大肠癌中VEGF和PTEN的表达及意义

目的探讨VEGF和PTEN蛋白在大肠癌中的表达情况以及临床病理意义。方法采用免疫组织化学方法检测95例大肠癌、20例正常大肠组织中VEGF和PTEN蛋白的表达情况。结果 95例大肠癌组织中VEGF和PTEN蛋白阳性表达率分别为67.4%和30.5%。大肠癌组织中VEGF表达阳性率显著高于正常大肠组织对照组（χ2=15.34,P〈0.01）,而PTEN表达阳性率显著低于正常大肠组织对照组（χ2=32.61,P〈0.01）。VEGF高表达和PTEN蛋白低表达与大肠癌的浸润深度、淋巴结转移及Dukes分期密切相关,而与肿瘤的位置、组织学分级、患者年龄和性别无关。大肠癌组织中VEGF与PTEN表达呈负相关（χ2=13.76,P〈0.01）。结论在大肠癌组织中VEGF的高表达与PTEN的低表达与大肠癌的发生、发展、浸润转移密切相关,检测VEGF和PTEN蛋白表达可作为评价大肠癌生物学行为及判断预后的参考指标,具有一定的临床意义。     

血清肿瘤标志物YKL-40与乳腺癌预后关系的研究

目的：探讨血清YKL-40水平与乳腺癌预后相关因素的关系。方法：采用酶联免疫吸附试验测定乳腺癌患者（实验组）及健康者（对照组）各40例的血清YKL-40水平,比较YKL-40水平在不同年龄、肿瘤直径、淋巴结转移、病理类型及TNM分期患者间的差异。结果：乳腺癌患者血清YKL-40水平明显高于健康对照组（P〈0.05）。肿瘤直径〉2 cm患者YKL-40水平明显高于直径≤2 cm组患者（P〈0.01）。淋巴结转移阳性患者血清YKL-40水平明显高于淋巴结转移阴性患者（P〈0.05）。随着肿瘤TNM分期进展,血清YKL-40水平逐渐升高（P〈0.01）。不同年龄及病理类型患者间血清YKL-40水平无明显差异。结论：血清YKL-40水平与乳腺癌预后相关,可望成为乳腺癌新的肿瘤标志物及治疗靶点。     

术前区域动脉灌注化疗对大肠癌患者血清血管内皮生长因子和内皮抑素的影响

目的研究术前区域动脉灌注化疗（PRAC）后大肠癌患者血清血管内皮生长因子（s—VEGF）、血清内皮抑素（s—endostatin）的变化。方法以酶联免疫吸附试验（ELISA）法检测22例大肠癌患者手术前后s—VEGF和s—endostatin的水平。结果大肠癌患者化疗前s—VEGF、s—endostatin水平与Dukes分期显著相关（P〈0．01）。在根治性手术组患者中，化疗前s-VEGF、s-endostatin水平明显高于化疗后7d、术后1d和术后14d（P〈0．05）。姑息性手术组仅有化疗前s-endostatin水平明显高于术后1d（P〈0．05）。结论PRAC可能通过抑制肿瘤血管生成而具有抗肿瘤作用；而化疗后s-endostatin的水平下降，提示联合应用化疗药物和抗血管生成制剂可能获得更好的抗肿瘤效果。     

25 大肠癌p27kip1，Skp2蛋白表达及临床意义

为探讨p27kip1和Skp2在正常大肠黏膜、大肠腺瘤、大肠癌之间的表达差异及其表达与大肠癌临床病理特征的关系,笔者采用免疫组化S P法检测15例正常大肠黏膜、15例大肠腺瘤、50例结直肠癌组织中p27kip1和Skp2的表达情况。结果示,（1）p27kip1在大肠癌组织中的表达明显低于大肠黏膜、大肠腺瘤组（P<0.05），在各病理分化程度的大肠癌组织中表达无明显差异（P>0.05），在有淋巴结转移的大肠癌组织中p27kip1表达明显低于无淋巴结转移组（P< 0.05），DukesC，D期大肠癌组织中p27kip1表达明显低于DukesA，B期大肠癌组织（P< 0.05）;（2）Skp2在大肠癌组织中的表达明显高于正常大肠黏膜、大肠腺瘤组（P< 0.05），在低分化大肠癌组织中的表达明显高于高分化大肠癌组织（P< 0.05），在有无淋巴结转移大肠癌组织中，在DukesA，B期及C，D期大肠癌组织表达均无明显差异（P> 0.05）;（3）在大肠癌中p27kip1与Skp2表达呈显著负相关(r＝－0.470，P<0.01)。 提示 (1) p27kip1的低表达与大肠癌淋巴结转移、Dukes分期有关，p27kip1低表达可能合并淋巴结转移或高Dukes分期。 (2) 在大肠癌组织中Skp2与p27kip1的表达呈负相关。     

