Clinicopathological and Prognostic Implications of Progranulin in Breast Carcinoma

Background Progranulin, an 88-kDa glycoprotein originally purified from the highly tumorigenic mouse teratoma-derived cell line P, which is newly discovered and closely correlated with the development and metastasis of several several cancers. But, as much information as we gathered, no immunohistochemical evidence for the correlation of progranulin expression with clinicopathological features in breast carcinoma pathological biopsies has been provided until now, and whether progranulin can be a new marker of metastatic risk and prognosis in breast cancer has not been studied. The aim of this study was to investigate the clinicopathological and prognostic implications of progranulin expression in breast carcinoma and its correlation with tumour angiogenesis. Methods The expression of progranulin in 183 surgical specimens from patients with breast cancer and 20 fibroadenoma breast tissue were detected by immunohistochemistry. The tumour angiogenesis related biomarker vascular endothelial growth factor was assayed and vascular endothelial cells in tumor tissues were labeled by antibody to CD105 for counting microvessel density (MVD). Results The relationship between expression of progranulin and the clinicopathological data was analysed. Progranulin proteins were overexpressed in breast cancer. The level of progranulin expression was found to be significantly correlated with tumour size (P = 0.004), lymph node metastasis (p<0.001) and TNM grading (p<0.001). High progranulin expression was associated with higher tumour angiogenesis as reflected by increased vascular endothelial growth factor expression (P < 0.001) and higher microvessel density (P = 0.002). Conclusions These results indicate that progranulin may be of great value in assessing the metastasis and prognosis of breast cancer, and could be taken as a new combination regimen for anti-angiogenic activity.     

c-met癌基因在乳腺癌增殖及血管生成中的作用

目的:探讨原癌基因c-met在乳腺癌增殖及微血管生成中的作用,为临床乳腺癌的病情预测及预后判断提供新的实验依据。方法:通过S-P免疫组织化学方法和微血管密度计数(MVD),检测75例乳腺浸润性导管癌和20例乳腺纤维腺瘤组织中原癌基因c-met的表达情况和微血管密度。结果:乳腺癌组织c-met阳性表达与组织学分级、淋巴结转移、肿瘤分期显著相关(P<0.05),而与年龄、病变部位、月经情况、雌激素水平、孕激素水平、肿瘤大小无关(P>0.05)。微血管计数与c-met阳性表达显著相关(P<0.01)。结论:c-met癌基因在乳腺癌中表达增强与乳腺癌肿瘤细胞增殖状态及微血管生成直接相关,可以成为判断乳腺癌预后的一个有价值的指标。     

血管内皮生长因子在非小细胞肺癌中的表达及其意义

探讨血管内皮生长因子在肺癌中的表达及与肿瘤生长转移,预后和新生血管形成的关系。方法对５３例周围型非小细胞肺癌患者,采用免疫组织化学法,进行ＶＥＧＦ抗体标记和肿瘤组织ＶＥＧＦ表达;用Ｆ８因子抗体标记瘤组织的血管生成。     

MVD和VEGF在乳腺癌组织中的表达及其临床意义

运用免疫组织化学方法研究了53例乳腺癌石蜡切片中微血管密度(MVD)和血管内皮生长因子(VEGF)的表达,探讨二者的关系及其在乳腺癌预后中的价值.结果发现腋下淋巴结阳性病例组的MVD明显高于腋下淋巴结阴性组(P<0.01).术后出现转移病例中的MVD高于无转移病例(P<0.001).VEGF的表达率为67.92%,且与MVD具有相关性.提示MVD与肿瘤的转移密切相关,是乳腺癌的一个预后指标,而VEGF对肿瘤内的血管生成可能起重要作用.     

