Macrophage inhibitory cytokine-1/growth differentiation factor-15 in premalignant and neoplastic tumours in a high-risk pancreatic cancer cohort

BACKGROUND Pancreatic cancer(PC)is a leading cause of cancer related mortality worldwide,with poor survival due to late diagnosis.Currently,biomarkers have limited use in early diagnosis of PC.Macrophage inhibitory cytokine-1 or growth differentiation factor-15(MIC-1/GDF15)has been implicated as a potential serum biomarker in PC and other malignancies.AIM To determine the role of MIC-1/GDF15 in detecting pre-malignant pancreatic lesions and neoplastic tumours in an asymptomatic high-risk cohort part of Australian Pancreatic Cancer Screening Program.METHODS A feasibility prospective single centre cohort study was performed.Participants recruited for yearly surveillance with endoscopic ultrasound(EUS)had serial fasting blood samples collected before EUS for MIC-1/GDF15,C-reactive protein and carbohydrate antigen 19-9.Patients were stratified into five groups based on EUS findings:Normal;pancreatic cysts,branch-duct intraductal papillary mucinous neoplasm;diffuse non-specific abnormalities;and neoplastic tumours.MIC-1/GDF15 serum levels were quantified using ELISA.Participants in whom EUS demonstrated abnormalities but not malignancy were closely followed up with magnetic resonance imaging(MRI)or computed tomography.RESULTS One hundred twenty participants were prospectively recruited from 2011-2018.Forty-seven participants(39.2%)had an abnormal EUS and five participants(4.2%)were diagnosed with neoplastic tumours,three by EUS(two pancreatic and one liver)and two by MRI/computed tomography(breast cancer,bladder cancer),which were performed for follow up of abnormal EUS.Baseline serum MIC-1/GDF15 was a significant predictor of neoplastic tumours on receiver operator characteristic curve analysis[area under curve(AUC)=0.814,P=0.023].Baseline serum MIC-1/GDF15 had moderate predictive capacity for branch-duct intraductal papillary mucinous neoplasm(AUC=0.644)and neoplastic tumours noted on EUS(AUC=0.793),however this was not significant(P=0.188 and 0.081 respectively).Serial serum MIC-1/GDF15 did not demonstrate a significant percentage change between a normal and abnormal EUS(P=0.213).Median baseline MIC-1/GDF15 was greater in those with neoplastic tumours(Median=1039.6,interquartile range=727.0-1977.7)compared to those diagnosed with a benign lesion(Median=570.1,interquartile range=460.7-865.2)on EUS and MRI(P=0.012).CONCLUSION In this pilot study MIC-1/GDF15 has predictive capacity for neoplastic tumours in asymptomatic individuals with a genetic predisposition for PC.Further imagining may be warranted in patients with abnormal EUS and raised serum MIC-1/GDF15.Larger multicentric prospective studies are required to further define the role of MIC-1/GDF15 as a serological biomarker in pre-malignant pancreatic lesions and neoplastic tumours.

Prognostic significance of S100A4 and vascular endothelial growth factor expression in pancreatic cancer

AIM: To investigate the expression of vascular endothelial growth factor (VEGF) and calcium-binding protein S100A4 in pancreatic cancer and their relationship to the clinicopathological parameters and prognosis of pancreatic cancer. METHODS: Expression status of VEGF and S100A4 was examined in 62 surgical specimens of primary pancreatic cancer by immunohistochemistry. Correlation between the expression of VEGF and S100A4 and clinicopathological parameters was analyzed. RESULTS: Thirty-eight of 62 (61.3%) specimens of primary pancreatic cancer were positive for S100A4. Thirty-seven (59.7%) specimens showed positive expression of VEGF. The positive correlation between S100A4 and VEGF expression was significant in cancer tissues (P < 0.001). S100A4 expression was significantly correlated with tumor size, TNM stage and poorer prognosis. VEGF expression had a significant correlation with poorer prognosis. The prognosis of 17 S100A4-and VEGF-negative cancer patients was significantly better than that of other patients (P < 0.05). Distant metastasis (P = 0.001), S100A4-(P = 0.008) and VEGF-positive expression (P = 0.016) were significantly independent prognostic predictors (P < 0.05). CONCLUSION: Over-expression of S100A4 and VEGF plays an important role in the development of pancreatic cancer. Combined examination of the two molecules might be useful in evaluating the outcome of patients with pancreatic cancer.