大肠癌组织中LYVE-1、HIF-1α和VEGF的表达及其临床意义

为探讨淋巴管内皮细胞透明质酸受体1（LYVE-1）、缺氧诱导因子-1α（HIF-1α）和血管内皮生长因子（VEGF）在大肠癌组织中的表达及其与大肠癌临床病理特征的关系,本研究应用免疫组化法检测78例大肠癌组织中LYVE-1、HIF-1α和VEGF蛋白的表达,并与38例正常大肠组织进行比较。结果显示,LYVE-1、HIF-1α和VEGF在大肠癌组织中的表达率分别为64．10％、56．41％和61．54％,均明显高于正常对照组21．05％、0和31．57％（P〈0．05）。三者表达与大肠癌患者性别、年龄、肿瘤大小、分化程度、远处转移均无关（P〉0．05）,与淋巴结是否转移和Dukes分期有关（P〈O．05）。HIF-1α与LYVE-1和VEGF均显著相关（P〈0．01）。结果表明,LYVE-1、HIF-1α及VEGF在肿瘤淋巴管、血管生成和转移过程中起重要作用,联合检测LYVE-1、HIF-1α和VEGF可作为判断大肠癌转移和预后的重要指标。     

胰腺癌组织中血管内皮生长因子和肿瘤相关巨噬细胞与淋巴结转移的关系

目的研究胰腺癌组织中血管内皮生长因子（vascular endothelial growth factor,VEGF）表达和肿瘤相关巨噬细胞（tumour-associated macrophages,TAMs）计数与淋巴结转移的关系。方法采用免疫组织化学染色,在光镜下对VEGF阳性细胞评分及TAMs计数进行分析。结果胰腺癌组织中VEGF表达阳性率明显高于正常组织（P〈0.01）;淋巴结转移组VEGF的表达和TAMs计数较未转移组明显增高（P〈0.05）;VEGF的表达与胰腺癌临床病理分期无明显关系（P〉0.05）;TAMs计数与胰腺癌临床病理分期有明显关系（P〈0.01）;VEGF的表达与TAMs计数呈正相关（r=0.663,P〈0.01）。结论VEGF和TAMs的表达均与胰腺癌淋巴结转移有密切关系。     

大肠癌组织中促红细胞生成素受体表达与微血管密度的关系

目的：探讨大肠癌组织中促红细胞生成素受体（erythropoietin receptors,Epo-R）表达与肿瘤微血管密度（microvessel density,MVD）和临床病理特征的关系。方法：采用免疫组织化学SP法对60例大肠癌组织、20例正常大肠组织中Epo-R和MVD进行检测。结果：60例大肠癌组织均检测到Epo-R的表达。大肠癌组织MVD值为30.8±9.5,显著高于正常大肠组织的4.1±2.5（P〈0.01）。MVD水平与大肠癌患者年龄、肿瘤浸润深度、淋巴结转移、远处转移、临床分期有显著相关性（P〈0.05）。Epo-R表达与大肠癌组织MVD成正相关。结论：Epo-R在大肠癌组织中有异常高表达,且与MVD和临床病理特征成正相关,可能在肿瘤新生血管形成中有重要作用。     

