乙酰肝素酶在卵巢癌血管生成中的作用及姜黄素抑制卵巢癌微血管内皮细胞生长实验研究
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摘要
卵巢癌(ovarian carcinoma)发病率在妇科恶性肿瘤中仅次于宫颈癌,具有起病隐匿、早期不易发现、易转移、预后差等特点,其发生机制及治疗的探索一直是生物医学研究的热点。乙酰肝素酶是一种内糖苷酶,可降解细胞外基质(extracellular matrix,ECM)和基底膜(basement membrane,BM)中的硫酸乙酰肝素(heparin sulfate,HS),在恶性肿瘤细胞中乙酰肝素酶普遍存在,卵巢癌中乙酰肝素酶的表达及与患者临床特征的关系值得进一步探索。
     实体肿瘤的生长必须依赖持续和广泛的肿瘤血管生成,新生血管为肿瘤组织提供营养物质和氧气,又是肿瘤组织发生转移的重要途径。血管内皮细胞生长因子通过与3种选择性表达在血管内皮细胞上的高亲和力酪氨酸受体VEGFR-1(FLT-1)、VEGFR-2(FLK-1)及VEGFR-3(FLT-4)结合,引起一系列的信号传导,促进血管内皮细胞的增殖与迁移,最终引起新生血管形成,在肿瘤的发生、发展以及转移中发挥重要作用。
     RNAi技术是一种比较新的生物医学研究方法,将与信使RNA(messenger RNA,mRNA)对应的正义RNA(sense RNA)和反义RNA(anti-senseRNA)组成的双链RNA(double strand RNA,dsRNA)导入细胞,可以使mRNA发生特异性降解,导致相应基因的沉默,这种转录后基因沉默机制(post-transcriptional gene silencing,,PTGS)被称为RNA干扰(RNA interference,RNAi)。RNAi技术将被广泛应用到功能基因组学、基因治疗学、新药开发研究等众多领域。
     姜黄素有重要的经济价值和广泛的药理作用,如抗氧化、抗炎、抗动脉粥样硬化、降血脂等,是一种具有良好发展前景的抗癌药物,其抗肿瘤作用日益引起人们的重视,成为研究的热点。
     本研究拟观察乙酰肝素酶在卵巢癌血管生成中的作用及姜黄素对卵巢癌微血管内皮细胞生长的影响。本实验分四部分:第一,选择65例经病理确诊的卵巢癌患者,采用免疫组化方法检测癌组织中乙酰肝素酶、VEGF、VEGFR1和F8因子的表达情况,探寻乙酰肝素酶表达与卵巢癌临床病理特征及肿瘤血管生成的关系。第二,进行卵巢癌微血管内皮细胞原代培养,观测其细胞生物学特性,采用免疫荧光方法及RT-PCR方法检测卵巢癌微血管内皮细胞乙酰肝素酶表达情况。第三,进行卵巢癌微血管内皮细胞乙酰肝素酶表达的RNA干扰实验,检测卵巢癌微血管内皮细胞形态变化、细胞活性、乙酰肝素酶基因mRNA水平及蛋白表达,VEGF蛋白表达及血管内皮细胞增殖和凋亡的变化。第四,在卵巢癌微血管内皮细胞中加入不同剂量的姜黄素共培养,观察卵巢癌微血管内皮细胞存活率、细胞增殖率等变化,采用免疫荧光染色和RT-PCR法检测血管内皮细胞中乙酰肝素酶表达变化,探讨姜黄素对卵巢癌微血管内皮细胞的影响。
     主要结果及结论如下:
     第一部分:卵巢癌乙酰肝素酶表达特征及与血管生成关系研究
     1.12例正常卵巢组织中乙酰肝素酶无阳性表达,阳性率为0%,65例卵巢癌中乙酰肝素酶阳性51例,阳性率为78.5%,两组乙酰肝素酶表达差异非常显著。提示卵巢癌中乙酰肝素酶表达具有肿瘤特异性。
     2.＜50岁组27例中21例乙酰肝素酶表达阳性,阳性率为77.8%,≥50岁组38例中30例阳性,阳性率为78.9%,无显著性差异。浆液性囊腺癌30例中25例乙酰肝素酶表达阳性,阳性率为83.3%,粘液性囊腺癌21例中16例阳性,阳性率为76.2%,其他类型14例卵巢癌腺癌中10例阳性,阳性率为71.4%,差异不显著。提示卵巢癌乙酰肝素酶表达与卵巢癌组织类型及患者的年龄无相关性。
     3.早期卵巢癌组织12例中乙酰肝素酶阳性3例,晚期卵巢癌组织53例中乙酰肝素酶阳性48例,组间差异显著。高分化卵巢癌5例中乙酰肝素酶阳性表达1例,中分化卵巢癌15例中乙酰肝素酶阳性表达6例,低分化卵巢癌45例中乙酰肝素酶阳性表达44例,组间差异显著。提示卵巢癌乙酰肝素酶表达与卵巢癌病理分级有显著相关性,分化越低的卵巢癌,乙酰肝素酶表达越强;卵巢癌乙酰肝素酶表达与卵巢癌临床分期有显著相关性,晚期卵巢癌乙酰肝素酶表达强于早期卵巢癌。
     4.VEGF表达强度在卵巢癌患者不同年龄组中无显著区别,在卵巢癌不同组织学类型中无显著差异,临床晚期卵巢癌中VEGF表达强度高于早期卵巢癌,高中分化卵巢癌和低分化卵巢癌组VEGF表达强度显著不同,以低分化癌组表达为高。卵巢癌乙酰肝素酶表达强度变化与VEGF表达强度呈相同趋势,统计分析表明,卵巢癌VEGF表达强度与乙酰肝素酶表达强度呈正相关,相关系数为0.647。
     5.卵巢癌不同年龄组及不同组织学类型中VEGFR1表达强度无显著区别,临床晚期卵巢癌VEGFR1表达强度显著高于早期卵巢癌,低分化卵巢癌VEGFR1表达强度显著高于高中分化卵巢癌组。统计分析表明,卵巢癌VEGFR1表达强度与乙酰肝素酶表达强度呈正相关,相关系数为0.612。
     6.卵巢癌不同年龄组及不同组织学类型中MVD无显著区别,临床晚期卵巢癌MVD显著高于早期卵巢癌,低分化卵巢癌MVD显著高于高中分化卵巢癌。统计分析表明,卵巢癌MVD与VEGF、VEGFR1及乙酰肝素酶表达强度呈正相关,相关系数分别为0.754,0.713和0.669。提示乙酰肝素酶通过释放、激活VEGF来促进血管的生成,乙酰肝素酶和VEGF在卵巢癌新生血管生成过程中发挥协同的作用。
     第二部分:人卵巢癌微血管内皮细胞分离培养及乙酰肝素酶表达研究
     1.成功进行人卵巢癌微血管内皮细胞原代培养,细胞形态学观察见人卵巢癌微血管内皮细胞呈短梭形或多边形,细胞排列紧密,边界清晰。细胞活力测定人卵巢癌微血管内皮细胞活力为95%以上。卵巢癌微血管内皮细胞FⅧ因子免疫荧光化学检测,细胞胞浆为绿色荧光,证实为内皮细胞。为研究肿瘤血管新生机制及抗血管生成治疗提供了理想的体外实验模型。
     2.乙酰肝素酶表达免疫荧光染色见乙酰肝素酶主要表达于血管内皮细胞胞浆,胞核未见染色,OdMEC组乙酰肝素酶表达明显高于HUVEC组。RT-PCR检测结果可见OdMEC组乙酰肝素酶mRNA表达明显高于HUVEC组,提示乙酰肝素酶是OdMEC组内皮细胞区别于HUVEC组内皮细胞的主要生物学标志之一。
     第三部分:RNA干扰沉默乙酰肝素酶基因表达对卵巢癌微血管内皮细胞影响实验研究
     1.应用含绿色荧光蛋白的载体作对照转染,发现血管内皮细胞乙酰肝素酶siRNA转染效率可达到95%以上。提示乙酰肝素酶siRNA得到了高效转染。
     2.实验组以乙酰肝素酶siRNA转染血管内皮细胞,并于2、4、6、8d检测乙酰肝素酶表达,结果发现微血管内皮细胞乙酰肝素酶mRNA水平显著降低、蛋白水平显著降低(免疫荧光法、WB法)。提示乙酰肝素酶siRNA转染可显著抑制卵巢癌微血管内皮细胞乙酰肝素酶的转录及蛋白表达。
     3.乙酰肝素酶siRNA转染后血管内皮细胞VEGF的WB检测发现,实验组加入不同浓度SiRNA处理后,随着时间增加,VEGF表达降低,对照组无显著改变。提示乙酰肝素酶转录水平及蛋白表达受抑制后降低了VEGF的表达。
