肝癌组织中HIF-1α与VEGF的表达及意义

目的探讨缺氧诱导因子-1α（HIF-1α）、血管内皮生长因子（VEGF）在肝细胞肝癌（HCC）发生、发展中的作用。方法采用免疫组化法检测30份HCC组织（HCC组）和10份正常肝组织（对照组）标本中HIF-1α和VEGF蛋白表达。结果HCC组HIF．10r．阳性率为73．3％,对照组为0％（P〈0．05）。HCC有肝内转移者HIF-1α表达明显高于无肝内转移者（P〈0．05）。HCC组VEGF阳性率为60．0％,对照组为10．0％（P〈0．05）。HCC有肝内转移、癌栓形成者VEGF表达明显高于无肝内转移及癌栓形成者（P均〈0．05）。HCC中HIF-1α与VEGF的表达呈正相关（r=0．431,P〈0．05）。结论HIF-1α、VEGF在HCC中表达上调,且在HCC的发生、发展中起促进作用。     

survivin和VEGF在胆囊癌中的表达及其与肿瘤微血管密度相关性研究

采用免疫组化sP法检测42例原发性胆囊癌患者癌组织标本（观察组）凋亡抑制基因（survivin）与血管内皮生长因子（VEGF）、肿瘤微血管密度（MVD）的相关性，将结果与40例胆囊息肉患者息肉组织（对照组）比较。免疫组织化学sP法检测survivin、VEGF和CD34在胆囊癌组织中的表达情况，用CD。单抗标记的血管计数MVD。结果：观察组survivin、VEGF阳性表达率及MVD明显高于对照组P〈0．01；观察组Ⅲ、Ⅳ期患者survivin和VEGF的阳性表达率明显高于Ⅰ、Ⅱ期患者P〈0．05；高分化者survivin和VEGF阳性表达率低于中、低分化者（P〈0．05）；有淋巴结转移者survivin和VEGF阳性表达率明显高于无淋巴结转移者（P〈O．01）；两者在腺癌中的阳性表达率无统计学意义（P〉0．05）；VEGF与survivin的阳性表达呈正相关。认为survivin、VEGF在胆囊癌组织中呈高表达，且与淋巴结转移和病理分级有关；两者表达成正相关，且与肿瘤微血管形成密切相关。     

肝细胞癌组织中Cyr61、VEGF和HSP27的表达及意义

目的观察富半胱氨酸蛋白61（Cyr61）、血管内皮生长因子（VEGF）和热休克蛋白27（HSP27）在肝细胞癌（HCC）中的表达,分析其与HCC病理学特征和转移的关系。方法采用免疫组化SP法分别检测34例HCC患者肝癌组织和癌旁肝组织中的Cyr61、VEGF和HSP27表达情况,并与HCC患者的临床、病理学特征进行相关性分析。结果VEGF和HSP27在肝癌组织中的表达显著高于癌旁组织（P〈0．05）,Cry61在癌旁组织中的表达显著高于肝癌组织（P〈0．05）;HCC转移者的Cyr61、VEGF和HSP27阳性表达率明显高于无转移者（P〈0．06）。结论Cyr61、VEGF和HSP27的表达与HCC转移密切相关;联合检测Cyr61、VEGF和HSP27的表达情况对判断HCC转移和预后有—定的临床价值。     

Galectin-3、VEGF和MVD在乳腺浸润性导管癌组织中的表达及意义

目的探讨Galectin-3、血管内皮生长因子（VEGF）和微血管密度（MVD）在乳腺浸润性导管癌组织中的表达及临床病理意义。方法应用免疫组织化学SP法检测Galectin-3和VEGF在63例乳腺浸润性导管癌组织（乳腺癌组）中的表达，并用CD34免疫组织化学染色计数肿瘤MVD；16例周围正常乳腺组织作对照（对照组）。结果乳腺癌组Galectin-3、VEGF表达阳性率和MVD均显著高于对照组（P均〈0．01）；Galectin-3、VEGF表达阳性率和MVD与乳腺癌组织学分级、TNM分期和淋巴结转移有关，而与患者年龄、肿瘤直径无明显相关；乳腺癌组Galectin-3和VEGF阳性者MVD明显高于阴性者（P〈0．05、0．01），Galectin-3与VEGF表达呈正相关（P〈0．01）。结论Galectin-3、VEGF在促进乳腺癌微血管形成中有协同作用；Galectin-3、VEGF和MVD对判断乳腺浸润性导管癌的恶性程度、浸润及转移有重要价值。     