大肠癌中VEGF-C分泌水平的检测及其意义

目的 检测大肠癌患者血清及不同的细胞系中血管内皮生长因子C（VEGF-C）和血管生长因子（VEGF）的分泌水平，评估其在诊断大肠癌淋巴结转移中的意义。方法 采用酶联免疫法检测66例大肠癌（观察组）和30例健康者（对照组）血清中及4株大肠癌细胞系培养液中VEGF-C和VEGF的分泌的水平。结果 观察组血清VEGF-C和VEGF均高于对照组（P〈0．01）；有淋巴结转移组的血清VEGF-C和VEGF均高于无淋巴结转移组（P〈0．01）；有淋巴管和／或血管浸润组上述两指标均高于无浸润组（P〈0．01）。血清VEGF-C水平在1438．0pg／mL以上者其灵敏度为81．0％。特异性为76．0％；血清VEGF水平在240．2pg／mL以上者其灵敏度为72．0％，特异性为74．0％。联合检测VEGF-C和VEGF对淋巴结转移阳性率的预测价值达84．6％，阴性预测价值达94．4％，精确度达93．7％。LoVo及LOVo-5FU培养液中VEGF-C分泌水平明显升高（P〈0．01）。结论 检测VEGF-C为判断大肠癌患者淋巴结是否转移可能提供新的诊断依据。VEGF-C可望成为治疗大肠癌淋巴道转移的新靶点。     

膀胱移行细胞癌患者血清骨形成蛋白-2和血管内皮生长因子水平变化

目的：检测骨形成蛋白-2和血管内皮生长因子水平在膀胱移行细胞癌患者血清中的水平。方法：采用ELISA法检测20例健康人、58例膀胱移行细胞癌患者术前的血清BMP-2和VEGF的含量,评价二者在膀胱移行细胞癌发生发展中的意义。结果：膀胱移行细胞癌患者血清中BMP-2和VEGF的水平明显高于健康人,并与肿瘤的浸润深度和分化程度及淋巴结转移、远处转移和临床病理分期密切相关（P〈0.05）,且两者存在明显相关性（P〈0.05）。结论：检测膀胱移行细胞癌患者血清中VEGF、BMP-2的水平,有助于临床诊疗和预后评估。     

脂联素、CEA及CA19—9在结直肠癌患者血清中的表达及其意义

通过研究脂联素、CEA及CA19—9在结直肠腺瘤和结直肠癌患者血清中的表达变化及其与临床病理指标的关系,以探讨其在结直肠癌发生、发展和转移中的作用。采用电化学发光法及酶联免疫法分别检测30例结直肠腺瘤患者（A组）和54例结直肠癌患者（B组）血清中脂联素、CEA及CA19—9的含量,对结直肠癌不同临床病理特征下的血清脂联素、CEA及CA19—9水平差异进行统计分析。结果显示,B组血清脂联素水平为（998．28±78．33）pg／ml明显低于A组（1529．59±81．79）pg／ml（P〈0．05）。B组随着肿瘤Dukes分期进展,血清脂联素水平呈现进一步下降的趋势（P〈0．05）,与肿瘤的发病部位、分化程度及有无淋巴结转移的血清脂联素水平无明显差异（P〉0．05）。A组血清CEA、CA19-9的水平明显低于B组（P〈0．05）。结果表明,结直肠癌患者血清的脂联素水平明显低于结直肠腺瘤患者,且随着肿瘤分期进展,血清脂联素水平呈现进一步下降的趋势。     

Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma

BACKGROUND: Vascular endothelial growth factor (VEGF) and endostatin stimulate and inhibit tumour angiogenesis respectively. Recent studies have demonstrated the prognostic value of serum levels of both VEGF and endostatin in patients with various types of cancer. Their significance in patients with hepatocellular carcinoma (HCC) remains unclear. METHODS: Serum VEGF and endostatin levels were measured by enzyme immunoassay in 108 patients with HCC before surgical resection and in 20 healthy controls. Preoperative serum VEGF and endostatin levels were correlated with clinicopathological features and long-term survival. RESULTS: Serum VEGF levels in patients with HCC were significantly higher than those in controls, but serum levels of endostatin were similar in the two groups. High serum levels of VEGF, but not endostatin, were significantly associated with venous invasion and advanced tumour stage. Patients with a serum VEGF level higher than median (over 245.0 pg/ml) had significantly worse overall and disease-free survival than those with a lower level (P = 0.012 and P = 0.022 respectively). On multivariate analysis, serum VEGF level was an independent prognostic factor (hazard ratio 1.86 (95 per cent confidence interval 1.10 to 3.92); P = 0.032). Serum endostatin levels did not have significant prognostic influence on overall or disease-free survival. CONCLUSION: A high serum level of VEGF is a predictor of poor outcome after resection of HCC. Serum VEGF, but not endostatin, may be a useful prognostic marker in patients with HCC.     