     4.MTT法检测细胞活力发现乙酰肝素酶siRNA转染后血管内皮细胞活力降低,随着时间增加,MTT检测吸光度值变化不大,而正常组和对照组随时间增加呈上升趋势。细胞增殖指数检测发现乙酰肝素酶siRNA转染后血管内皮细胞增殖指数显著下降。流式细胞仪检测发现乙酰肝素酶siRNA转染后血管内皮细胞凋亡指数显著上升。提示RNAi可有效沉默血管内皮细胞乙酰肝素酶表达,降低VEGF表达,抑制血管内皮细胞增殖,并诱导细胞凋亡,RNAi可能为肿瘤治疗提供新的途径。
     第四部分:姜黄素对卵巢癌微血管内皮细胞生物学特性及乙酰肝素酶表达的影响
     1.细胞形态观察见姜黄素组培养细胞增殖速度减慢,细胞生长密度减小,细胞出现皱缩,折光性减低,随姜黄素浓度增加可见细胞脱落、脱壁漂浮甚至破碎现象,72h可见细胞成大片脱落,有明显的时间和浓度依赖关系。提示姜黄素(2-250ug/ml)能显著抑制人卵巢癌微血管内皮细胞的活性,具有剂量和时间依赖性。
     2.细胞生长抑制率检测结果表明,姜黄素对卵巢癌血管内皮细胞抑制作用明显,与阴性对照比较差异显著,有显著的剂量依赖效应。姜黄素组对血管内皮细胞增殖指数影响检查可见姜黄素组细胞增殖指数显著下降,同时观察到G0/G1期前出现明显亚二倍体峰,即凋亡峰。提示姜黄素(2-250ug/ml)能显著抑制人卵巢癌微血管内皮细胞的增殖活性,降低增殖指数,具有剂量和时间依赖性。
     3.免疫荧光法检测内皮细胞乙酰肝素酶表达结果显示,姜黄素组内皮细胞乙酰肝素酶表达显著下降,有显著的剂量依赖抑制效应。提示姜黄素(2-250ug/ml)能显著降低人卵巢癌微血管内皮细胞乙酰肝素酶基因mRNA转录和蛋白的表达。
     4.细胞培养上清液MDA及LDH活力检测结果显示,姜黄素组细胞培养液上清LDH活性显著升高,MDA含量显著增加。提示高浓度姜黄素具有显著的细胞损伤效应。
Background and Aims
     The incidence of ovarian cancer is the second in the malignant tumor of department of gynecology,just next to uterine cervix cancer.It has some characteriscs such as earlier occurrence and metastasis.The development mechanisms and therapeutic study is the topic of biomedicine investigation.Heparanase is a kind of glucosidase,which can degrade heparin sulfate in extracellular matrix and basement membrane.Heparanase exist in malignant tumor widespreadly.The expression of heparanase in ovarian cancer and the relationship with clinical characteriscs of patients need more study.
     The growth of tumor depended on the persistence and extensive angiogenesis of tumor. New vessels not only provide tumor for nutrient substance and oxygen,but also is the important pathway of tumor metastasis.Vascular endothelial cell growth factor(VEGF) bind with receptorVEGFR-1,VEGFR-2 and VEGFR-3 on the cell membrane.The binding cause a serial signal conduction,which promote the proliferation and migration of vascular endothelial cell and neovascularization.VEGF play an important role in the occurrence, development and metastasis of tumor.
     RNAi technology is a new biomedical research method.Double strand RNA(dsRNA) consists of sense RNA and anti-senseRNA corresponding to messenger RNA(mRNA).The mRNA was degraded after double strand RNA imported into cells.The result is the gene silenced.This technology is called RNA interference.RNAi technology will be used in functional gene study,gene therapy and new drug research widespreadly.
     Curcumine has significant economic value and extensive pharmacological action,such as antioxygen,anti-inflammatory,anti-artherosclerosis and degradation of blood fat. Curcumine is an anticancer drug.More attention was paid to its anti-tumor effect.
     The aim of this research is to observe the role of heparanase in the angiogenesis of ovarian cancer and the effect of curcumine on the growth of blood vessel endothelium cell from ovarian cancer.The study was divided into four parts.
     In the 1~(st) part,65 cases of ovarian cancer were included into the experiment. Immunohistochemistry staining was used to detect the expression of heparanase,VEGF, VEGFR1 and Factor 8 of ovarian cancer.The relationship of heparanase with ovarian cancer clinical pathological characteristics and with the tumor angiogenesis was investigated.
