Ki-67、VEGF在胃肠间质瘤中表达及与MVD的相关性

目的:探讨Ki-67和VEGF在胃肠间质瘤中的表达及与临床病理因素的关系,VEGF、微血管密度(MVD)和细胞增殖之间的相关性。方法:采用免疫组化S-P法检测44例胃肠间质瘤组织中Ki-67、VEGF表达及计数MVD值和Ki-67PI。结果:VEGF、Ki-67在GIST组织中阳性表达分别为77.3%、63.6%,VEGF、Ki-67表达在不同大小的肿块之间有统计学差异(P<0.01);MVD值和Ki-67PI在VEGF阳性和阴性组的比较有统计学差异(P<0.01);VEGF、MVD和Ki-67PI之间呈显著正相关(相关系数分别为0.26、0.44和0.84,P<0.01)。结论:VEGF促进GIST组织中的新生血管形成,为肿瘤组织提供了丰富的血液和营养,并使细胞增殖活性增强,促进肿瘤细胞的增殖、肿瘤的生长、发展和转移;Ki-67PI为GIST的预后判断提供了比较客观的依据。     

GaIectin-3 VEGF Ki-67 MVD在青年乳腺癌淋巴结转移灶中的表达及意义

目的：探讨青年乳腺癌淋巴结转移灶Galectin-3、VEGF、Ki-67、MVD的表达及意义。方法：应用免疫组化SP法检测35例青年乳腺癌淋巴结转移灶（青年组）和35例其它年龄组乳腺癌淋巴结转移灶（对照组）Galectin-3、VEGF、Ki-67、MVD的表达情况。结果：Galectin-3在青年组的表达水平明显高于对照组（P〈O．01），而VEGF的表达水平在两组之间无明显差异（P〉0．05）；青年组Ki-67和MVD明显高于对照组，差异有极显著性（P〈0．01和P〈0．01）。Galectin-3表达与Ki-67和MVD呈显著正相关（P〈0．01和P〈0．01）。结论：Galectin-3可能参与了瘤细胞的增殖和血管形成；青年乳腺癌淋巴结转移灶的癌细胞有更强的增殖、浸润和血管形成能力，这是青年乳腺癌恶性度高，预后差的重要因素。     

宫颈癌组织中Endoglin和VEGF表达与血管生成和癌细胞增殖及侵袭转移的关系

目的：探讨Endoglin和血管内皮生长因子（VEGF）在宫颈癌组织中的表达及意义。方法：采用免疫组织化学SP法检测75例宫颈癌（ICC）、18例宫颈上皮内瘤变（CIN）和15例正常宫颈上皮（NCE）组织中Endoglin和VEGF的表达情况，并检测其中微血管密度（MVD）（CD34标记）和Ki-67表达。结果：从NCE到CIN再到ICC，Endoglin和VEGF的阳性率显著升高，P〈0.05。Endoglin和VEGF在ICC组织中表达均与MVD显著正相关，P=0.000。Endoglin在ICC组织中表达与间质浸润深度和Ki-67表达有关，P〈0.05。ICC突破深肌层间质浸润和Ki-67高度表达者，其Endoglin阳性率分别显著高于未突破深肌层间质浸润和Ki-67表达在中度以内者，P〈0.05。VEGF在ICC组织中表达与盆腔淋巴结转移、脉管浸润、组织学分级及Ki-67表达有关，P〈0，05。ICC伴有盆腔淋巴结转移、脉管浸润、组织学分级为Ⅲ级及Ki-67高度表达者，其VEGF阳性率分别显著高于无盆腔淋巴结转移、无脉管浸润、组织学分级在Ⅱ级以内及Ki-67表达在中度以内者，P〈0.05。Endoglin在ICC组织中表达与VEGF显著正相关，P=0.021。宫颈癌Endoglin和VEGF均阳性表达者，其Ki-67高度表达率及MVD均显著高于两者均阴性表达者，P〈0.05。结论：宫颈癌组织Endoglin和VEGF均过度表达，其血管生成显著增加，癌细胞增殖活跃，更易发生侵袭转移。     