A prospective analysis of plasma endostatin levels in colorectal cancer patients with liver metastases

Background: Circulating inhibitors of angiogenesis have been suggested to affect the growth of distant micrometastatic disease in patients with cancer. This study was designed to evaluate circulating endostatin levels in colorectal cancer patients with liver metastases.Methods: Plasma samples from 30 colorectal cancer patients with liver metastases were analyzed for endostatin and vascular endothelial growth factor (VEGF) by using competitive enzyme immunoassays. Samples were compared with plasma from age- and sex-matched healthy controls; values >2 SD above the control mean were considered elevated.Results: Plasma endostatin levels were significantly higher in the 30 cancer patients than controls (P < .0001) and correlated with preoperative VEGF levels (P = .0008). Eighteen patients underwent surgical treatment (liver resection, n = 10; or isolated hepatic perfusion with melphalan, n = 8). Seventeen treated patients were available for follow-up. Eight of 11 patients who progressed had elevated plasma endostatin levels at the time of progression. None of six patients who remained progression free had elevated endostatin levels at last follow-up (P = .02).Conclusions: Plasma endostatin levels are elevated in colorectal cancer patients with liver metastases and correlate with VEGF levels. Elevated endostatin levels during follow-up are associated with disease progression. Understanding the role of endogenous endostatin in cancer patients may lead to novel strategies to inhibit tumor angiogenesis.     

Serum levels of vascular endothelial growth factor (VEGF) and endostatin in renal cell carcinoma patients compared to a control group

OBJECTIVES: Renal cell carcinoma (RCC) is a vascularised neoplasm. The importance of the angiogenic process in its growth and metastatic spreading is widely recognised. We assessed serum levels of endogenous endostatin and vascular endothelial growth factor (VEGF) in RCC patients and healthy volunteers, and evaluated the factors' prognostic role for patients' survival, distinguishing histologic subtypes with respect to correlation with tumour stage, grade, and size. METHODS: We considered 146 consecutive patients with RCC and 110 healthy volunteers. Serum samples from all subjects were analysed for endostatin and VEGF by using competitive enzyme immunoassays. RCC samples were compared with serum from the control group and with clinicopathologic factors and clinical outcome. RESULTS: Mean age was 63 years (range: 37-85 years) in RCC patients and 62 years (range: 23-88 years) in the control group. VEGF levels (median: 3.6 ng/ml+/-6.97; range: 0-48.4 ng/mL) were significantly higher in RCC patients, compared with controls (p=0.001). Endostatin levels did not differ significantly between the two groups (p=0.9) without correlation between endostatin and VEGF levels (p=0.09). No significant difference was found in the endostatin levels among the histologic subtypes (p=0.973) and VEGF (p=0.232). The median follow-up was 27 months (range: 1-57 months). CONCLUSIONS: Serum VEGF levels are elevated in RCC patients, compared with controls, and do not correlate significantly with circulating endostatin levels. No difference in preoperative serum VEGF and endostatin levels among the different histologic subtypes was found. In multivariate analysis VEGF and endostatin failed to be prognostic; only tumour stage and grade remained independent predictors of survival.     

大肠癌患者血清血管内皮生长因子和内皮抑素水平的变化

目的探讨大肠癌患者血清血管内皮生长因子(sVEGF)和血清内皮抑素水平。方法采用酶联免疫吸附试验检测48例大肠癌患者手术前、后和30例对照组的sVEGF、血清内皮抑素水平,分析二者的相关性及与临床病理分期的关系。结果大肠癌患者sVEGF和内皮抑素水平呈正相关关系(P<0.01);大肠癌患者sVEGF和内皮抑素水平均显著高于对照组(P<0.01);大肠癌患者sVEGF和内皮抑素水平与病理分期相关。结论大肠癌患者sVEGF和血清内皮抑素水平明显升高,二者可能共同调控肿瘤新生血管生成。     

Lowering homocysteine decreases levels and expression of VEGF(165) and endostatin