     In the 2~(nd) part,the blood vessel endothelium cell from ovarian cancer was primary cultured.The cell bionomics was observed.Immunofluorescence method and RT-PCR method were used to detect the heparanase expression in blood vessel endothelium cell from ovarian cancer.
     In the 3~(rd) part,the RNAi experiment of heparanase expression in the blood vessel endothelium cell from ovarian cancer was performed.The cell activity,heparanase mRNA level and protein expression,VEGF expression,cell proliferation and apoptosis were detected.
     In the 4~(th) part,curcumine of different dose was added to the the blood vessel endothelium cell from ovarian cancer.The cell survival rate,cell proliferation were observed.Immunofluorescence and RT-PCR were used to detect heparanase expression.
     The main results and conclusions were summarized as follows:
     The 1~(st) part:expression characteristic of heparanase in ovarian cancer and the relationship with angiogenesis
     1.In the 12 cases of normal ovary,heparanase expression was not observed.The poaitive rate was 0%.In the 65 cases of ovarian cancer,heparanase was positive in 51 cases.The positive rate was 78.5%.The heparanase expression difference was significant.
     2.In the group of 27 cases whose ages were younger than 50,heparanase expression of 21 cases were positive.The positive rate was 77.8%.In the group of 38 cases whose ages were older than 50,heparanase expression of 30 cases were positive.The positive rate was 78.9%.In the 30 cases of serous cystadenocarcinom,25 cases were heparanase expression positive.The positive rate was 83.3%.In the 21 cases of serous cystadenoma, 16 cases were heparanase expression positive.The positive rate was 76.2%.In the 14 cases of other type groupof ovarian cancer,10 cases were positive.The positive rate was 71.4%. There was not significant difference with them.It shows that there is not dependablity between heparanase expression and ovarian cancer tissue type and patients age.
     3.In the earlier period group of 12 cases of ovarian cancer,heparanase was positive in 3 cases.In the advanced stage group of 53 cases of ovarian cancer,heparanase was positive in 48 cases.The difference was significant.In the well-differentiated group of 5 cases, heparanase expression was positive in 1 case.In the moderately differentiated group of 15 cases,heparanase expression was positive in 6 cases.In the poorly differentiated group of 45 cases,heparanase expression was positive in 44 cases.The difference was significant.It shows that there was dependablity between heparanase expression and ovarian cancer tissue pathological grade and clinical stage.
     4.VEGF expression had not significant difference within patients of ovarian cancer of different age.There was not dependablity between VEGF expression and ovarian cancer tissue type.The VEGF expression of ovarian cancer in advanced stage was higher than that of earlier period.The VEGF expression of well-differentiated and moderately differentiated group was lower than that of poorly differentiated group.The VEGF expression of ovarian cancer had the same tendency as heparanase expression.They were positive correlation. The coefficient correlation was 0.647.
     5.VEGFR1 expression had not significant difference within patients of ovarian cancer of different age.There was not dependablity between VEGFR1 expression and ovarian cancer tissue type.The VEGFR1 expression of ovarian cancer in advanced stage was higher than that of earlier period.The VEGFR1 expression of well-differentiated and moderately differentiated group was lower than that of poorly differentiated group.The VEGFR1 expression of ovarian cancer had the same tendency as heparanase expression.They were positive correlation.The coefficient correlation was 0.612.
     6.MVD had not significant difference within patients of ovarian cancer of different age.There was not dependablity between MVD and ovarian cancer tissue type.The MVD of ovarian cancer in advanced stage was higher than that of earlier period.The MVD of well-differentiated and moderately differentiated group was lower than that of poorly differentiated group.The MVD ovarian cancer had the same tendency as VEGF,VEGFR1 and heparanase expression.They were positive correlation.The coefficient correlation was 0.754,0.713 and 0.669.It shows that heparanase and VEGF have congenerous effect in the angiogenesis of ovarian cancer.
     The 2~(nd) part:blood vessel endothelium cell isolated culture and heparanase expression observation of ovarian cancer
     1.The blood vessel endothelium cell of ovarian cancer was primary cultured.The cellactivity was above 95%.The 1FⅧimmunofluorescence detection was positive.The blood vessel endothelium cell of ovarian cancer can be used in the study of tumor angiogenesis.
     2.Heparanase was positive in the cytoplasm of blood vessel endothelium cell in the detection of immunofluorescence.The heparanase expression in the OdMEC group was higher than that in the HUVEC group.In the RT-PCR detection,the heparanase level in the OdMEC group was higher than that in the HUVEC group too.It shows that heparanase maybe the biological marker in the OdMEC.
     The 3~(rd) part:The effect of RNA interference on the heparanase expression of blood vessel endothelium cell of ovarian cancer
     1.The transfection rate of heparanase siRNA in blood vessel endothelium cell of ovarian cancer was above 95%.
     2.In the experiment group,the blood vessel endothelium cell of ovarian cancer was transfected by heparanase siRNA;the heparanase expression was detected at 2,4,6 and 8 day.The results showed that heparanase mRNA level and protein significantly decreased.It shows that heparanase siRNA transfection can significantly inhibit the heparanase of blood vessel endothelium cell of ovarian cancer.
     3.In the experiment group of the blood vessel endothelium cell of ovarian cancer transfected by heparanase siRNA,VEGF expression significantly decreased.It shows that heparanase siRNA transfection can significantly inhibit the VEGF expression of blood vessel endothelium cell of ovarian cancer.
     4.In the MTT detection of the experiment group,cell activity had not significant changes.but in the normal group and the control group,cell activity increased.In the experiment group,the proliferation index significantly decreased and apoptosis index significantly increased.It shows that RNAi interference can inhibit heparanase expression efficiently,and inhibit VEGF expression and cell proliferation too.The cell apoptosis was induced.RNAi maybe is one way for the treatment of tumor.
     The 4~(th) part:The effect of curcumine on the bionomics and heparanase expression of blood vessel endothelium cell of ovarian cancer
     1.In the cfurcumine group,cell proliferation step down and cell growth density decreased.With the dose increase of the curcumine,cells shed,floated or broke into pieces. It shows that curcumine(2-250ug/ml) can significant inhibit the activity of blood vessel endothelium cell of ovarian cancer dose dependently and time dependently.
     2.In the curcumine group,curcumine can inhibit the cell proliferation significantly.It shows that curcumine(2-250ug/ml) can significant inhibit the proliferation of blood vessel endothelium cell of ovarian cancer dose dependently and time dependently.
     3.In the curcumine group,the cell proliferation index decreased significantly.The subdiploid was observed.