Insulin-like growth factor-I receptor in proliferation and motility of pancreatic cancer

AIM:To develop a molecular therapy for pancreatic cancer, the insulin-like growth factor-I (IGF-I) signaling pathway was analyzed.METHODS: Pancreatic cancer cell lines (MIA-Paca2, NOR-P1, PANC-1, PK-45H, PK-1, PK-59 and KP-4) were cultured in media with 10 mL/L fetal bovine serum. Western blotting analysis was performed to clarify the expression of IGF-I receptor (IGF-IR). Picropodophyllin (PPP), a specific inhibitor of IGF-IR, LY294002, a specific inhibitor of phosphatidylinositol3 kinase (PI3K), and PD98059, a specific inhibitor of mitogen-activated protein kinase, were added to the media. After 72 h, a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay was performed to analyze cell proliferation. A wound assay was performed to analyze cell motility with hematoxylin and eosin (HE) staining 48 h after addition of each inhibitor. RESULTS: All cell lines clearly expressed not only IGF-IR but also phosphorylated IGF-IR. PPP significantly suppressed proliferation of MIA-Paca2, NOR-P1, PANC-1, PK-45H, PK-1, PK-59 and KP-4 cells to 36.9% ± 2.4% (mean ± SD), 30.9% ± 5.5%, 23.8% ± 3.9%, 37.1% ± 5.3%, 10.4% ± 4.5%, 52.5% ± 4.5% and 22.6% ± 0.4%, at 2 μmol/L, respectively (P < 0.05). LY294002 significantly suppressed proliferation of MIA-Paca2, NOR-P1, PANC-1, PK-45H, PK-1, PK-59 and KP-4 cells to 44.4% ± 7.6%, 32.9% ± 8.2%, 53.9% ± 8.0%, 52.8% ± 4.0%, 32.3% ± 4.2%, 51.8% ± 4.5%, and 30.6% ± 9.4%, at 50 μmol/L, respectively (P < 0.05). PD98059 did not significantly suppress cell proliferation. PPP at 2 μmol/L suppressed motility of MIA-Paca2, NOR-P1, PANC-1, PK-45H, PK-1, PK-59 and KP-4 cells to 3.0% ± 0.2%, 0%, 0%, 2.0% ± 0.1%, 5.0% ± 0.2%, 3.0% ± 0.1%, and 5.0% ± 0.2%, respectively (P < 0.05). LY294002 at 50 μmol/L suppressed motility of MIA-Paca2, NOR-P1, PANC-1, PK-45H, PK-1, PK-59 and KP-4 to 3.0% ± 0.2%, 0%, 3.0% ± 0.2%, 0%, 0%, 0% and 3% ± 0.1%, respectively (P < 0.05). PD980509 at 20 μmol/L did not suppress motility. Cells were observed by microscopy to analyze the morphological changes induced by the inhibitors. Cells in medium treated with 2 μmol/L PPP or 50 μmol/L LY294002 had pyknotic nuclei, whereas those in medium with 20 μmol/L PD98059 did not show apoptosis.CONCLUSION: IGF-IR and PI3K are good candidates for molecular therapy of pancreatic cancer.

Expression of c-erbB-2 oncogene protein, epidermal growth factor receptor, and TGF-β1 in human pancreatic ductal adenocarcinoma