肝癌组织中Ki-67表达水平及微血管密度与患者年龄的相关性

目的探讨原发性肝癌中Ki-67表达水平及微血管密度（MVD）与患者年龄的相关性。方法应用免疫组织化学法检测肝癌切除标本癌组织Ki-67表达水平及MVD,并分析其与年龄的相关性。结果48例肝癌组织中Ki-67有程度不同的表达,阳性率为83．3％（40／45）,在相应的癌旁组织中Ki-67无表达（P〈0．01）。在癌组织及癌旁组织CD34标记的MVD分别为32．17±8．06、10．83±2．85,癌组织的MVD要高于癌旁组织（P〈0．01）。肝癌组织中年龄与Ki．67表达水平及MVD均呈负相关（r=-0．418,P：0．003;r=-0．443,P=0．002）。结论肝癌组织中Ki-67表达水平及MVD与患者年龄呈负相关,提示年轻的肝癌患者可能预后更差。     

膀胱移行细胞癌的CT表现与Ki-67、VEGF和MVD表达的相关性

[目的]探讨膀胱移行细胞癌（BTCC）的CT表现与Ki-67、血管内皮生长因子（VEGF）和微血管密度（MVD）表达的关系。[方法]对41例经手术病理证实的BTCC，采用LDP免疫组化法，检测肿瘤标本中Ki-67、VEGF和MVD的表达，并分析其与术前CT征象的关系。[结果]Ki-67LI与VEGF、Ki-67LI与MVD、VEGF与MVD呈显著性正相关（r值分别为0．548、0．603、0．705，P均〈0．001）。Ki-67LI、VEGF和MVD表达与肿瘤呈分叶状、肿瘤多发、膀胱壁增厚、浆膜受侵、邻近器官受累等CT征象均有关（P〈0．05）。[结论]BTCC的CT征象与Ki-67LI、VEGF和MVD表达密切相关，当肿瘤有分叶征、肿瘤多发、相邻膀胱壁增厚、浆膜层受侵、邻近器官受累等CT征象时，提示肿瘤可能有较高的恶性程度、浸润能力及较差的预后。     

Ki-67和微血管密度在膀胱移行细胞癌中的表达及其相互关系

目的：探讨Ki-67抗原和微血管密度（MVD）在膀胱移行细胞癌中的表达及临床意义，并评价两者的相互关系。方法：利用鼠抗人Ki-67抗原单克隆抗体和鼠抗人FⅧ因子相关抗原（FⅧRAg）单克隆抗体对65例膀胱移行细胞癌和8例正常膀胱黏膜进行免疫组化染色。结果：Ki-67与MVD在癌组织中表达均显著高于正常黏膜（P＜0．01）。肿瘤中Ki-67指数和MVD之间存在正相关性，两者的表达均与膀胱移行细胞癌的病理分级显著相关，Ⅰ级与Ⅱ级、Ⅲ级与Ⅳ级之间存在显著差异（P＜0．01）；浸润性肿瘤组高于表浅肿瘤组（P＜0．01）；术后2年随访复发组高于未复发组（P＜0．01）。MVD与肿瘤大小有关，肿瘤直径大于2cm组MVD高于肿瘤直径小于2cm组（P＜0．05）。结论：Ki-67的表达为膀胱移行细胞癌的恶性表型，且与膀胱肿瘤血管形成有关。Ki-67指数和MVD对评价膀胱移行细胞癌的生物学形为和预后判断具有重要意义。     

TL对人胰腺癌细胞裸鼠移植瘤的治疗作用及抑制血管生成的研究

目的：探讨雷公藤内酯醇（TL）对人胰腺癌细胞SW1990移植瘤的生长及新生血管生成的抑制作用。方法：通过人胰腺癌裸鼠皮下移植实验，观察不同剂量TL对移植瘤生长抑制作用；应用免疫组化和RT-PCR研究裸鼠移植瘤组织VEGF表达变化，计算肿瘤组织微血管密度（MVD）。结果：各实验组（TL0．125、0．25和0．5mg·^-1kg·day^-1）抑瘤率分别达到66．16％、78．14％和89．92％，与对照组相比，肿瘤生长明显受抑，并具有剂量和时间依赖性。对照组和各实验纽瘤组织MVD分别为36．25±8．64、22．75±6．67、17．65±7．11和9．87±3．34（P〈0．01）；TL抑制移植瘤VEGF基因和蛋白表达．且VEGF基因下调与MVD的减少具有相关性（r=0．7424，P〈0．01）．结论：TL具有显著的抗胰腺癌移植瘤作用．其机制可能与抑制肿瘤新生血管生成有关。     