     4.According to the immunofluorescence detection,the heparanase expression in the curcumine group decreased significantly.The effect was dose dependent and time dependent.It shows that curcumine(2-250ug/ml) can significant inhibit the heparanase expression of blood vessel endothelium cell of ovarian cancer.
     5.In the curcumine group,the MDA content and LDH activity of cell culture supernatant significant increased.
引文
1. Liu J,Xu Y,Wang J. Ultrasonography, computed tomography and magnetic resonance imaging for diagnosis of ovarian carcinoma. Eur J Radiol 2007,62(3):328-334.
    2. Raspollini MR, Taddei GL. Tumor markers in ovarian carcinoma. Int J Gynaecol Obstet, 2007, 97(3):175-181.
    3. Lage H, Denkert C. Resistance to chemotherapy in ovarian carcinoma. Recent Results Cancer Res, 2007, 176:51-60.
    4. McKenzie EA.Heparanase: a target for drug discovery in cancer and inflammation. Br J Pharmacol, 2007, 151(1):1-14.
    5. Ilan N, Elkin M, Vlodavsky I. Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis. Int J Biochem Cell Biol, 2006, 38(12):2018-2039.
    6. Miao HQ,Liu H,Navarro E,et al. Development of heparanase inhibitors for anti-cancer therapy. Curr Med Chem, 2006, 13(18):2101-2011.
    7. Naomoto Y, Takaoka M, Okawa T, et al.The role of heparanase in gastrointestinal cancer (Review). Oncol Rep, 2005, 14(1):3-8.
    8. Kryczek I, Wei S,Keller E,et al.Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis. Am J Physiol Cell Physiol, 2007, 292(3):C987-995.
    9. Liu Y, Deisseroth A.Tumor vascular targeting therapy with viral vectors. Blood,2006, 107(8):3027-3033.
    10. Su JL, Yen CJ, Chen PS, et al.The role of the VEGF-C/VEGFR-3 axis in cancer progression. Br J Cancer, 2007, 96(4):541-545.
    11. Reuter CW, Morgan MA, Grunwald V, et al. Targeting vascular endothelial growth factor (VEGF)-receptor-signaling in renal cell carcinoma. World J Urol, 2007, 25(1):59-72.
    12. Chang H.RNAi-mediated knockdown of target genes: a promising strategy for pancreatic cancer research.Cancer Gene Ther, 2007, 14(8):677-685.
    13. Li W, Cha L.Predicting siRNA efficiency. Cell Mol Life Sci, 2007, 64(14): 1785-1792.
    14. Aagaard L, Rossi JJ.RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev, 2007, 59(2-3):75-86.
    15. Mao CP, Lin YY, Hung CF, et al.Immunological research using RNA interference technology. Immunology, 2007, 121(3):295-307.
    16. Efferth T, Fu YJ, Zu YG,et al.Molecular target-guided tumor therapy with natural products derived from traditional Chinese medicine. Curr Med, Chem, 2007, 14(19): 2024-2032.
    17. Li J, Xia X, Ke Y, et al.Trichosanthin induced apoptosis in HL-60 cells via mitochondrial and endoplasmic reticulum stress signaling pathways. Biochim Biophys Acta, 2007, 1770(8): 1169-1180.
    18. Shishodia S, Chaturve MM, Aggarwal BB.Role of curcumin in cancer therapy. Curr Probl Cancer, 2007, 31(4): 243-305.
    19. 姚运红, 余健华,熊晖. 姜黄素体内外对鼻咽癌的抗癌作用. 肿瘤防治研究,2006,33(7):487-489.
    20. Simizu S, Ishida K, Osada H.Heparanase as a molecular target of cancer chemotherapy. Cancer Sci, 2004, 95(7):553-538.
    21. Zhang J, Peng B.In vitro angiogenesis and expression of nuclear factor kappaB and VEGF in high and low metastasis cell lines of salivary gland Adenoid Cystic Carcinoma. BMC Cancer, 2007, 7:95.
    22. Cohen I, Maly B, Simon I, et al.Tamoxifen induces heparanase expression in estrogen receptor-positive breast cancer. Clin Cancer Res, 2007, 13(14):4069-4077.
    23. Yang Y, Macleod V, Miao HQ, et al.Heparanase enhances syndecan-1 shedding: a novel mechanism for stimulation of tumor growth and metastasis. J Biol Chem, 2007, 282(18): 13326-13333.
    24. Theodoro TR, Luongo ML, Sant, AV, et al.Heparanase expression in circulating lymphocytes of breast cancer patients depends on the presence of the primary tumor and/or systemic metastasis. Neoplasia. 2007, 9(6):504-510.
    25. Zhang Y, Li L, Wang Y, et al.Downregulating the expression of heparanase inhibits the invasion, angiogenesis and metastasis of human hepatocellular carcinoma. Biochem Biophys Res Commun, 2007, 358(1):124-129.
    26. Nadir Y, Brenner B, Zetser A, et al.Heparanase induces tissue factor expression in vascular endothelial and cancer cells.J Thromb Haemost, 2006, 4(11): 2443-2451.
    27. Davidson B, Shafat I, Risberg B, et al.Heparanase expression correlates with poor survival in metastatic ovarian carcinoma. Gynecol Oncol, 2007, 104(2):311-319.
    28. Backen AC, Cole CL, Lau SC, et al.Heparan sulphate synthetic and editing enzymes in ovarian cancer. Br J Cancer, 2007, 96(10):1544-1548.
    29. Ginath S, Menczer J, Friedmann Y, et al. Expression of heparanase, Mdm2, and erbB2 in ovarian cancer. Int J Oncol, 2001, 18(6):1133-1144.
    30. Vlodavsky I, Elkin M, Pappo O, et al .Mammalian heparanase as mediator of tumor metastasis and angiogenesis. Isr Med Assoc J, 2000,2 S:37-45.
    31. Ogishima T, Shiina H, Breault JE, et al. Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer. Oncogene, 2005, 24(45):6765-6772.
    32. Nadir Y, Brenner B, Zetser A, et al. Heparanase induces tissue factor expression in vascular endothelial and cancer cells. J Thromb Haemost, 2006,4(11): 2443-2451.
    33. Kelly T,Suva LJ,Huang Y,et al. Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases. Cancer-Res. 2005,65(13): 5778-5784.
    34. Kragh M, Loechel F.Non-anti-coagulant heparins: a promising approach for prevention of tumor metastasis (review). Int J Oncol, 2005, 27(4):1159-1167.
    35. Hu L, Hofmann J, Holash J, et al. Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model. Clin Cancer Res, 2005, 11(19 Pt 1):6966-6971.