Objective: To detect the relations of c-erbB-2 onco-gene protein, epidermal growth factor receptor (EG-FR) and transforming growth factor-β1 (TGF-β1)to the progression or metastasis of pancreatic carci-noma.Methods: Using streptavidinbiotin complex (SABC)method, c-erbB-2 oncongene protein, we examinedimmunohistochemically EGFR and TGF-β1 expres-sions in wax-tissue sections from 10 individuals withnormal pancreas (NP), 13 patients with chronic pan-creatitis (CP) and 36 patients with pancreatic ductaladenocarcinoma (PC).Results: The positive expression rates of c-cerbB-2oncogene protein, EGFR and TGF-β1 in the NP, CPand PC groups were 0, 0, 10%; 7.7%, 7.7%,7.7%; and 41.7%, 50.0%, 44.4%, respectively.The positive expression rates of the three specific pro-teins increased more significantly in the PC groupthan in the NP and CP groups (P【0.05). The indi-vidual expression of c-erbB-2, EGFR and TGF-β1was not related to the age and sex of the patients aswell as the site, size and histopathological grade oftumors (P】0.05), but to the clinical stage of tumors(P【0.01). The coexpression rate of the three pro-teins was 27.8 % (10/36). This coexpression in thePC group was correlated with the histopathologicalgrades and clinical stages of tumors (P【0.01).Conclusion: Detection of c-erbB-2 oncogene protein,EGFR, and TGF-β1 expressions in pancreatic tissueis helpful to judge the malignancy, progression, andmetastasis of PC.

Insulin-like growth factor binding protein-5 influences pancreatic cancer cell growth

AIM: To investigate the functional significance of insulin-like growth factor binding protein-5 (IGFBP-5) overexpression in pancreatic cancer (PaC).METHODS: The effects of IGFBP-5 on cell growth were assessed by stable transfection of BxPC-3 and PANC-1 cell lines and measuring cell number and DNA synthesis. Alterations in the cell cycle were assessed by flow cytometry and immunoblot analyses. Changes in cell survival and signal transduction were evaluated after mitogen activated protein kinase and phosphatidylinositol 3-kinase (PI3K) inhibitor treatment.RESULTS: After serum deprivation, IGFBP-5 expression increased both cell number and DNA synthesis in BxPC-3 cells, but reduced cell number in PANC-1 cells. Consistent with this observation, cell cycle analysis of IGFBP-5-expressing cells revealed accelerated cell cycle progression in BxPC-3 and G2/M arrest of PANC-1 cells. Signal transduction analysis revealed that Akt activation was increased in BxPC-3, but reduced in PANC-1 cells that express IGFBP-5. Inhibition of PI3K with LY294002 suppressed extracellular signal-regulated kinase-1 and -2 (ERK1/2) activation in BxPC-3, but enhanced ERK1/2 activation in PANC-1 cells that express IGFBP-5. When MEK1/2 was blocked, Akt activation remained elevated in IGFBP-5 expressing PaC cells; however, inhibition of PI3K or MEK1/2 abrogated IGFBP-5-mediated cell survival.CONCLUSION: These results indicate that IGFBP-5 expression affects the cell cycle and survival signal pathways and thus it may be an important mediator of PaC cell growth.

Prognostic significance of epidermal growth factor-like domain 7 in pancreatic cancer

BACKGROUND： Recent studies have shown the clinical significance of epidermal growth factor-like domain 7（EGFL7）in a variety of cancers. However, the relationship between EGFL7 and the prognosis of pancreatic cancer（PC） remains unclear. The present study was undertaken to investigate the role of EGFL7 in the prognosis of PC.METHODS： The expression of EGFL7 in nine PC cell lines was first determined by Western blotting analysis. Tissue microarray-based immunohistochemical staining was performed in paired formalin-fixed paraffin-embedded tumor and non-tumor samples from 83 patients with PC. Finally,correlations between EGFL7 expression and clinicopathological variables as well as overall survival were evaluated.RESULTS： EGFL7 was widely expressed in all PC cell lines tested.EGFL7 expression in tumor tissues was significantly higher than that in non-tumor tissues（P0.040）. In addition, univariate analysis revealed that high EGFL7 expression in tumor tissues was significantly associated with poor overall survival,accompanied by several conventional clinicopathological variables, such as gender, histological grade and lymph node metastasis. In a multivariate Cox regression test, EGFL7 expression was identified as an independent marker for longterm outcome of PC.CONCLUSION： Our data showed that EGFL7 is extensively expressed in PC and that EGFL7 is associated with poor prognosis.