75例胃肠间质瘤临床病理分析

对75例胃肠间质瘤（GIST）进行常规病理及免疫组化CD117、CD34、SNA、S-100、Ki-67等染色特点分析,胃肠间质瘤由梭形细胞和上皮样细胞组成．其中66例CD117和56例CD34标记阳性,阳性表达率分别为88％和74．7％。胃肠间质瘤缺乏定向分化．CD117和CD34标记阳性对胃肠间质瘸的诊断具有重要价值．检测Ki-67对预测GIST恶性潜能非常有用,Ki-67标记阳性病例更具有复发的倾向。     

胃肠道间质瘤40例Ki-67、PCNA的表达及意义

目的：探讨Ki-67、PCNA的表达与胃肠道间质瘤（GIST）临床病理特征的关系。方法：应用免疫组化SP法检测40例胃肠道间质瘤中Ki-67、PCNA的表达。结果：40例胃肠道间质瘤中Ki-67、PCNA阳性表达率分别为60．0％、65．0％。Ki-67、PCNA表达与GIsT的性别、年龄、部位、组织学分型无关,与肿瘤大小、组织学分级有关。Ki-67、PCNA的表达呈正相关。结论：Ki-67、PCNA联合检测可作为判定GIST良恶性、恶性程度、肿瘤分级及预后的重要指标。     

PCNA和Ki-67在涎腺良、恶性多形性腺瘤中的表达及意义

目的：研究涎腺良、恶性多形性腺瘤的临床病理特点,生物学行为及细胞增殖活性,为其临床诊断及预后评估提供依据。方法：对114例涎腺良、恶性多形性腺瘤进行回顾性分析,对其中20例多形性腺瘤、9例多形性腺瘤生长活跃型及9例恶性多形性腺瘤采用SABC和LSAB免疫组化法观察增殖细胞核抗原（PCNA）和增殖细胞核相关抗原（Ki-67）的表达和分布。结果：恶性多形性腺瘤的PCNA及Ki-67表达水平显著高于多形性腺瘤及多形性腺瘤生长活跃型,其PI值较后二者差异有显著性（P〈0．01）;良性多形性腺瘤的复发组PCNA和Ki-67的表达明显高于原发组,二者之间有显著性差异（P〈0．01）。结论：PCNA和Ki-67检测在判断多形性腺瘤恶性增殖方面有重要意义,对良性多形性腺瘤复发预测有重要的参考价值。     

肝细胞癌中血管内皮生长因子及其受体的表达与意义

目的 :探讨血管内皮生长因子(VEGF)和血管内皮生长因子受体 (VEGFRs)在肝细胞癌 (HCC)肿瘤血管生成中的调节作用。方法 :采用免疫组化法检测 3 9例 (男 3 4例 ,女 5例 )共 41个经手术病理证实的HCC病灶VEGF、Flt 1和KDR/Flk 1的蛋白表达。观察病灶肿瘤大小、包膜、子灶、门静脉癌栓、肝门淋巴结转移和肝硬化等。记录HCC患者的临床资料 ,如年龄、HBsAg、HBV和AFP情况。手术结果记录病灶大小、数目、肝硬化和包膜情况。病理结果记录病理分级、肝硬化等情况。结果 :在转移高危组、包膜欠完整和 (或 )无包膜组、小肝癌组中VEGF表达阳性率均高于转移低危组、包膜完整组和大肝癌组 ,差异有统计学意义 ,P <0 0 5。而VEGF的表达与Ed mondson分级、HBV、HBsAg、AFP水平以及肝硬化之间差异均无统计学意义 ,P >0 0 5。KDR/Flk 1表达阳性病灶 2 9个 ,阳性率为 70 73 %( 2 9/4 1) ;KDR/Flk 1在转移高危组、包膜欠完整和 (或 )无包膜组、小肝癌组中表达的阳性率也均高于转移低危组、包膜完整组和大肝癌组 ,差异有统计学意义 ,P <0 0 5。KDR/Flk 1蛋白的表达亦与Edmondson分级、HBV、HBsAg、AFP水平、肝硬化之间差异无统计学意义 ,P >0 0 5。Flt 1阳性病灶 2 8个 ,阳性率为 68 2 9% ( 2 8/4 1) ;Flt 1的表达与转移     

VEGF and myeloid leukemias

Vascular endothelial growth factor and vascular endothelial growth factor receptors participate in the growth and survival of myeloid leukemic progenitors. With the development of multiple anti-angiogenic agents, there is potential that some of these novel agents will have anti-leukemic activity. Since these agents work by mechanisms distinct from current cytotoxic chemotherapies, they may be useful both in chemoresistant leukemia patients and in combinations to improve remission rates and remission durations.     