EIF-5A2在肝细胞癌中的表达及其与VEGF、MVD的关系

目的:探讨真核翻译起始因子-5A2(eukaryotic initiation factor 5A2,EIF-5A2)在肝癌内的表达及其与VEGF表达、血管密度和临床病理指标的关系.方法:用免疫组织化学方法检测49例HCC组织及6例正常肝组织中EIF-5A2、VEGF和CD34的表达,计数微血管密度(MVD),并结合临床病理特征进行比较分析.结果:49例HCC组织中EIF-5A2、VEGF、CD34阳性表达率分别为87.7%、89.7%及100.0%,正常肝组织EIF-5A2、CD34表达呈阴性,VEGF表达为阴性或弱阳性.肝癌组织中EIF-5A2蛋白表达与VEGF表达及MVD间均呈正相关(r=0.416,0.321,均P<0.05);不同肿瘤灶数量的HCC组织EIF-5A2、VEGF蛋白表达及MVD差别无显著性,不同直径HCC的EIF-5A2、VEGF蛋白表达差别亦无显著性,而不同直径的HCC的MVD差别有显著性(P<0.05).有癌栓形成组与无癌栓组相比EIF-5A2、VEGF蛋白表达及MVD差别均有显著性(均P<0.05).肿瘤包膜完整组与无胞膜/包膜不完整组两组间EIF-5A2、VEGF蛋白表达及MVD差别均有显著性(均P<0.05).结论:肝癌组织中有较高的EIF-5A2阳性表达;EIF-5A2表达与VEGF表达及MVD呈正相关,与HCC组织血管侵犯和转移倾向有关.     

VEGF和Ang-2与甲状腺乳头状癌血管生成和转移的相关性探讨

采用免疫组化S-P法检测20例甲状腺乳头状癌（PTC，A组）、15例结节性甲状腺肿（B组）、15例甲状腺腺瘤（C组）和15例正常甲状腺组织（D组）中血管内皮生长因子（VEGF）、促血管生成素-2（Ang-2）蛋白的表达和微血管密度（MVD）。结果A组VEGF和Ang-2表达均显著高于其他组（P均〈0．05）；A组VEGF、Ang-2与MVD呈正相关（P均〈0．05），而Ang-2与MVD无相关性；A组有淋巴结转移者VEGF表达和MVD均显著高于无转移者（P均〈0．05），但Ang-2无显著差异。提示VEGF和Ang-2在PTC血管生成中起重要作用；VEGF与PTC转移密切相关。     

HIF-2α、VEGF与非小细胞肺癌中微血管生成及生物学转移的关系

应用免疫组化技术检测48例小细胞肺癌（NSCLC）中缺氧诱导因子-2α（HIF-2α）和血管内皮生长因子（VEGF）的表达，用CD34单克隆抗体标记血管内皮细胞并计数微血管密度（MVD）。结果48例NSCLC的HIF-2α和VEGF阳性表达率分别为72．9％和75％，与正常肺组织相比有统计学意义（P＜0．01）；HIF-2α和VEGF的表达呈正相关（r=0．721，P＜0．01）；HIF-2α或VEGF阳性NSCLC组织中MVD明显高于阴性组织；NSCLC转移者与未转移者的HIF-2α和VEGF比值有显著性差异（P＜0.01）。结论HIF-2α参与丁济导VEGF表达，促进NSCLC血管生成及转移的过程．可能在NSCLC早期形成和发展阶段有重要作用。     

血管内皮生长因子在食管癌中的表达及意义

为探讨血管内皮生长因子（VEGF）与食管癌生物学行为之间的关系,采用免疫组化SABC法检测了46例食管癌患者癌组织标本中的VEGF表达情况及微血管密度（MVD）。结果21例（45．65％）VEGF呈阳性表达;肿瘤浸润深度局限于肌层以内者的阳性表达率为30．43％,侵及外膜及邻近器官者为60．87％,差异有显著意义（P＜0．05）;肿瘤分化程度为Ⅱ、Ⅲ级者的VEGF阳性表达率显著高于I级者（P分别＜0．05、0．01）;各食管癌分期（PTNM）VEGF阳性表达率之间无显著差异（P＞0．05）;有、无淋巴结转移者的VEGF阳性表达率无显著差异（P＞0．05）。VEGF阳性者MVD值明显高于阴性者（P＜0．05）,其5年生存率（14．29％）低于VEGF阴性者（56％）,P＜0．05）。认为VEGF阳性表达与食管癌的分化程度、浸润深度有关,与食管癌的肿瘤大小、临床病理分期、淋巴结转移无关;VEGF阳性表达与食管癌的MVD密切相关;VEGF阳性表达者术后预后差;VEGF可为食管癌的诊断、预后判断及治疗方案选择提供重要依据。     