BACKGROUND: Homocysteine, vascular endothelial growth factor (VEGF), and endostatin have been implicated in angiogenesis and in the development and progression of atherothrombotic vascular disease. We sought to determine whether homocysteine modulates plasma levels of VEGF and endostatin and their expression in leukocytes in patients with peripheral arterial disease (PAD) or diabetes mellitus (DM). MATERIALS AND METHODS: Ten patients with PAD and 15 patients with type 2 DM were evaluated before and 6 wk after oral administration of folic acid and B vitamins. Evaluation included measurements of plasma levels of homocysteine, VEGF, and endostatin by enzyme-linked immunosorbent assay and the expression of VEGF and endostatin mRNAs in leukocytes using RT-PCR. The measurements were compared with baseline findings in 12 healthy subjects. RESULTS: Basal homocysteine (P < 0.001) and VEGF (P < 0.01) levels were elevated in all patients versus healthy subjects. Basal endostatin levels were lower in patients with PAD but were higher in patients with DM compared with healthy subjects (P < 0.001). In patients with PAD or DM, folic acid and B vitamins administration resulted in significant reduction (P < 0.001) of plasma levels of homocysteine (20.9% and 26.2%), VEGF (29.7% and 40.4%) and endostatin (9.4% and 5.7%), respectively. Moreover, VEGF and endostatin mRNA expression in leukocytes was down-regulated in all patients after B vitamins and folate treatment. CONCLUSION: These findings demonstrate that lowering of homocysteine with B vitamins and folic acid resulted in substantial reduction of plasma levels of VEGF but minimal reduction of endostatin and in down-regulation of their expression in leukocytes in patients with PAD or DM.     

Comparison of Angiogenic Factor Levels in Tumor Drainage and Peripheral Venous Blood From Colorectal Cancer Patients

Background The main objective of this study was to determine whether there was a correlation in the levels of various angiogenesis-related factors between the tumor drainage and peripheral venous blood and whether appraisal of angiogenic factor levels in the tumor drainage venous blood could provide better prognostic information for patients with colorectal cancer than assessment of the peripheral venous blood.Methods Plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and endostatin were measured and compared in both tumor drainage and peripheral venous blood from 52 patients with colorectal cancer. Plasma levels of angiogenesis-related factors were also correlated with tumor stage and clinical outcomes.Results The plasma endostatin level was significantly higher in peripheral blood than in tumor drainage venous blood (P < .001). The plasma VEGF level was significantly correlated with plasma endostatin levels (P = .028 in tumor drainage venous blood and P = .002 in peripheral venous blood). In both tumor drainage and peripheral venous blood, the VEGF level (but not the basic fibroblast growth factor or endostatin level) was significantly correlated with tumor stage and disease recurrence. However, in multivariate analysis, only plasma VEGF level in tumor drainage venous blood remained an independent predictor of disease recurrence.Conclusions The plasma VEGF level in tumor drainage venous blood provided better prognostic information than that in peripheral venous blood. The plasma endostatin level was paradoxically significantly higher in peripheral than in tumor drainage blood, and this strongly suggests additional sources of endostatin in peripheral blood.     

Clinical significance of preoperative serum vascular endothelial growth factor levels in patients with colorectal cancer and the effect of tumor surgery

BACKGROUND: Vascular endothelial growth factor (VEGF) is an angiogenic cytokine involved in the progression of solid tumors. In this study we evaluated the clinical usefulness of preoperative serum VEGF concentrations in patients with colorectal cancer. The changes in serum VEGF levels after tumor surgery were also evaluated. METHODS: Serum VEGF levels were determined by an enzyme-linked immunosorbent assay in the sera of 61 healthy control subjects and 67 patients with colorectal cancer preoperatively and 7 and 30 days after surgery. RESULTS: Serum VEGF levels in patients with colorectal cancer (median, 492 pg/mL; interquartile range, 281 to 737 pg/mL) were higher (P <.0001) than in control subjects (median, 186 pg/mL; interquartile range, 100 to 273 pg/mL). There was a significant association between serum VEGF levels and disease stage, invasion depth of the tumor, the presence of lymph node and distant metastases, and the degree of differentiation. Curative but not palliative resection of the primary tumor resulted in a significant decrease of preoperative serum VEGF levels but normalized in only 72% of patients. Failure of a return of VEGF to normal after resection for cure was associated with an increased although not statistically significant risk of metastasis during follow-up. Univariate analysis showed a lower survival rate for patients with increased preoperative serum VEGF levels (P <.002). Multivariate regression analysis showed that the prognostic value of serum VEGF level was not independent of tumor stage. CONCLUSIONS: These findings suggest that VEGF plays an important role in tumor progression and the formation of distant metastases in colorectal cancer. It is at present unclear whether serial estimation of serum VEGF is clinically useful in the prediction of tumor relapse.     