Serum interleukin 6, plasma VEGF, serum VEGF, and VEGF platelet load in breast cancer patients

Serum and plasma concentrations of vascular endothelial growth factor (sVEGF and pVEGF), serum concentrations of interleukin 6 (IL-6), and VEGF platelet load (VEGF/pl) in the blood of healthy controls (n = 26), breast cancer patients with locoregional disease (n = 31), and patients with progressive advanced disease (n = 73) have been compared. The 95th percentile values for the control population were 250 pg/mL for sVEGF, 30 pg/mL for pVEGF, and 1.6 pg/mL for IL-6. The 95th percentile value of the calculated VEGF/pl was 1.0 pg/10(6) platelets in the control population. Serum VEGF concentrations correlated with platelet number in all the groups. Patients with thrombocytosis had a median sVEGF concentration of 833 pg/mL, compared to 249 pg/mL in other patients (P = 0.018). Serum IL-6 levels correlated with sVEGF levels and with the calculated VEGF/pl. Serum IL-6 concentration was significantly higher in patients with breast cancer compared to healthy controls (P < 0.0001). Median IL-6 serum levels were nearly 10 times higher in patients with metastatic breast cancer as compared to the those with locoregional disease (6.0 pg/mL versus 0.7 pg/mL, respectively). Plasma VEGF and the VEGF/pl were also significantly different in the 3 groups. The ratio between sVEGF and pVEGF tended to be smaller in the metastatic breast cancer group compared to the patients with locoregional disease (median, 7.5 versus 10.1, respectively; P = 0.066), suggestive of more intravasal platelet degranulation in the former group. Serum IL-6 level is the most discriminative factor separating healthy controls and the locoregional and metastatic breast cancer patient groups. These results suggest a role for tumor-derived IL-6 in regulating VEGF expression in platelets and their precursors and also confirm the role of circulating platelets in the storage of VEGF.     

Effect of VEGF and VEGF Trap on vascular endothelial cell signaling in tumors

Vascular endothelial growth factor (VEGF) A is a major promoter of tumor angiogenesis and a prime target of antiangiogenic cancer therapy. To examine whether endothelial cell signaling might provide histological biomarkers of angiogenesis and VEGF activity in vivo, normal mouse organs and multiple tumor models were studied immunohistochemically for endothelial expression of activated ERK, STAT3, and AKT. Phospho(p)-ERK and p-STAT3 expression was negligible in the endothelia of normal organs but was significantly elevated in tumor endothelium. p-AKT was present at significant and comparable levels in both tumor and normal endothelia. In K1735 tumors induced to express more VEGF, endothelial p-ERK, p-STAT3 and p-AKT increased accompanied by signs of accelerated angiogenesis. Treatment of K1735 and Colo-205 tumors with the VEGF inhibitor, VEGF Trap (aflibercept), decreased tumor endothelial p-ERK, p-STAT3 and p-AKT expression accompanied by signs of antiangiogenic effect. These results show that endothelial p-ERK and p-STAT3 (but not p-AKT) distinguish tumor from normal vessels and that the presence of these two signaling intermediates may be useful indicators of tumor angiogenic activity and angiogenesis inhibition by VEGF antagonist.     

Effect of VEGF and VEGF Trap on vascular endothelial cell signaling in tumors

Vascular endothelial growth factor (VEGF) A is a major promoter of tumor angiogenesis and a prime target of antiangiogenic cancer therapy. To examine whether endothelial cell signaling might provide histological biomarkers of angiogenesis and VEGF activity in vivo, normal mouse organs and multiple tumor models were studied immunohistochemically for endothelial expression of activated ERK, STAT3 and AKT. Phospho(p)-ERK and p-STAT3 expression was negligible in the endothelia of normal organs but was significantly elevated in tumor endothelium. p-AKT was present at significant and comparable levels in both tumor and normal endothelia. In K1735 tumors induced to express more VEGF, endothelial p-ERK, p-STAT3 and p-AKT increased accompanied by signs of accelerated angiogenesis. Treatment of K1735 and Colo-205 tumors with the VEGF inhibitor, VEGF Trap (aflibercept), decreased tumor endothelial p-ERK, p-STAT3 and p-AKT expression accompanied by signs of antiangiogenic effect. These results show that endothelial p-ERK and p-STAT3 (but not p-AKT) distinguish tumor from normal vessels and that the presence of these two signaling intermediates may be useful indicators of tumor angiogenic activity and angiogenesis inhibition by VEGF antagonists.Key words: VEGF, VEGF Trap, endothelial cells, signal transduction, angiogenesis, biomarker, p-ERK, p-STAT3, p-AKT     