Serum vascular endothelial growth factor is a potential biomarker of metastatic recurrence after curative resection of hepatocellular carcinoma

INTRODUCTIONHepatocellular carcinoma(HCC)is one of the mostcommon malignancies in China.To date,surgery is stillthe best solution to it.However,metastatic recurrencesafter curative hepatic resections are very common.Tang etal have reported that recurrence rate within 5 years

Expression of Ezrin,HGF,C-met in pancreatic cancer and non-cancerous pancreatic tissues of rats

BACKGROUND: Recent studies have confirmed that the expression of Ezrin, hepatocyte growth factor (HGF) and its receptor (C-met) is related to the genesis, progress, invasion and metastasis of some malignant tumors. Researches have also found that the biological function of Ezrin is closely related to HGF/C-met in malignant tumors. However, there is no report on the expression levels of Ezrin, HGF and C-met in rat pancreatic cancer induced by dimethylbenzanthracene (DMBA). This study aimed to detect the expression of Ezrin, HGF and C-met in rat pancreatic cancer and non-cancerous pancreatic tissues, and assess its effect in cancer induction by DMBA. METHODS: Ninety Sprague-Dawley rats were divided into 3 groups randomly: 40 in a pancreatic cancer model group (group A), 40 in a trichostatin A (TSA) intervention group (group B), and 10 in a control group (group C). DMBA was directly implanted into the parenchyma of rat pancreas in group A+group B. The rats of group B were treated with 1 ml of TSA saline solution (1 mu g/ml) via intraperitoneal injection weekly. The carcinogenesis of rats executed within 3-5 months in groups A and B was observed by macrograph and microscopy. Meanwhile, the rats in group C were executed within 5 months. The EnVision (TM) immunohistochemistry for detecting the expression levels of Ezrin, HGF and C-met was used in paraffin-embedded sections of the pancreatic specimens. RESULTS: The incidence of pancreatic cancer in group A was 48.6% and in group B 33.3%. The maximal diameter of tumor mass was significantly larger in group A than that in group B (P<0.05). No pathological changes were observed in the pancreas of group C and other main organs of groups A and B. The positive rates of Ezrin, HGF and C-met were significantly higher in ductal adenocarcinoma than in non-cancerous pancreatic tissues of groups A and B (P<0.01). The positive rates of Ezrin, HGF and C-met were significantly higher in ductal adenocarcinoma of group A than those in non-cancerous pancreatic tissues of group A (P<0.05), but there was no significant difference in group B (P>0.05). The positive rates of Ezrin, HGF and C-met in non-cancerous pancreatic tissues proved mild to severe atypical hyperplasia of the ductal epithelia. The pancreas of group C and 2 cases of fibrosarcoma showed the negative expression of Ezrin, HGF and C-met. There was a trend of consistency in the expression of Ezrin, HGF and C-met in ductal adenocarcinoma (P<0.05 or P<0.01). CONCLUSIONS: DMBA directly implanted into the parenchyma of the pancreas can produce a model of pancreatic cancer with a high incidence in a short time. TSA might inhibit the carcinogenesis and growth of pancreatic cancer, and its effects may be related to the inhibition of the expression of Ezrin, HGF and C-met during the process. Ezrin, HGF and C-met may have positive effects on the carcinogenesis of rat pancreas. (Hepatobiliary Pancreat Dis Int 2010; 9: 639-644)

Human epidermal growth factor receptor type 2 protein expression in Chinese metastatic prostate cancer patients correlates with cancer specific survival and increases after exposure to hormonal therapy

Aim： To investigate human epidermal growth factor receptor type 2 （HER2） protein expression and gene amplification in Chinese metastatic prostate cancer patients and their potential value as prognostic factors. Methods： Immunohistochemistry （IHC） was performed to investigate HER2 protein expression in prostate biopsy specimens from 104 Chinese metastatic prostate cancer patients. After 3-11 months of hormonal therapy, 12 patients underwent transurethral resection of the prostate （TURP）. HER2 protein expression of TURP specimens was compared with that of the original biopsy specimens. Of these, 10 biopsy and 4 TURP specimens with HER2 IHC staining scores ≥ 2＋ were investigated for HER2 gene amplification status by fluorescent in situ hybridization （FISH）. Results： Of the 104 prostate biopsy specimens, HER2 protein expression was 0, 1＋, 2＋ and 3＋ in 49 （47.1%）, 45 （43.3%）, 8 （7.7%） and 2 （1.9%） cases, respectively. There was a significant association between HER2 expression and Gleason score （P = 0.026）. HER2 protein expression of prostate cancer tissues increased in 33.3% of patients after hormonal therapy. None of the 14 specimens with HER2 IHC scores 〉 2＋ showed HER2 gene amplification. Patients with HER2 scores 〉 2＋ had a significantly higher chance of dying from prostate cancer than those with HER2 scores of 0 （P = 0.004） and 1＋ （P = 0.034）. Multivariate Cox regression analysis showed that HER2 protein expression intensity was an independent predictor of cancer-related death （P = 0.039）. Conclusion： An HER2 IHC score 〉 2＋ should be defined as HER2 protein overexpression in prostate cancer. Overexpression of HER2 protein in cancer tissue might suggest an increased risk of dying from prostate cancer. HER2 protein expression increases in some individual patients after hormonal therapy.