Evaluation of peri-operative peripheral and renal venous levels of pro- and anti-angiogenic factors and their relevance in patients with renal cell carcinoma

OBJECTIVE: To evaluate peri-operative peripheral and renal venous plasma levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor type BB (PDGF-BB), transforming growth factor (TGF)-beta1, endostatin, and thrombospondin-1 (TSP-1) in relation to pathological variables and prognosis, as pro- and anti-angiogenic factors are important for tumour growth and treatment of patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: The study included 74 consecutive patients with sporadic RCC who had tumour nephrectomy. Peripheral venous blood was drawn 1 day before, immediately and 1, 3 and 5 days after surgery. Renal venous blood was collected in a subgroup of 33 patients during surgery. The variables were analysed using quantitative enzyme-linked immunoassay kits, and associated with pathological variables and disease-specific survival. RESULTS: Soon after surgery, peripheral venous VEGF, PDGF-BB and TGF-beta1 levels were decreased, whereas endostatin levels were significantly increased. Renal venous VEGF, PDGF-BB and TGF-beta1 levels were higher than in the general venous blood pool. Renal venous VEGF levels were correlated with tumour diameter and associated with grade and vascular invasion. After a mean follow-up of 30 months, higher peripheral preoperative, early peripheral postoperative and renal venous VEGF levels were associated with a poorer prognosis. However, in a multivariate analysis only Tumour-Node-Metastasis stage and Eastern Cooperative Oncology Group performance status were independent prognosticators of disease-specific survival. CONCLUSIONS: Circulating pro- and anti-angiogenic factors change early after nephrectomy. VEGF, PDGF-BB and TGF-beta1 are higher in the renal vein than in the general venous blood pool. Higher renal venous and peripheral levels of VEGF might be associated with a poorer prognosis.     

Raised plasma endostatin levels correlate inversely with breast cancer angiogenesis

BACKGROUND: Angiogenesis is essential for solid tumors, such as breast cancer, to grow. The effect of surgical removal of breast tumors on plasma endostatin and vascular endothelial growth factor (VEGF) levels was evaluated. Tumor tissues were analyzed for expression of Intratumoral microvessel density (IMVD) and endostatin. The effect of VEGF and endostatin in inducing apoptosis on human liver microvascular endothelial cells (HLMVEC) was investigated. MATERIALS AND METHODS: Plasma from healthy volunteers, patients with fibroadenomas and breast cancer patients were assayed for endostatin and VEGF via immunoassay, pre-operatively and four weeks post-operatively. Expression of endostatin in tumor tissue was determined by Western blotting. IMVD was assessed following immunohistochemical staining with anti-CD34 antibody. RESULTS: Plasma endostatin levels, in breast cancer patients, were significantly elevated (P = 0.015) in the post-operative (60.59 +/- 7.70 etag/ml) compared with the pre-operative group (30.62 +/- 4.54 etag/ml) and with normal age-matched controls (34.97 +/- 3.76 etag/ml). In patients with high pre-operative plasma endostatin value, IMVD was decreased to 20.1 +/- 3.2 counts compared with 41.9 +/- 5.4 counts in those with low pre-operative endostatin value (P = 0.006). Neither plasma endostatin nor VEGF levels correlated with routine clinico-pathological parameters. Endostatin induced endothelial cell apoptosis and modulated the cytoprotective effect of VEGF in HLMVEC survival. CONCLUSIONS: Plasma endostatin levels are increased in patients following surgical removal of the primary tumor. The decreased IMVD seen in patients with higher endostatin levels may be due to the apoptosis-inducing effect of endostatin on microvascular endothelial cells.