    36. Vuento MH, Pirhonen JP, Makinen JI, et al. Evaluation of ovarian findings in asymptomatic postmenopausal women with color Doppler ultrasound.Cancer,1995, 76(7):1214-1218.
    37. Nagengast WB, Vries EG, Hospers GA, et al. In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. J Nucl Med, 2007, 48(8): 1313-1319.
    38. Mikami S, Ohashi K,Katsube K,et al.Coexpression of heparanase, basic fibroblast growth factor and vascular endothelial growth factor in human esophageal carcinomas. Pathol Int, 2004, 54(8):556-563.
    39. Cohen I, Pappo O, Elkin M, et al. Heparanase promotes growth, angiogenesis and survival of primary breast tumors. Int J Cancer, 2006, 118(7): 1609-1617.
    40. Vlodavsky I, Ilan N, Naggi A, et al.Heparanase: structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate.Curr Pharm Des,2007,13(20):2057-2073.
    41.Edovitsky E,Elkin M,Vlodavsky I,et al.Heparanase gene silencing,tumor invasiveness,angiogenesis,and metastasis.J Natl Cancer Inst,2004,96(16):1219-1230.
    42.Goldshmidt O,Zcharia E,Vlodavsky I,et al.Cell surface expression and secretion of heparanase markedly promote tumor angiogenesis and metastasis.Proc Natl Acad Sci USA,2002,99(15):10031-10036.
    43.Detwiller KY,Fernando NT,Segal NH,et al.Analysis of hypoxia-related gene expression in sarcomas and effect of hypoxia on RNA interference of vascular endothelial cell growth factor A.Cancer Res,2005,65(13):5881-5889.
    44.Langley RR,Ramirez KM,Tsan RZ,et al.Tissue-specific microvascular endothelial cell lines from H-2K(b)-tsA58 mice for studies of angiogenesis and metastasis.Cancer Res,2003,63(11):2971-2976.
    45.Alessandri G,Chirivi RG,Fiorentini S,et al.Phenotypic and functional characteristics of tumour-derived microvascular endothelial cells.Clin Exp Metastasis,1999,17(8):655-662.
    46.蒋雪峰,白家驷,卞修武.血管内皮生长因子诱导的胶质瘤源性微血管内皮细胞体外三维成型特性.中华病理学杂志,2005,34(9):579-582.
    47.Bouis D,Hospers GA,Meijer C,et al.Endothelium in vitro:a review of human vascular endothelial cell lines for blood vessel-related research.Angiogenesis,2001,4(2):91-102.
    48.Loffek S,Zigrino P,Steiger J,et al.Melanoma cell-derived vascular endothelial growth factor induces endothelial tubulogenesis within fibrin gels by a metalloproteinase mediated mechanism.Eur J Cell Biol,2006,85(11):1167-1177.
    49.Ek ET,Ojaimi J,Kitagawa Y,et al.Does the degree of intratumoural microvessel density and VEGF expression have prognostic significance in osteosarcoma? Oncol Rep,2006,16(1):17-23.
    50.Li Q,Yu Y,Bischoff J,et al.Differential expression of CD146 in tissues and endothelial cells derived from infantile haemangioma and normal human skin.J Pathol,2003,201(2):296-302.
    51. Dudley AC, Thomas D, Best J,et al.A VEGF/JAK2/STAT5 axis may partially mediate endothelial cell tolerance to hypoxia. Biochem J, 2005, 390(Pt 2):427-436.
    52. Richardson TB, Kaspers J, Porter CD.Retroviral hybrid LTR vector strategy: functional analysis of LTR elements and generation of endothelial cell specificity.Gene Ther, 2004, 11(9):775-783.
    53. Cemazar M, Parkins CS, Holder AL, et al.Electroporation of human microvascular endothelial cells: evidence for an anti-vascular mechanism of electrochemotherapy. Br J Cancer, 2001, 84(4):565-570.
    54. Nakagawa M, Emoto A, Hanada T, et al.Tubulogenesis by microvascular endothelial cells is mediated by vascular endothelial growth factor (VEGF) in renal cell carcinoma. Br J Urol, 1997, 79(5):681-687.
    55. Cohen I, Maly B, Simon I, et al. Tamoxifen induces heparanase expression in estrogen receptor-positive breast cancer. Clin Cancer Res, 2007, 13(14):4069-4077.
    56. Theodoro TR, Luongo ML, Sant AV, et al. Heparanase expression in circulating lymphocytes of breast cancer patients depends on the presence of the primary tumor and/or systemic metastasis.Neoplasia, 2007,9(6):504-510.
    57. Zhang Y, Li L, Wang Y,et al.Downregulating the expression of heparanase inhibits the invasion, angiogenesis and metastasis of human hepatocellular carcinoma. Biochem Biophys Res Commun, 2007, 358(1): 124-129.
    58. Zhang Y, Li L, Wang Y, et al.Downregulating the expression of heparanase inhibits the invasion, angiogenesis and metastasis of human hepatocellular carcinoma. Biochem Biophys Res Commun, 2007,358(1): 124-129.
    59. Doweck I,Kaplan V,Naroditsky I,Sabo E,et al. Heparanase localization and expression by head and neck cancer: correlation with tumor progression and patient survival. Neoplasia, 2006,8(12):1055-1061.
    60. Imada T, Matsuoka J, Nobuhisa T, et al.COX-2 induction by heparanase in the progression of breast cancer. Int J Mol Med, 2006, 17(2):221-228.
    61. Joyce JA, Freeman C,Meyer N,et al.A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer. Oncogene, 2005, 24(25):4037-4051.
    62. Sinowatz F,Schams D,Habermann F,et al. Localization of fibroblast growth factor I (acid fibroblast growth factor) and its mRNA in the bovine mammary gland during mammogenesis, lactation and involution.Anat Histol Embryol,2006,35(3):202-207.
    63. Davidson B, Vintman L, Zcharia E, et al.Heparanase and basic fibroblast growth factor are co-expressed in malignant mesothelioma.Clin Exp Metastasis,2004,21(5):469-476.
    64. Mikami S, Ohashi K,Katsube K,et al.Coexpression of heparanase, basic fibroblast growth factor and vascular endothelial growth factor in human esophageal carcinomas. Pathol Int, 2004,54(8):556-563.
    65. Saijo M, Kitazawa R, Nakajima M, et al.Heparanase mRNA expression during fracture repair in mice. Histochem Cell Biol, 2003, 120(6):493-503.
    66. Chamberlain A, Gronvall GK.The science of biodefense: RNAi.Biosecur, Bioterror, 2007,5(2):104-106.
    67. Widmer N,Rumpold H,Untergasser G,et al. Resistance reversal by RNAi silencing of MDR1 in CML cells associated with increase in imatinib intracellular levels. Leukemia, 2007, 21(7): 1561- 1564.