Expression of PC cell-derived growth factor and vascular endothelial growth factor in esophageal squamous cell carcinoma and their clinicopathologic significance

Background Esophageal carcinoma is a common kind of malignant tumor and about 90% of which is esophageal squamous cell carcinoma （ESCC）, and it has a high incidence in China. In recent years it has been argued that angiogenesis plays a key role in tumor growth and metastasis and it is a complex process influenced by many factors. This study was aimed to investigate the expression of PC cell-derived growth factor （PCDGF or progranulin） and vascular endothelial growth factor （VEGF） in ESCC tissue and their relationship with clinical pathological parameters of ESCC, clarify the role of PCDGF and VEGF in the angiogenesis of ESCC.
Methods The expression of PCDGF and VEGF in 50 surgical specimens from patients with ESCC and 20 with normal esophageal mucosa were detected by immunohistochemistry. The vascular endothelial cells in tumor tissues were labeled by antibody to CD105 for counting microvessel density （MVD）.
Results The expression of PCDGF and VEGF in ESCC was significantly higher than that in normal mucosa. Expression correlated with the depth of tumor invasion, lymph node metastasis, and TNM （classification tumor, nodes, metastasis）. In ESCC, both the expression level of PCDGF and VEGF had a positive correlation with MVD and the expression of PCDGF had a significant correlation with the expression of VEGF.
Conclusions These results show that both of PCDGF and VEGE have higher expression in ESCC, which indicate that they have a close relationship with angiogenesis. They may be involved in tumor growth, infiltration and metastasis through promoting tumor angiogenesis and may be an important index reflecting biological behavior and prognosis of ESCC.     

乙酰肝素酶在食管癌中的表达及其与食管癌浸润、转移、血管生成和PCNA指数之间的相关性

目的：恶性肿瘤的浸润与转移是其难以治愈的主要原因。近年发现降解细跑外基质的酶与肿瘤的浸润和转移密切相关。乙酰肝素酶是降解细胞外基质中多糖成分的酶，具有促进肿瘤浸润、转移和血管生成的作用。该实验通过在食管癌组织中对乙酰肝素酶的检测，探讨乙酰肝素酶与食管癌浸润、转移、血管生成和食管癌增殖之间的关系。方法：我们用逆转录聚合酶链式反应(RT—PCR)在47例食管癌组织标本和其相应的正常食管黏膜个对乙酰肝素酶mRNA表达情况进行检测，分析乙酰肝素酶在食管癌组织和正常食管黏膜中的表达差异，对乙酰肝素酶与食管浸润、转移的相关性进行分析；同时应用免疫组织化学的方法对食管癌组织进行FVⅢ相关抗原和PCNA的染色，了解食管癌组织中微血管密度和肿瘤细胞增殖情况，分析二者与乙酰肝素酶表达之间的相关性。结果：乙酰肝素酶主要在食管癌组织中表达；乙酰肝素酶的表达与食癌管的浸润和转移具有明显的相关性(P＜0．001)；乙酰肝素酶与食管癌的最大微血管密度密切相关(P＝0．002)，而且乙酰肝素酶mRNA表达的量与最大微血管密度计数之间呈线性相关(R＝0．52)；乙酰肝素酶与PCNA指数之间具有明显的相关性(P＝0．03)。结论：乙酰肝素酶可促进食管癌的浸润、转移和血管生成，并与肿瘤的增殖活性有关，有可能成为一项反映食管癌生物学行为的有用指标。     

血管内皮细胞生长因子和血管生成与胃癌发展的关系

目的　探讨血管内皮细胞生长因子(VEGF)和血管生成与胃癌发展的关系。方法　应用免疫组织化学技术,检测42例胃癌组织VEGF蛋白表达和微血管密度(MVD),分析VEGF和MVD及其与胃癌各临床病理指标间关系。结果　VEGF阳性者MVD值显著高于阴性者(P＜0.01),VEGF表达和MVD与肿瘤大小、浸润深度、淋巴结转移密切相关(皆P＜0.05),与肿瘤分化无关(P＞0.05)。结论　VEGF与胃癌的血管生成密切相关,对胃癌的生长和浸润转移有促进作用,VEGF或MVD可作为反映胃癌生物学行为的指标之一。     