Effect of endothelial PAS domain protein 1 and hypoxia inducible factor 1~ on vascular endothelial growth factor expression in human pancreatic carcinoma

Background Transcription factors hypoxia inducible factor 1α （HIF 1α） and endothelial PAS domain protein 1 （EPAS1） promote the transcription of vascular endothelial growth factor （VEGF）. VEGF enhances angiogenesis and vascular permeability of tumours, which promotes tumour growth and facilitates entry of cancer cells into blood circulation and metastasizing. This study examined whether HIF 1α and EPAS1 stimulated angiogenesis through activation of VEGF in human pancreatic carcinoma. Methods Specimens from pancreatic carcinoma and healthy parts of same pancreas were taken from 60 patients. Real time quantitative reverse transcription polymerase chain reaction estimated expression of HIF 1α, EPAS1, and VEGF mRNAs. Western blotting and immunohistochemical, streptavidin peroxidase method assessed expression of HIF 1α, EPAS1, and VEGF proteins. Microvessel density （MVD） was assessed. Results Highly significant increases in expression of EPAS1, VEGF, and MVD were found in pancreatic carcinoma tissue but not in normal pancreatic tissue： VEGF at mRNA and protein levels （t=17.32, P=-0.0001; t=98.41, P=0.0001）; EPAS1 protein level （t=22.51, P=0.0001）. Expression of HIF la was similar in pancreatic carcinoma and normal pancreatic tissues at both mRNA and protein levels. Significant correlations were observed between EPAS1 and VEGF （r=0.736, P=0.0041）, between VEGF and MVD （r=0.858, P=0.0001）, and between EPAS1 and MVD （r=0.641, P=0.0003）. No significant correlations were observed between HIF la and VEGF, or between HIF 1α and MVD. MVD and expression of EPAS1 and VEGF were significantly related with TNM staging, so was EPASI and VEGF with size of tumour. Conclusions EPAS1 and VEGF, but not HIFla, are overexpressed in pancreatic carcinoma. The expression of EPAS1 is correlated with that of VEGF and MVD. EPAS1 may be involved in the angiogenesis of pancreatic carcinoma by upregulating the expression of VEGE Targeting EPAS1 may be a new method of antiangiogenic tumour therapy for pancreatic carcinoma.

VEGF与MMP-9在肝癌组织中的表达及其临床意义

背景与目的:血管内皮生长因子(vascularendothelialgrowthfactor,VEGF)及基质金属蛋白酶-9(matrixmetalloproteinase-9,MMP-9)与恶性肿瘤的侵袭、血管生成及预后有一定关系。VEGF与MMP-9表达对预测肝细胞癌(以下简称“肝癌”)患者预后的报道结果不一。本研究旨在探讨VEGF与MMP-9在肝癌组织中的表达及其预测肝癌患者预后的意义。方法:按是否复发将80例肝癌患者分为复发组与未复发组,采用免疫组化方法检测两组手术切除标本中VEGF及MMP-9的表达情况,分析两者的表达与临床病理指标的关系,建立Cox比例风险模型进行肝癌术后复发风险的多因素分析。结果:MMP-9及VEGF表达于肿瘤细胞浆中,复发组的阳性率分别为50.0%(24/48)及87.5%(42/48),未复发组分别为15.6%(5/32)及59.4%(19/32),差异均有显著性(P<0.05)。VEGF与MMP-9的表达呈正相关(rs=0.36,P<0.01),并均与复发呈正相关(P<0.01)。VEGF阴性患者的1、2、3年累积无瘤生存率分别是85.7%、71.4%及66.3%,VEGF阳性患者分别为58.0%、38.9%及33.9%,差异有显著性(P<0.01);MMP-9阴性组分别为72.4%、63.8%及55.5%,MMP-9阳性组分别为50.0%、14.1%及14.1%,差异有显著性(P<0.01)。多因素分析发现,肝癌组织中VEGF和MMP-9的表达、术前播散结节及镜下微转移灶是肝癌术后复发的独立危险因素。结论:肿瘤组织中VEGF及MMP-9的表达与肝癌患者的术后复发密切相关,为预测肝癌患者术后复发的指标之一。