    68. Zhang S, Yang JH, Guo CK, et al.Gene silencing of TKTL1 by RNAi inhibits cell proliferation in human hepatoma cells. Cancer Lett, 2007, 253(1): 108-114.
    69. Colmenares SU, Buker SM, Buhler M, et al.Coupling of double-stranded RNA synthesis and siRNA generation in fission yeast RNAi.Mol Cell, 2007,27(3):449-461.
    70. Akhtar S, Benter I.Toxicogenomics of non-viral drug delivery systems for RNAi: potential impact on siRNA-mediated gene silencing activity and specificity. Adv Drug Deliv Rev, 2007,59(2-3):164-182.
    71. Fujii N,Inui T,Iwasa K,et al. Knockdown of berberine bridge enzyme by RNAi accumulates (S)-reticuline and activates a silent pathway in cultured California poppy cells. Transgenic Res, 2007, 16(3): 363-375.
    72. Kalinna BH, Brindley PJ. Manipulating the manipulators: advances in parasitic helminth transgenesis and RNAi.Trends Parasitol, 2007,23(5): 197-204.
    73. Wu RH,Cheng TL,Lo SR,et al.A tightly regulated and reversibly inducible siRNA expression system for conditional RNAi-mediated gene silencing in mammalian cells. J Gene Med, 2007,9(7): 620-34.
    74. Amarzguioui M, Lundberg P, Cantin E,et al.Rational design and in vitro and in vivo delivery of Dicer substrate siRNA.Nat Protoc, 2006,1(2):508-517.
    75. Comes N, Borras T.Functional delivery of synthetic naked siRNA to the human trabecular meshwork in perfused organ cultures. Mol Vis, 2007, 13:1363-1374.
    76. Li Y, Li H,Yao G,et al. Inhibition of telomerase RNA (hTR) in cervical cancer by adenovirus-delivered siRNA. Cancer Gene Ther, 2007, 14(8):748-755.
    77. Boldbaatar D, Battsetseg B, Hatta T, et al.Valosin-containing protein from the hard tick Haemaphysalis longicornis: effects of dsRNA-mediated HlVCP gene silencing. Biochem Cell Biol, 2007, 85(3):384-394.
    78. Kim DH, Behlke MA, Rose SD,et al.Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. Nat Biotechnol, 2005, 23(2): 222-226.
    79. Anderson PH, Atkins GJ, Findlay DM, et al.RNAi-mediated silencing of CYP27B1 abolishes 1,25(OH)2D3 synthesis and reduces osteocalcin and CYP24 mRNA expression in human Osteosarcoma (HOS) cells. J Steroid Biochem Mol Biol, 2007,103(3-5): 601-605.
    80. Fan Y, Xin XY, Chen BL,et al.Knockdown of RAB25 expression by RNAi inhibits growth of human epithelial ovarian cancer cells in vitro and in vivo. Pathology, 2006,38(6): 561-567.
    81. Gao J, Su L, Qin R,et al. Transfection of antisense oligodeoxynucleotide inhibits heparanase gene expression and invasive ability of human pancreatic cancer cell in vitro. J Huazhong Univ Sci Technolog Med Sci, 2006,26(1 ):72-74.
    82. Kondraganti S, Gondi CS, McCutcheon I,et al.RNAi-mediated downregulation of urokinase plasminogen activator and its receptor in human meningioma cells inhibits tumor invasion and growth. Int J Oncol, 2006, 28(6):1353-1360.
    83. Cesarone G, Garofalo C, Abrams MT, et al.RNAi-mediated silencing of insulin receptor substrate 1 (IRS-1) enhances tamoxifen-induced cell death in MCF-7 breast cancer cells. J Cell Biochem, 2006, 98(2): 440-450.
    84. Gao LF, Wen LJ, Yu H,et al.Knockdown of Stat3 expression using RNAi inhibits growth of laryngeal tumors in vivo.Acta Pharmacol Sin, 2006, 27(3):347-352.
    85. Kawasaki H,Taira K. Short hairpin type of dsRNAs that are controlled by tRNA(Val) promoter significantly induce RNAi-mediated gene silencing in the cytoplasm of human cells.Nucleic Acids Res, 2003, 31(2):700-707.
    86. Cesarone G, Garofalo C, Abrams MT, et al.RNAi-mediated silencing of insulin receptor substrate 1(IRS-1) enhances tamoxifen-induced cell death in MCF-7 breast cancer cells.J Cell Biochem,2006,98(2):440-450.
    87.布日额.蒙药材姜黄本草考证.中药材,2007,30(2):239-240.
    88.赵东利,谢小卫,李明众,等.姜黄素对 S180 小鼠体内抗肿瘤作用的实验研究.西安交通大学学报,2007,29(1):79-82.
    89.Cheng Y,Kozubek A,Ohlsson L,et al.Curcumin decreases acid sphingomyelinase activity in colon cancer Caco-2 cells.Planta Med,2007,73(8):725-730.
    90.Moragoda L,Jaszewski R,Majumdar AP.Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells.Anticancer Res,2001,21(2A):873-838.
    91.Siwak DR,Shishodia S,Aggarwal BB,et al.Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IkappaB kinase and nuclear factor kappaB activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway.Cancer,2005,104(4):879-90.
    92.Zheng M,Ekmekcioglu S,Walch ET,Tang CH,et al.Inhibition of nuclear factor-kappaB and nitric oxide by curcumin induces G2/M cell cycle arrest and apoptosis in human melanoma cells.Melanoma Res,2004,14(3):165-71.
    93.Bush JA,Cheung KJ,Li G.Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53.Exp Cell Res,2001,271(2):305-14.
    94.Notarbartolo M,Poma P,Perri D,et al.Antitumor effects of curcumin,alone or in combination with cisplatin or doxorubicin,on human hepatic cancer cells.Analysis of their possible relationship to changes in NF-kB activation levels and in IAP gene expression.Cancer Lett,2005,224(1):53-65.
    95.Lin JK.Molecular targets of curcumin.Adv Exp Med Biol,2007,595:227-43.
    96.Dhandapani KM,Mahesh VB,Brann DW.Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFkappaB transcription factors.J Neurochem,2007,102(2):522-38.
    97.Vartanian SM,Sarkar R.Therapeutic angiogenesis.Vasc Endovascular Surg,2007,41(3):173-85.
    98.Lafleur MA,Drew AF,Sousa EL,et al.Upregulation of matrix metalloproteinases (MMPs) in breast cancer xenografts: a major induction of stromal MMP-13. Int J Cancer, 2005, 114(4): 544-54.