血管内皮生长因子在乳腺癌中的表达及其与P53蛋白的关系

目的 :探讨血管内皮生长因子 (vascularendotherialgrowthfactor ,VEGF)在乳腺癌中的表达及其与乳腺癌P5 3蛋白在乳腺癌中的表达之间的关系 ,以及它们与乳腺癌临床病理特征间的关系。方法 :采用免疫组织化学方法检测 88例乳腺癌 ,10例正常乳腺组织以及 10例乳腺良性肿瘤手术标本的VEGF和P5 3蛋白的表达。结果 :在 88例乳腺癌病例中 ,有淋巴结转移的VEGF阳性表达率 (94.2 9% )明显高于无淋巴结转移的VEGF阳性表达率 (49.0 6 % ) (P <0 .0 0 1) ,VEGF阳性表达率与乳腺癌肿瘤大小无关系 (P >0 .1)。P5 3蛋白表达与乳腺癌淋巴结状况 (P >0 .5 )及肿瘤大小 (P >0 .1)无关系。在VEGF表达阳性患者的P5 3蛋白表达阳性率 (45 .76 % )明显高于VEGF表达阴性患者的P5 3蛋白表达阳性率 17.2 4% (P <0 .0 1)。结论 :VEGF在乳腺癌的发生发展及转移中发挥重要作用 ;P5 3基因失活和突变能降低血管生成阻止因子的分泌从而激发VEGF在肿瘤中的表达 ,促使乳腺癌的发生发展和转移。     

唇鳞癌中VEGF表达和微血管密度的临床意义

目的：研究微血管密度(microvessel density,MVD)和血管内皮生长因子(vascular endothelial growth factor,VEGF)在唇鳞癌中的表达，探讨其临床意义。方法:采用SABC免疫组织化学染色方法检测37例唇鳞癌中MVD和VEGF的表达，采用SPSS软件行统计分析。结果：62．16％唇癌组织呈VEGF阳性表达。VEGF表达阳性的唇癌组织MVD显著高于VEGF表达阴性者(P＜0．05)。VEGF表达与肿瘤的分化程度、淋巴结转移及浸润深度密切相关，而与肿瘤的临床分期无关。MVD记数与肿瘤的分化程度、淋巴结转移、浸润深度及临床分期密切相关。结论：唇癌组织VEGF表达与微血管密度有明显的相关性，是唇癌主要的新生血管诱导因子之一，VEGF、MVD可做为反映唇癌生物学行为的一个有效指标。     

涎腺腺癌中VEGF表达与微血管密度及预后的关系

目的　研究微血管密度 (MVD)和血管内皮生长因子 (VEGF)在涎腺腺癌中的表达 ,探讨其与预后关系。方法　采用SABC免疫组织化学染色方法检测 4 3例涎腺腺癌中MVD和VEGF的表达 ,采用SPSS软件行统计分析。结果　 6 5 .12 %的涎腺腺癌组织呈VEGF阳性表达。VEGF表达阳性的涎腺腺癌组织MVD显著高于VEGF表达阴性者 (P <0 .0 5 )。VEGF表达与肿瘤的分化程度、淋巴结转移密切相关 ,而与肿瘤的临床分期无关。VEGF阴性表达的病人术后 5年生存率较阳性表达者高。结论　涎腺腺癌组织VEGF表达与微血管密度有明显的相关性 ,是涎腺腺癌主要的新生血管诱导因子之一 ,VEGF可做为涎腺腺癌预后的一个有效指标。     