肝癌组织中PEDF、VEGF的表达及意义

目的探讨色素衍生上皮因子（PEDF）、血管内皮生长因子（VEGF）在肝癌发生、发展中的作用。方法采用免疫组化法检测72份肝癌组织标本中PEDF、VEGF的表达,用CD31标记免疫组化法检测微血管密度（MVD）。结果PEDF、VEGF在肝癌组织中的阳性率分别为41．67％（30／72）、83．33％（60／72）;MVD值PEDF阴性者高于阳性者、VEGF阳性者高于阴性者;PEDF、VEGF表达均与术后复发、肝外转移、临床分期、门静脉癌栓有关;两者表达呈负相关。结论PEDF、VEGF在血管生成过程中具有拮抗作用;PEDF可能通过抑制MVD生成起抑癌作用。     

肾细胞癌组织中内皮抑素、VEGF、MVD的表达变化及意义

目的观察肾细胞癌（RCC）组织中内皮抑素、VEGF、微血管密度（MVD）表达变化,并探讨其意义。方法采用免疫组化SABC法检测50例肾细胞癌（RCC）及30例正常肾组织的内皮抑素、VEGF、CD34。结果内皮抑索和VEGF在癌旁正常肾脏组织中的阳性表达率分别为37％和20％,在肾癌组织中阳性表达率分别为76％和74％,在肾癌组织中的表达强度显著高于癌旁正常肾脏组织（P均〈0．05）。内皮抑素和VEGF表达水平在高分期的病例中呈高表达,与低分期的病例比较,P〈0．05。RCC组织中的MVD均值为（35．62±11．38）条／HP,明显高于癌旁正常肾脏组织的（18．71±9．53）条／HP,P〈0．01。临床分期为Ⅲ～Ⅳ期RCC组织MVD为（41．29±10．65）条／HP,显著高于Ⅰ－Ⅱ期的（24．74±7．83）条／HP,P〈0．01。内皮抑素和VEGF与MVD的表达有关（P均〈0．05）。结论RCC组织中内皮抑素、VEGF阳性表达率和MVD升高。三者可作为评估RCC恶性程度、转移及预后的重要指标。     

Expression of vascular endothelial growth factor-C in human hepatocellular carcinoma

Background/Aims: Vascular endothelial growth factor‐C (VEGF‐C) is thought to be an important factor in tumor angiogenesis/lymphangiogenesis, but its role in hepatocellular carcinoma (HCC) has not yet been fully investigated. Methods: We immunohistochemically examined VEGF‐C expression in surgically resected tissues of 90 HCC. Results: In the 78 HCC with a single histological grade, VEGF‐C expression was significantly stronger in poorly differentiated HCC than in well‐ (P = 0.003) or moderately differentiated HCC (P = 0.0002). A ‘nodule‐in‐nodule’ case presented VEGF‐A expression in the well‐differentiated component and VEGF‐C expression in the moderately–poorly differentiated component. According to nodular diameter, VEGF‐C expression was significantly higher in nodules of 3.0 cm or larger (P = 0.0263). Extrahepatic metastases seen in seven cases expressed VEGF‐C. In 20 of the 28 cases who were able to be followed up, the frequency of intrahepatic recurrence tended to be higher and extrahepatic metastasis was significantly higher in the cases who had VEGF‐C expression in the tumor casts of the intrahepatic portal/hepatic vein branches than other cases without the expression (P = 0.0139). Disease‐free survival time tended to be shorter in cases with VEGF‐C expression in tumor casts of the portal/hepatic vein than in those without VEGF‐C expression (P = 0.053; log–rank test). Conclusions: VEGF‐C expression is related to the progression of HCC, and VEGF‐C expression in tumor casts of the intrahepatic portal/hepatic vein is considered to be a factor indicating recurrence/metastasis sites.     