    99. Prusty BK, Das BC. Constitutive activation of transcription factor AP-1 in cervical cancer and suppression of human papillomavirus (HPV) transcription and AP-1 activity in HeLa cells by curcumin. Int J Cancer, 2005, 113(6): 951-960.
    100.Esmat A, Demerdash E, Mesallamy H, et al. Toxicity and oxidative stress of acrylonitrile in rat primary glial cells: preventive effects of N-acetylcysteine. Toxicol Lett, 2007, 171(3): 111-118.
    101.Sohn JH, Han KL, Choo JH, et al. Macelignan protects HepG2 cells against tert-butylhydroperoxide-induced oxidative damage. Biofactors, 2007, 29(1): 1-10.
    1. Takahashi Y, Akishima FY, Kobayashi N, et al. Prognostic value of tumor architecture, tumor-associated vascular characteristics, and expression of angiogenic molecules in pancreatic endocrine tumors. Clin Cancer Res, 2007, 13(1): 187-196.
    2. Kunisaki C, Shimada H, Nomura M, et al. Lymph node dissection in surgical treatment for remnant stomach cancer. Hepatogastroenterology, 2002, 49(44): 580-584.
    3. Rouzaut A, Irigoyen M, Montuenga LM. Lymphangiogenesis and lung cancer. J Thorac Oncol, 2007, 2(5): 384-6.
    4. Davern SM, Lankford PK, Foote LJ, et al. Monoclonal antibodies to CD44 epitopes on mouse endothelium. Hybrid Hybridomics, 2002, 21(5): 339-349.
    5. Trojan L, Rensch F, Voss M, et al. The role of the lymphatic system and its specific growth factor, vascular endothelial growth factor C, for lymphogenic metastasis in prostate cancer. BJU Int, 2006, 98(4): 903-906.
    6. Weber T, Lacroix J, Worner S, et al. Detection of hematogenic and lymphogenic tumor cell dissemination in patients with medullary thyroid carcinoma by cytokeratin 20 and preprogastrin-releasing peptide RT-PCR. Int J Cancer, 2003, 103(1): 126-131.
    7. Dunne AA, Mandic R, Ramaswamy A, et al. Lymphogenic metastatic spread of auricular VX2 carcinoma in New Zealand white rabbits. Anticancer Res, 2002, 22(6A): 3273-3279.
    8. Cabebe E, Fisher GA. Clinical trials of VEGF receptor tyrosine kinase inhibitors in pancreatic cancer. Expert Opin Investig Drugs, 2007, 16(4): 467-476.
    9. Johnson BF, Clay TM, Hobeika AC, et al. Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy. Expert Opin Biol Ther, 2007, 7(4): 449-460.
    10. Yoo PS, Mulkeen AL, Cha CH. Post-transcriptional regulation of vascular endothelial growth factor: implications for tumor angiogenesis. World J Gastroenterol, 2006, 12(31): 4937-4942.
    11. Mercurio AM, Lipscomb EA, Bachelder RE. Non-angiogenic functions of VEGF in breast cancer. J Mammary Gland Biol Neoplasia, 2005, 10(4): 283-290.
    12. Pradeep CR, Sunila ES, Kuttan G. Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor angiogenesis and malignancies. Integr Cancer Ther, 2005, 4(4): 315-321.
    13. Affara NI, Robertson FM. Vascular endothelial growth factor as a survival factor in tumor-associated angiogenesis. In Vivo, 2004, 18(5): 525-542.
    14. Guba M, Seeliger H, Kleespies A, et al. Vascular endothelial growth factor in colorectal cancer. Int J Colorectal Dis, 2004, 19(6): 510-517.
    15. Hao X, Mansson BA, Grinnemo, et al. Myocardial angiogenesis after plasmid or adenoviral VEGF-A(165) gene transfer in rat myocardial infarction model. Cardiovasc Res, 2007, 73(3): 481-487.
    16. Otrock ZK, Makarem JA, Shamseddine AI. Vascular endothelial growth factor family of ligands and receptors: review. Blood Cells Mol Dis, 2007, 38(3): 258-268.
    17. Betsholtz C, ArmulikA. Homeostatic functions of vascular endothelial growth factor in adult microvasculature. Am J Physiol Heart Circ Physiol, 2006,290(2): H509-511.
    18. Moreira IS, Fernandes PA, Ramos MJ. Vascular endothelial growth factor (VEGF) inhibition—a critical review. Anticancer Agents Med Chem, 2007, 7(2): 223-245.
    19. Ball SG, Shuttleworth CA, Kielty CM. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors. J Cell Biol, 2007,177(3): 489-500.
    20. Ushio FM. VEGF signaling through NADPH oxidase-derived ROS. Antioxid Redox Signal, 2007, 9(6): 731-739.
    21. Eskens FA, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer, 2006, 42(18): 3127-3139.
    22. Bourlev V, Volkov N, Pavlovitch S, et al. The relationship between microvessel density, Proliferative activity and expression of vascular endothelial growth factor-A and its receptors in eutopic endometrium and endometriotic lesions. Reproduction, 2006, 132(3): 501-509.
    23. Kiselyov AS, Piatnitski EL, Samet AV, et al. ortho-Substituted azoles as selective and dual inhibitors of VEGF receptors 1 and 2. Bioorg Med Chem Lett, 2007, 17(5): 1369-1375.
    24. Byun JH, Park BW, Kim JR, et al. Expression of vascular endothelial growth factor and its receptors after mandibular distraction osteogenesis. Int J Oral Maxillofac Surg, 2007, 36(4): 338-344.
    25. Goldman J, Rutkowski JM, Shields JD, et al. Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis. FASEB J, 2007, 21(4): 1003-1012.
    26. Inai T, Mancuso M, Hashizume H, et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol, 2004, 165(1): 35-52.
    27. Neagoe PE, Lemieux C, Sirois MG. Vascular endothelial growth factor (VEGF)-A165-induced prostacyclin synthesis requires the activation of VEGF receptor-1 and -2 heterodimer. J Biol Chem, 2005, 280(11): 9904-9012.
    28. Stimpfl M, Tong D, Fasching B, et al. Vascular endothelial growth factor splice variants and their prognostic value in breast and ovarian cancer. Clin Cancer Res, 2002, 8(7): 2253-2259.
    29. Neufeld G, Kessler O, Herzog Y. The interaction of Neuropilin-1 and Neuropilin-2 with tyrosine-kinase receptors for VEGF. Adv Exp Med Biol, 2002; 515: 81-90.