AEG-1在子宫颈癌组织中的表达及与微血管生成的相关性

目的 观察星形胶质细胞上调基因1(AEG-1)在子宫颈癌组织中的表达及其与微血管密度、血管内皮生长因子(VEGF)和核因子κB(NF-κB p65)的相关性。 方法 收集温州医科大学附属第一医院手术切除的45例浸润性子宫颈癌标本和12例慢性子宫颈炎标本作为研究对象。采用免疫组化MaxVision法检测AEG-1,NF-κB p65和VEGF蛋白的表达水平,采用肿瘤微血管内皮标志物(CD34)结合Weidner计数法检测子宫颈癌组织新生的微血管密度(MVD)。在光学显微镜下观察AEG-1、NF-κB p65和VEGF在子宫颈癌组织中的阳性表达以及染色情况。采用Pearson相关性分析子宫颈癌组织中AEG-1表达与NF-κB p65、VEGF表达的相关性。 结果 AEG-1在子宫颈癌和慢性子宫颈炎的表达差异有统计学意义(P＜0.01),其表达水平与子宫颈癌患者发生脉管浸润和淋巴结转移有关(P＜0.01),与患者年龄、分化程度、肿瘤大小、病理分型、宫旁浸润等因素无关(P＞0.05)。经Pearson相关性分析发现,子宫颈癌组织中AEG-1表达与NF-κB p65(r=0.501,P＜0.001)、VEGF(r=0.718,P＜0.001)和MVD(r=0.815,P＜0.001)呈正相关。 结论 AEG-1在子宫颈癌组织中高表达,可促进子宫颈癌的微血管生成,其机制可能与AEG-1激活NF-κB信号途径进而上调VEGF水平有关。      

MMP-2和MMP-13与乳腺癌腋窝淋巴结转移的相关性

目的本研究按照病理诊断中有无脉管癌栓分组,通过检测基质金属蛋白酶（MMPs）重要家族成员MMP、2,-9,-13,-14的表达;探讨乳腺癌转移中MMPs作用及其与淋巴结转移的关系。方法采用荧光定量RT—PCR检测30例乳腺癌组织MMP-2,一9,-13,一14mRNA表达情况;用免疫组化S-P方法检测乳腺癌组织中雌激素受体（ER）、孕激素受体（PR）、癌基因（HER2）、抑癌基因（P53）、核增殖抗体（Ki一67）的表达;采用t检验等方法处理实验数据。结果乳腺癌脉管癌栓阳性组淋巴结转移个数显著多于阴性组;脉管癌栓阴性组中MMP一2和MMP一13的表达较阳性组显著增高且差异有统计学意义（P〈0．05）。结论乳腺癌脉管癌栓阳性组有更明显的淋巴结转移趋势。肿瘤组织中MMP．2和MMP．13对肿瘤细胞的内渗起着负调控的作用。     

MVD 、VEGF 在前列腺癌组织中的表达及相关性研究

【目的】探讨微血管密度（MVD）、血管内皮生长因子（VEGF）在前列腺癌组织中表达及意义。【方法】选取本院2007～2012年收治的56例前列腺癌患者为观察组,30例良性前列腺增生患者为对照组。应用免疫组织化学法检测患者前列腺组织中VEGF及MVD的表达情况,并对MVD、VEGF表达水平与肿瘤转移关系进行分析比较。【结果】观察组组织中VEGF及MVD的表达均明显高于对照组,且二者相比较差异均有显著性（ P＜0．01）;在肿瘤不同TNM分期和有无淋巴结转移前列腺癌患者中VEGF及MVD表达相比较差异有显著性（ P ＜0．05）。【结论】VEGF参与了前列腺癌患者的血管再生过程,与前列腺癌的生长及淋巴结转移密切相关,VEGF及MVD可作为判断前列腺癌预后的重要参考指标。     

直肠癌血管生成与肿瘤细胞增殖和转移的关系

目的 :探讨血管生成在直肠癌细胞增殖、浸润和淋巴结转移中的意义。　方法 :免疫组化法检测和分析 4 6例直肠癌标本中的微血管密度 (MVD)值、血管内皮细胞生长因子 (VEGF)阳性表达率、Ki 6 7标记指数 (Ki 6 7LI)与肿瘤浸润深度和淋巴结转移的关系。　结果 :MVD值、VEGF阳性表达率和Ki 6 7LI随肿瘤浸润深度的增加而增加 (P <0 .0 1)。MVD值、VEGF阳性表达率和Ki 6 7LI在淋巴结转移阳性组显著高于阴性组 (P <0 .0 1)。MVD值、Ki 6 7LI在VEGF表达阳性组显著高于VEGF表达阴性组 (P <0 .0 1)。MVD值与Ki 6 7LI之间呈显著正相关(r =0 .36 ,P <0 .0 1)。　结论 :直肠癌血管生成可促进癌细胞增殖、浸润和淋巴结转移     