Prognostic signif icance of HIF-2α/EPAS1 expression in hepatocellular carcinoma

AIM: To evaluate the prognostic signif icance of HIF- 2α/EPAS1 expression in hepatocellular carcinoma (HCC). METHODS: Surgical specimens from 315 patients with HCC as well as 196 adjacent noncancerous lesions and 22 cases of normal liver tissue were investigated by immunohistochemistry (IHC) for HIF-2α/EPAS1 using a standard detection system. Correlations with clinicopathological factors, VEGF, microvessel density (MVD), and prognosis were analyzed. RESULTS: Immunoreactivity of HIF-2α/EPAS1 was positive in 69.5% of HCC, 55.6% of adjacent noncancerous tissue, and 0% of normal liver tissue. And it was significantly correlated with tumor grade, venous invasion, intrahepatic metastasis, necrosis, and capsule infiltration. Correlation analysis of HIF-2α/EPAS1 with angiogenic factor VEGF (P < 0.001), and MVD (P = 0.016) was also noted. HIF-2α/EPAS1 protein was less frequently expressed in low MVD cases, whereas a high rate of expression was noted in cases with both medium and high MVD (P = 0.042). By Kaplan-Meier analysis, strong HIF-2α/EPAS1 staining (> 50% of tumor cells) in HCC correlated with a shortened survival in patients (Cox's regression, P < 0.001, r = 3.699). CONCLUSION: We conclude that HIF-2α/EPAS1 expression may play an important role in tumor progression and prognosis of HCC. Assessment of HIF-2α/EPAS1 expression in HCC may be used as a diagnostic tool and possibly a target in the treatment of HCC.     

肝细胞癌门静脉主干癌栓微血管形成和细胞增殖的关系

目的 研究肝细胞癌血管内皮生长因子（vascular endothelial growth factor,VEGF)、增殖细胞核抗原（proliferating cell nuclear antigen,PCNA)和微血管密度（micro-vessel density,MVD)的关系，及其对肝癌门静脉主干癌栓形成和转移的影响。方法 用原位杂交等技术检测16例肝癌PVTT（A1组）、其原发癌（A2组）和20例无转移肝癌（B组）VEGF、PCNA表达。结果 A1组、A2组VEGF mRNA和蛋白质阳性表达率均高于B组，A1组细胞平均吸光度高于A2组（t=8.83,P值均＜0．01）。B组、A2组、A1组PCNA阳性表达和MVD均呈升高趋势（P值均＜0．01）。A1组、A2组VEGF mNRA、蛋白质表达与MVD、增殖细胞核抗原标记指数（PCNA－LI）有良好相关性，r在0.65-0.95范围，P值均＜0．01。在A1、A2、B组MVD、PCNA－LI之间存在良好的相关性，r在0．78－0．97范围，P值均＜0．01。结论 VEGF过量表达是肝细胞癌微血管形成和癌细胞增生活跃的重要原因；丰富的微血管形成和癌细胞的快速生长是肝癌转移和门静脉主干癌栓形成的重要机制之一。     

Prognostic significance of HIF-2α/EPAS1 expression in hepatocellular carcinoma

AIM: To evaluate the prognostic significance of HIF-2α/EPAS1 expression in hepatocellular carcinoma(NCC).METHODS: Surgical specimens from 315 patients with HCC as well as 196 adjacent noncancerous lesions and 22 cases of normal liver tissue were investigated by immunohistochemistry (IHC) for HIF-2α/EPAS1 using a standard detection system. Correlations with clinicopathological factors, VEGF, microvessel density(MVD), and prognosis were analyzed.RESULTS: Immunoreactivity of HIF-2α/EPAS1 was positive in 69.5% of HCC, 55.6% of adjacent noncancerous tissue, and 0% of normal liver tissue. And it was significantly correlated with tumor grade, venous invasion, intrahepatic metastasis, necrosis, and capsule infiltration. Correlation analysis of HIF-2α/EPAS1 with angiogenic factor VEGF (P＜0.001), and MVD (P =0.016) was also noted. HIF-2α/EPAS1 protein was less frequently expressed in low MVD cases, whereas a high rate of expression was noted in cases with both medium and high MVD (P=0.042). By Kaplan-Meier analysis,strong HIF-2α/EPAS1 staining (＞ 50% of tumor cells) in HCC correlated with a shortened survival in patients (Cox's regression, P＜0.001, r= 3.699).CONCLUSION: We conclude that HIF-2α/EPAS1 expression may play an important role in tumor progression and prognosis of HCC. Assessment of HIF-2α/EPAS1 expression in HCC may be used as a diagnostic tool and possibly a target in the treatment of HCC.     

Clinicopathological significance of expression of paxillin, syndecan-1 and EMMPRIN in hepatocellular carcinoma