Simultaneous targeting of VEGF message and VEGF receptor signaling as a therapeutic anticancer approach

BACKGROUND: Vascular endothelial growth factor (VEGF) is one of the most important factors involved in tumor angiogenesis. MATERIALS AND METHODS: Antisense phosphorothiolate oligodeoxynucleotides (PS-ODNs) were used to reduce VEGF production while the small molecule PD0203359-0002 (PD203359) was used to inhibit VEGF/bFGF receptor tyrosine kinase activity. RESULTS: PD203359 exposure was found to profoundly impair the growth of human endothelial cells (HMVEC-L) at doses 20-fold less than those affecting human renal cell carcinoma (Caki-1) cell growth. In vivo, treatment with PD203359 inhibited tumor cell-induced angiogenesis and resulted in a significant tumor growth delay. Treatment with VEGF antisense PS-ODNs also significantly increased the time for tumors to grow to five times the starting size. Most importantly, when the PD203359 and VEGF antisense treatments were combined, a greater antitumor response than could be achieved with either therapy alone was observed. CONCLUSION: Simultaneously targeting VEGF production and VEGF receptor signaling enhances the anticancer efficacy of either therapy alone.     

VEGF特异性核酶对Hela细胞VEGF表达的调节

目的：构建VEGF特异性发夹状核酶基因真核表达载体，观察其对Lela细胞VEGF表达的调节。方法：将核酶基因克隆入pcDNA3中，构建了抗VEGF发夹状核酶真核表达载体pcDNA3-RZ,并进行了核酶的体外切割活性检测。将真核表达载体转染人宫颈癌Hela细胞，采用RNA斑点杂交、流式细胞仪免疫荧光及免疫细胞化学方法，检测Hela细胞中VEGFmRNA和VEGF蛋白的表达水平。结果：所构建的重组表达载体pcDNA3-RZ正确，体外切割检测该核酶具有较高的切割活性。转染了pcDNA-RZ的Hela细胞中VEGFmRNA和VEGF蛋白的表达水平明显下降。结论：成功地构建了抗VEGF发夹状核酶基因真核表达载体，该载体能明显抑制Hela细胞VEGF的表达。     

乳腺癌血清VEGF水平与癌组织中VEGF和COX-2表达及微血管密度的关系

目的探讨乳腺癌患者血清血管内皮生长因子(sVEGF)水平与乳腺癌血管生成的关系。方法采用酶联免疫吸附试验(ELISA)检测68例乳腺癌、35例乳腺良性病变和20例健康女性的sVEGF水平,免疫组化S-P法检测相应乳腺癌组织中VEGF、环氧合酶-2(COX-2)及微血管密度(MVD)表达水平,并分析sVEGF水平与VEGF、COX-2及MVD表达的关系。结果(1)健康女性组、乳腺良性病变组和乳腺癌组sVEGF浓度中位数分别为105.93、150.82和306.51 pg/ml,乳腺癌组明显高于健康女性组。(2)乳腺癌组VEGF和COX-2表达阳性率分别为67.6%和44.1%,乳腺良性病变组VEGF和COX-2表达阳性率分别为42.9%和11.4%,两组间差异有统计学意义(P值分别为0.015和0.002)。(3)乳腺癌患者sVEGF水平与癌组织中VEGF、COX-2及MVD表达均呈正相关。(4)乳腺癌患者中,VEGF表达阳性组COX-2阳性率(65.21%)明显高于VEGF表达阴性组(18.18%); COX-2表达阳性组MVD(22.94±5.51)明显高于COX-2表达阴性组(10.30±4.42)。结论乳腺癌患者sVEGF水平明显增高于健康女性,并与癌组织中VEGF、COX-2及MVD表达呈正相关。