非小细胞肺癌组织中VEGF-C和VEGFR-3的表达及其临床意义

背景与目的:血管内皮生长因子-C(vascularendothelialgrowthfactorC,VEGF-C)和VEGFR-3是促进恶性肿瘤淋巴管形成的重要因子,其表达与恶性肿瘤的淋巴结转移关系密切。本文旨在研究VEGF-C和VEGFR-3蛋白在非小细胞肺癌(non-smallcelllungcancer,NSCLC)组织中的表达及其临床意义。方法:应用免疫组化方法检测77例NSCLC组织中VEGF-C和VEGFR-3表达情况,分析其与肿瘤淋巴管密度(lymphaticvesseldensity,LVD)、肿瘤的大小、癌的组织类型、组织分化程度、淋巴结转移情况、临床复发和术后生存期的关系。结果:77例NSCLC组织中有45例(58%)VEGF-C阳性,32例(42%)VEGFR-3阳性。NSCLC组织中VEGF-C表达与肿瘤组织的分化程度有关(r=-0.32,P=0.018);VEGF-C及VEGFR-3表达与肿瘤的淋巴结转移、LVD、肿瘤大小及术后生存期有关。NSCLC组织中VEGF-C与VEGFR-3表达相关(r=0.23,P=0.045)。结论:VEGF-C和VEGFR-3表达与NSCLC的淋巴结转移、预后相关,它的高表达提示肺癌患者容易出现淋巴结转移和预后不良。

血管内皮细胞生长因子及其受体在大肠癌组织中的表达

目的观察血管内皮生长因子（ＶＥＧＦ）及其受体（ＫＤＲ）在大肠癌组织中的表达情况。方法利用免疫组化ＳＡＢＣ 法检测８０例大肠癌组织及１０例正常大肠组织中的ＶＥＧＦ及ＫＤＲ的表达。结果ＶＥＧＦ染色性物质主要位于肿瘤细胞 膜及胞浆，ＫＤＲ染色性物质主要位于癌组织及癌组织旁的血管内皮细胞上，大肠癌组织中ＶＥＧＦ和ＫＤＲ的表达阳性 率显著高于正常对照组织（Ｐ＜０．０１），ＶＥＧＦ和ＫＤＲ的表达与肿瘤的分化程度及Ｄｕｋｅｓ分期密切相关（Ｐ＜０．０５），与病理 分型无关（Ｐ＞０．０５）。结论ＶＥＧＦ和ＫＤＲ在大肠癌的发生和发展中起着重要作用，可反映大肠癌的恶性程度和进展情 况，并作为预后的指标。

免疫组化染色评分对EGFR突变检测的影响

背景与目的恰当的免疫组化染色评分可确保突变检测结果的可靠性,目前大多数研究认为"四分法"是所有评分系统中最佳的方法。本研究旨在探讨不同四分法染色评分对检测结果的影响。方法用三种不同的四分法免疫组化染色评分标准评价83例非小细胞肺癌标本表皮生长因子受体(epidermal growth factor receptor,EGFR)突变情况,并以液相芯片法作为金标准进行比较,计算每种方法的灵敏度、特异度、阳性预测值(positive predictive value,PPV)、阴性预测值(negative predictive value,NPV)、与金标准间一致度及三种标准间是否存在统计学差异。结果三种标准在检测EGFR突变方面不存在统计学差异,每种标准检测结果的特异度均明显优于灵敏度。染色为"3+"的标本,PPV均可高达100%。结论不同的四分法评分没有绝对的最佳标准,但无论用何种标准,免疫组化法(immunohistochemistry,IHC)检测EGFR突变的特异度均明显优于灵敏度。评分为"3+"的标本,可认为实际确实存在突变,直接接受EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)治疗。