AIM: To evaluate the relationship of expression of paxillin, syndecan-1 and EMMPRIN proteins with clinicopathological features in hepatocellular carcinoma (HCC). METHODS: Fifty-one patients who underwent HCC resection were recruited in the study. Paxillin, syndecan-1 and EMMPRIN proteins in HCC tissues were detected with immunohistochemical staining. RESULTS: Of 51 cases of HCC, 23 (45%) exhibited paxillin protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 24 (57%) exhibited positive expression. Positive paxillin protein expression was associated with low differentiation (r= 0.406, P= 0.004), with the presence of portal vein thrombosis (r = 0.325, P = 0.021), with extra-hepatic metastasis (r=0.346, P=0.014). Of 51 cases of HCC, 28 (55%) exhibited syndecan-1 protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 23 (55%) exhibited positive expression. Positive snydecan-1 protein expression was associated with well differentiation (r=0.491, P=0.001), with no extra-hepatic metastasis (r=0.346, P=0.014). Of 51 cases of HCC, 28 (55%) exhibited EMMPRIN protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 21 (50%) exhibited positive expression. Expression of EMMPRIN protein was not associated with serum AFP level, HBsAg status, presence of microsatellite nodule, tumor size, presence of cirrhosis and necrosis, differentiation, presence of portal vein thrombosis, extra-hepatic metastasis, disease-free survival and overall survival (P>0.05). Expression of paxillin protein was correlated conversely with the expression of syndecan-1 protein in HCC (r = -0.366, P = 0.010). CONCLUSION: Expression of paxillin and syndecan-1 proteins in HCC may affect its invasive and metastatic ability of the tumor. There may be a converse correlation between the expression of paxillin and syndecan-1 protein in HCC. Expression of EMMPRIN protein may be detected in HCC, but it may play little role in the invasion and metastasis of HCC.     

The role of des-gamma-carboxyprothrombin expression in hepatocellular carcinoma

BACKGROUND/AIMS: Des-gamma-carboxyprothrombin (DCP), is a well-known tumor marker of hepatocellular carcinoma (HCC). On the other hand, some reports suggest that tissue expression of DCP is more useful as a prognostic factor than the serum DCP value. The aim of this study is to clarify the clinicopathological role of expression of DCP on HCC, especially when there is a low serum level of DCP. METHODOLOGY: Fifty-one patients with HCC who underwent curative hepatectomy were included in this study. Immunohistochemical staining was performed using anti-DCP monoclonal antibody, which was classified into 2 groups (strong and weak) by a pathologist. The immunohistochemical expression of tumor microvessel density (MVD) was evaluated using CD34 monoclonal antibody, and counted with specific staining of the capillary-like vessels in the tumor. The clinicopathological variables were compared between the strong and weak-staining groups. RESULTS: A strong DCP expression was recognized in 31 patients. DCP expression was associated with tumor size (p < 0.05) and portal vein infiltration (p < 0.01). In addition, serum DCP levels and alpha-fetoprotein levels tended to be higher in the strong group. In 16 patients whose serum DCP level was < 200mAU/ml, the recurrence-free survival rate was significantly lower in the strong group. No correlation was observed between DCP expression and MVD. CONCLUSIONS: DCP expression in HCC is useful for the prediction of early recurrence in patients with a low serum DCP level.     

Pathological observations of sinusoid lining endothelial cells and the basement membrane in human hepatocellular carcinoma

OBJECTIVE : To observe changes in sinusoid lining endothelial cells (SEC), type IV collagen (CoIV) and laminin (LM) in chronic liver disease and hepatocellular carcinoma (HCC). To assess the clinicopathological significance of these changes in HCC. METHODS : Thirty specimens were taken from 30 cases of HCC (together with corresponding non‐cancerous tissues), 10 cases of liver cirrhosis, five cases of mild chronic hepatitis and and four cases of normal liver tissues. The specimens were tested for CD34, CoIV and LM by using immunohistochemical methods. CD34, CoIV and LM were semiquantitatively analyzed and assessed in the context of the clinical and pathological features of HCC. RESULTS : CD34 and LM were not present along the sinusoidal walls in normal human liver, however, CoIV was weakly and discontinuously distributed along the sinusoidal walls. In cirrhosis, positive expression of CoIV increased significantly in the sinusoidal walls and became continuous and homogeneous. CD34 and LM were weakly present in the perinodules in a few cases of cirrhosis with obvious inflammatory infiltration. Hepatocellular carcinoma showed a diffuse capillarization, with overexpression of CD34, CoIV and LM. CoIV and LM expression were reduced in poorly differentiated HCC and HCC with portal vein thrombosis. This was frequently accompanied by breaks and losses in the basement membrane. The expression of CD34 in tumors of < 2 cm in diameter was significantly lower than that in tumors of > 5 cm in diameter. The expression of CD34 and LM was markedly increased in HCC compared with non‐cancerous liver tissues. CONCLUSIONS : Diffuse capillarization with overexpression of CD34, CoIV and LM are features of HCC. Frequent breaks in, loss of and decrease of the basement membrane in poorly differentiated tumors and tumors with portal vein infiltration suggests potential metastasis of tumor cells and may play a major role in the metastasis of HCC. CD34 is a useful marker for distinguishing HCC from non‐cancerous liver tissues.