Effects of cloned tumstatin-related and angiogenesis-inhibitory peptides on proliferation and apoptosis of endothelial ceils

Background Tumstatin is a recently developed endogenous vascular endothelial growth inhibitor that can be applied as an anti-angiogenesis and antineoplastic agent.The study aimed to design and synthesize the small molecular angiogenesis inhibition-related peptide (peptide 21),to replicate the structural and functional features of the active zone of angiogenesis inhibition using tumstatin and to prove that synthesized peptide 21 has a similar activity:specifically inhibiting tumor angiogenesis like tumstatin.Methods Peptide 21 was designed and synthesized using biological engineering technology.To determine its biological action,the human umbilical vein endothelial cell line ECV304,the human ovarian cancer cell line SKOV-3 and the mouse embryo-derived NIH3T3 fibroblasts were used in in vitro experiments to determine the effect of peptide 21 on proliferation of the three cell lines using the MTT test and growth curves.Transmission electron microscopy (TEM) and flow cytometry (FCM) were applied to analyze the peptide 21-induced apoptosis of the three cell lines qualitatively and quantitatively.In animal experiments,tumor models in nude mice subcutaneously grafted with SKOV-3 were used to observe the effects of peptide 21 on tumor weight,size and microvessel density (MVD).To initially investigate the role of peptide 21,the effect of peptide 21 on the expression of vascular endothelial growth factors (VEGFs) by tumor tissue was semi-quantitatively analyzed.Results The in vitro MTT test and growth curves all indicated that cloned peptide 21 could specifically inhibit ECV304 proliferation in a dose-dependent manner (P ＜0.01);TEM and FCM showed that peptide 21 could specifically induce ECV304 apoptosis (P ＜0.01).Results of in vivo experiments showed that tumors in the peptide 21 group grew more slowly.The weight and size of the tumors after 21 days of treatment were smaller than those in the control group (P ＜0.05),with a mean tumor inhibition rate of 67.86%;MVD of the tumor tissue in the peptide 21 group was significantly lower than in the control group (P＜0.05);the number of cells positive for VEGF in the peptide 21 group was significantly fewer than in the control group (P ＜0.01).Conclusions Similar to the activity of tumstatin in specifically inhibiting tumor angiogenesis,peptide 21 may specifically inhibit tumor endothelial cell proliferation and induce their apoptosis,thereby suppressing tumor angiogenesis and indirectly inhibit the growth,infiltration and metastasis of tumors.Peptide 21 may exert its effect through down-regulating the VEGF expression of tumor cells and vascular endothelial cells.     

Expression of cyclooxygenase-2 and vascular endothelial growth factor-C correlates with lymphangiogenesis and lymphatic invasion in human gastric cancer

BACKGROUND: Recent observations have suggested that overexpression of cyclooxygenase-2 (COX-2) promotes tumor lymphangiogenesis through an upregulation of vascular endothelial growth factor-C (VEGF-C) expression. It is unclear whether this mechanism also acts in gastric cancer. The aim of this study was to determine the relationship between COX-2 and VEGF-C expression in human gastric cancer, as well as to correlate with lymph node involvement, prognosis, and other clinicopathologic parameters. METHODS: Sixty-eight primary gastric cancers were immunohistochemically examined for COX-2, VEGF-C, vascular endothelial growth factor receptor-3 (VEGFR-3, also known as Flt-4), and CD34 expressions. Assessment of Flt-4-positive vessel density (FVD) and microvessel density (MVD) was performed. Then we analyzed their relationships and correlations with clinicopathologic findings and patients' survival time. RESULTS: The positivity rate of COX-2 and VEGF-C in the primary tumor was 67.7 and 54.4 percent, respectively. A significant correlation was found between the expression of VEGF-C and COX-2, and both were also correlated to MVD, FVD, lymphatic invasion, and TNM stage (p<0.05). COX-2 immunoreactivity was also associated with lymph node metastasis and serosa invasion. Increased MVD was significantly associated with lymph node metastasis and TNM stage. Both COX-2 and VEGF-C expression significantly correlated with poorer prognosis. CONCLUSIONS: Our data suggest that the expression of COX-2 correlates with VEGF-C expression and both of them correlate with the presence of lymphatic invasion and prognosis in gastric cancer. COX-2-mediated VEGF-C overexpression might promote lymphatic invasion via lymphangiogenesis pathway in patients with gastric cancer.     