胰腺上皮内瘤变和胰腺癌组织中TGF-β/Smad信号通路相关蛋白表达

目的探讨转化生长因子(TGF)β/Smad信号传导通路中Smad相关蛋白、TGFβ1及其Ⅰ、Ⅱ型受体在胰腺上皮内瘤变(PanIN)和胰腺癌组织中表达的意义。方法用免疫组化EnVision法和SP法检测266灶不同级别PanINs和121例胰腺癌组织中Smad相关蛋白、TGFβ1及其Ⅰ、Ⅱ型受体的表达,并联系临床病理学指标进行相关分析。结果高级别PanIN病灶Smad4表达率(60.6%,20/33)低于低级别PanINSmad4表达率(79.8%,186/233)(P<0.05);而高级别PanIN中Smad7,TGFβ1,TGFβRⅡ表达率明显高于低级别PanIN(P<0.05)。胰腺癌组织中,Smad4蛋白表达率在淋巴结转移组和神经受累组低于各自对照组(P<0.05);Smad7、TGFβ1及其Ⅰ、Ⅱ型受体的表达率在淋巴结转移组和神经受累组则分别高于各自对照组(P<0.05)。PanIN和胰腺癌组织中Smad2、4、7蛋白,TGFβ1及其Ⅰ、Ⅱ型受体表达率的差异具有显著性(P<0.01)。结论从低级别PanINs到高级别PanINs再到胰腺癌中,Smad4蛋白表达率逐渐降低,而Smad7、TGFβ1及其Ⅰ、Ⅱ型受体表达率逐渐升高,支持胰腺癌形成的分子模型。

金属硫蛋白与血管内皮生长因子在前列腺癌中的表达及临床意义

目的探讨金属硫蛋白(MT)与血管内皮生长因子(VEGF)在前列腺癌(PCa)组织中的表达及意义。方法应用免疫组织化学方法观察不同Gleason分级的66例PCa组织、20例前列腺增生(BPH)组织MT和VEGF的表达情况。结果MT在BPH组织和PCa组织中的阳性表达率分别为100%(20/20)和59.1%(39/66),差异有统计学意义(P<0.01);VEGF在BPH组织和PCa组织中的阳性表达率分别为15%(3/20)和69.7%(46/66),差异有统计学意义(P<0.01);不同Gleason评分及临床分期的PCa组织中MT和VEGF的表达阳性率比较差异有统计学意义(P<0.05),MT和VEGF的表达呈正相关(P=0.004)。结论MT的高表达可能是PCa发生的一种生物学标志,且与VEGF存在协同作用。联合检测MT及VEGF对诊断PCa,判断其恶性程度及预后均有一定参考价值。

VEGF、VEGF-C和VEGF-D在甲状腺乳头状癌组织中的表达及意义

背景与目的:研究表明血管内皮生长因子C和D(vascularendothelialgrowthfactor-Cand-D,VEGF-C,VEGF-D)与淋巴管的生成有关。局部淋巴结转移是甲状腺乳头状癌的特征,本研究的目是探讨血管内皮生长因子及其C和D(VEGF、VEGF-C和VEGF-D)蛋白在甲状腺乳头状癌的表达及其意义。方法:应用免疫组织化学SP法检测115例甲状腺乳头状癌和20例结节性甲状腺肿中VEGF、VEGF-C和VEGF-D蛋白的表达。结果:甲状腺乳头状癌VEGF、VEGF-C和VEGF-D的阳性率分别为79.1%、87.0%和72.2%。结节性甲状腺肿组织中VEGF、VEGF-C和VEGF-D的阳性率分别为30.0%、15.0%和20.0%。甲状腺乳头状癌VEGF、VEGF-C和VEGF-D的阳性率较结节性甲状腺肿明显增高。VEGF的表达与甲状腺癌的大小有关。VEGF、VEGF-C和VEGF-D在淋巴结转移组和非转移组的阳性率分别为84.7%、93.2%、83.1%和73.2%、80.4%、60.7%。VEGF-C和VEGF-D的阳性表达与甲状腺乳头状癌的淋巴结转移显著相关(P<0.05;P<0.01)。结论:VEGF与甲状腺乳头状癌的生长有关。VEGF-C和VEGF-D与淋巴结转移密切相关,提示甲状腺乳头状癌标本VEGF-C和VEGF-D的检测可作为预测肿瘤转移的指标之一。

