a decrease in NRP-1 expression in an orthotopic model of human pancreatic carcinoma. CONCLUSIONS: NRP-1 is expressed in most human pancreatic adenocarcinomas and cell lines but not in nonmalignant pancreatic tissue. EGF regulates NRP-1 expression through the PI-3K/Akt and MAPK/Erk signaling pathways, and blockade of the EGF receptor is associated with decreased expression of NRP-1 in vivo. NRP-1 may act as a coreceptor for VEGF in pancreatic carcinoma, as it does in other tumor systems, thereby enhancing angiogenesis and the effect of VEGF on the growth of pancreatic adenocarcinoma.