碱性成纤维细胞生长因子在结直肠癌中的表达及其与肿瘤血管生成的关系

目的探讨碱性成纤维细胞生长因子（bFGF）在结直肠癌中的表达及与肿瘤血管生成、临床病理因素和预后的关系。方法免疫组织化学SP法检测80例结直肠癌、30例结直肠腺瘤、30例结直肠正常组织中bFGF的表达情况,并检测CD34标记的肿瘤微血管密度（MVD）。结果 bFGF在结直肠癌的阳性表达率显著高于结直肠腺瘤及正常结直肠组织（P〈0.05）。结直肠癌bFGF阳性表达组的MVD明显高于bFGF阴性组（P〈0.05）;高MVD组bFGF阳性表达率显著高于低MVD组（P〈0.05）。bFGF的表达与结直肠癌Dukes分期、肿瘤浸润深度、淋巴结转移显著相关（P〈0.05）。结直肠癌bFGF阳性表达组的5年生存率明显低于bFGF阴性组（P〈0.01）。结论 bFGF与肿瘤血管生成密切相关,其过度表达提示肿瘤具有更高的恶性潜能及不良预后。     

肺癌血管生成与淋巴结转移的关系

目的探讨肺癌血管生成与淋巴结转移的关系.方法我们采用免疫组织化学的方法检测了1997～1999年手术切除的50例肺癌病人石蜡标本中微血管密度和血管内生长因子及其受体蛋白的表达,其中有肺门淋巴结转移者24例,光镜下行MVD、VEGF、Flt、KDR蛋白表达细胞的计数.结果肺门淋巴结转移组的MVD、VEGF、Flt、KDR蛋白表达均高于未转移组.结论肺癌中MVD、VEGF、Flt、KDR蛋白表达与肿瘤转移行为密切相关,有可能作为判定肿瘤生物学行为、转移潜能及预后的指标.     

淋巴管内皮细胞透明质酸受体-1标记的乳腺癌微淋巴管密度测定及其临床意义

目的 探讨淋巴管内皮细胞透明质酸受体1 (LYVE-1)标记的乳腺癌微淋巴管密度测定(MLD)在乳腺癌表达的临床意义.方法 采用免疫组化方法检测54例乳腺癌组织和40例正常乳腺组织的LYVE-1的表达,光镜下观察计数MLD,评价淋巴管增殖情况.结果 LYVE-1阳性表达于肿瘤边缘组织淋巴管内皮细胞,表现为淋巴管扩张明显...     

CEACAM1在肺癌组织的表达及其与VEGF和MVD的相关性

目的检测肺癌组织中癌胚抗原相关细胞粘附因子1(carcinoembryonic antigen-related cell adhesionmolecule 1,CEACAM1)的表达,探讨其与血管内皮细胞生长因子(vascular endothelial growth factor,VEGF)的表达及微血管密度(microvessel density,MVD)值的相互关系。方法应用免疫组织化学方法(S-P法)检测50例肺癌组织、10例正常肺组织中CEACAM1、VEGF的表达及MVD值。结果 CEACAM1在肺癌组织中的阳性表达率较在正常肺组织中的阳性表达率增高(P0.01),VEGF在肺癌组织中的阳性表达率较在正常肺组织中的阳性表达率增高(P0.05),肺癌组织中MVD值较正常肺组织中MVD值增高(P0.01)。肺癌组织中CEACAM1的表达与VEGF的表达存在正相关关系(r=0.59,P0.01),肺癌组织中CEACAM1的表达与MVD值存在的正相关关系(r=0.44,P0.01)。结论肺癌组织中CEACAM1的表达增高,提示CEACAM1可能参与了肺癌的发生发展。肺癌组织中CEACAM1的表达与VEGF的表达及MVD值均呈正相关关系,提示CEACAM1可能参与肺癌血管生成。