HIF-1α与VEGF在子宫内膜癌组织血管生成中的作用

目的:研究HIF-1α与VEGF在正常子宫内膜、子宫内膜不典型增生和子宫内膜癌组织中的表达情况及在肿瘤血管生成中的作用。方法:应用免疫组织化学SP法分别检测各类子宫内膜组织中的HIF-1α和VEGF的表达,并计数MVD。结果:子宫内膜癌HIF-1α阳性表达率63.6%(28/44),正常子宫内膜为21.4%(3/14),两者差异有统计学意义,P<0.01。VEGF在子宫内膜癌、子宫内膜非典型增生和正常子宫内膜组织中的阳性率分别是56.8%、25.0%和14.3%,差异有统计学意义,P<0.01。HIF-1α与VEGF均与MVD呈正相关(rs=0.579,P<0.01;rs=0.607,P<0.01)。结论:HIF-1α及其靶基因VEGF可能在子宫内膜病变由良性到恶性转变过程中,以及恶性肿瘤的进展中起了重要作用,可能作为肿瘤生物学行为的标志,并成为抗肿瘤治疗的新靶向。

EGFR、COX-2及P63蛋白在非小细胞肺癌中的表达及其意义

目的检测表皮生长因子受体（epidermal growth factor receptor，EGFR）、环氧合酶-2（cyclooxygenase-2，COX-2）及P63蛋白在人非小细胞肺癌（non—small cell lung cancor，NSCLC）中的表达情况，探讨其与NSCLC临床TNM分期及淋巴结转移的关系。方法采用免疫组化（S-P法）检测EGFR、COX-2及P63蛋白在78例NSCLC中的表达情况。结果EGFR、COX-2及P63蛋白在NSCLC组织中的阳性表达率分别为65．4％（51／78）、61．5％（48／78）和56．4％（44／78）。COX-2和P63的阳性表达在肺鳞癌和腺癌之间具有显著性差异（P〈0．01）。EGFR阳性表达在肺鳞癌和腺癌中无显著差异（P〉0．05）。EGFR和COX-2在NSCLC临床TNM Ⅲ～Ⅳ期和有淋巴结转移组阳性表达率均高于TNM Ⅰ～Ⅱ期和无淋巴结转移组（P〈0．01）。P63蛋白阳性表达率与TNM分期及淋巴结转移无显著差异（P〉0．05）。结论EGFR、COX-2在NSCLC组织中高表达可能促进肺癌的侵袭和转移，COX-2和P63可作为肺鳞癌和腺癌鉴别的参考指标。

肺癌血管内皮生长因子的表达及其意义

采用ＳＰ免疫组织化学方法观察血管内皮生长因子（ＶＥＧＦ）在９４例肺癌组织的表达。结果显示，ＶＥＧＦ在肺癌组织表达的阳性率为７０．２％，明显高于癌旁正常组织。鳞癌和腺癌ＶＥＧＦ阳性组，其微血管计数值和增殖细胞栓抗原（ＰＣＮＡ）标记指数均高于阴性组。腺癌ＶＥＧＦ的表达与转移、分期和病理学分级等因素均无关；在鳞癌，有淋巴结转移组ＶＥＧＦ的阳性率高于无淋巴结转移组，Ⅲ～Ⅳ期癌高于Ⅰ～Ⅱ期癌。结果提示，ＶＥＧＦ表达与肺癌的发生有关，并能促进肺癌血管形成，使癌细胞的增殖活性升高。ＶＥＧＦ表达与肺鳞癌淋巴结转移和进展有关。