    30. Robinson CJ, Das RG, Stammers R, et al. The World Health Organization reference reagent for vascular endothelial growth factor, VEGF165. Growth Factors.2006, 24(4): 285-290.
    31. Koolwijk P, Peters E, Vecht B, et al. Involvement of VEGFR-2 (kdr/flk-1) but not VEGFR-1 (fit-1) in VEGF-A and VEGF-C-induced tube formation by human microvascular endothelial cells in fibrin matrices in vitro. Angiogenesis, 2001, 4(1): 53-60.
    32. Cebe SS, Pieren M, Cariolato L, et al. A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2. Cell Mol Life Sci, 2006, 63(17): 2067-2077.
    33. Clermont AC, Cahill M, Salti H, et al. Hepatocyte growth factor induces retinal vascular permeability via MAP-kinase and PI-3 kinase without altering retinal hemodynamics. Invest Ophthalmol Vis Sci, 2006, 47(6): 2701-2708.
    34. Yang XH, Man XY, Cai SQ, et al. Expression of VEGFR-2 on HaCaT cells is regulated by VEGF and plays an active role in mediating VEGF induced effects. Biochem Biophys Res Commun, 2006, 349(1): 31-38.
    35. Roskoski RJ. PDGF FGF EGF Angiostatin IL-12 [35-38]. TI: Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun, 2007, 356(2): 323-328.
    36. Ishihara M, Fujita M, Obara K, et al. Controlled releases of FGF-2 and paclitaxel from chitosan hydrogels and their subsequent effects on wound repair, angiogenesis, and tumor growth. Curr Drug Deliv, 2006, 3(4): 351-358.
    37. Kim KS, Kim DS, Chung KH, et al. Inhibition of angiogenesis and tumor progression by hydrodynamic cotransfection of angiostatin K1-3, endostatin, and saxatilin genes. Cancer Gene Ther, 2006, 13(6): 563-571.
    38. Morini M, Albini A, Lorusso G, et al. Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immunogene therapy. Gene Ther, 2004, 11(3): 284-291.
    39. Moffat BA, Chen M, Kariaapper MS, et al. Inhibition of vascular endothelial growth factor (VEGF)-A causes a paradoxical increase in tumor blood flow and up-regulation of VEGF-D. Clin Cancer Res, 2006, 12(5): 1525-1532.
    40. Wong SY, Haack H, Crowley D, et al. Tumor-secreted vascular endothelial growth factor-C is necessary for prostate cancer lymphangiogenesis, but lymphangiogenesis is unnecessary for lymph node metastasis. Cancer Res, 2005, 65(21): 9789-9798.
    41. Chang YS, Adnane J, Trail PA, et al. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol, 2007, 59(5): 561-574.
    42. Bos R, Diest PJ, Jong JS, et al. Hypoxia-inducible factor-1alpha is associated with angiogenesis, and expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer. Histopathology, 2005, 46(1): 31-36.
    43. Dasgupta S, Bhattacharya CM, Malley BW, et al. Tumor metastasis in an orthotopic murine model of head and neck cancer: possible role of TGF-beta 1 secreted by the tumor cells. J Cell Biochem, 2006, 97(5): 1036-1051.
    44. Rishi AK, Parikh R, Wali A, et al. EGF receptor-related protein (ERRP) inhibits invasion of colon cancer cells and tubule formation by endothelial cells in vitro. Anticancer Res, 2006, 26(2A): 1029-1037.
    45. Wicki A, Lehembre F, Wick N, et al. Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell, 2006, 9(4): 261-272.
    46. Jackson DG, Prevo R, Clasper S, et al. LYVE-1, the lymphatic system and tumor lymphangiogenesis. Trends Immunol, 2001, 22(6): 317-321.
    47. Nishida N, Yano H, Komai K, et al. Vascular endothelial growth factor C and vascular endothelial growth factor receptor 2 are related closely to the prognosis of patients with ovarian carcinoma. Cancer, 2004, 101(6): 1364-1374.
    48. Cursiefen C, Maruyama K, Jackson DG, et al. Time course of angiogenesis and lymphangiogenesis after brief corneal inflammation. Cornea, 2006, 25(4): 443-447.
    49. Onogawa S, Kitadai Y, Amioka T, et al. Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in early gastric carcinoma: correlation with clinicopathological parameters. Cancer Lett, 2005, 226(1): 85-90.
    50. Donnini S, Monti M, CastagniniC, et al. Pyrazolo-pyrimidine-derived c-Src inhibitor reduces angiogenesis and survival of squamous carcinoma cells by suppressing vascular endothelial growth factor production and signaling. Int J Cancer, 2007, 120(5): 995-1004.
    51. Shibuya T, Watanabe K, Yamashita H, et al. Isolation and characterization of vasohibin-2 as a homologue of VEGF-inducible endothelium-derived angiogenesis inhibitor vasohibin. Arterioscler Thromb Vasc Biol, 2006, 26(5): 1051-1057.
    52. Jeong BC, Kim MY, Lee JH, et al. Brain-specific angiogenesis inhibitor 2 regulates VEGF through GABP that acts as a transcriptional repressor. FEBS Lett, 2006, 580(2): 669-676.
    53. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun, 2005, 333(2): 328-335.
    54. Matsuno A, Nagashima T. Specific gene suppression using antisense strategy for growth suppression of glioma. Med Electron Microsc, 2004, 37(3): 158-161.
    55. Sun X, Kanwar JR, Leung E, et al. Regression of solid tumors by engineered overexpression of von Hippel-Lindau tumor suppressor protein and antisense hypoxia-inducible factor-1alpha. Gene Ther, 2003, 10(25): 2081-2089.
    56. Bauer AJ, Patel A, Terrell R, et al. Systemic administration of vascular endothelial growth factor monoclonal antibody reduces the growth of papillary thyroid carcinoma in a nude mouse model. Ann Clin Lab Sci, 2003, 33(2): 192-199.
    57. Lichtenbeld HC, Ferarra N, Jain RK, et al. Effect of local anti-VEGF antibody treatment on tumor microvessel permeability. Microvasc Res, 1999, 57(3): 357-362.
    58. Cuneo KC, Fu A, Osusky KL, et al. Effects of vascular endothelial growth factor receptor inhibitor SU5416 and prostacyclin on murine lung metastasis. Anticancer Drugs, 2007, 18(3): 349-355.
    59. Goncalves M, Estieu GK, Berthelot T, et al. Design, synthesis, and evaluation of original carriers for targeting vascular endothelial growth factor receptor interactions. Pharm Res, 2005, 22(8): 1411-1421.
    60. Li QL, Chen FJ. Review of relationship between vascular endothelial growth factor C & D and lymph node metastasis of malignant tumor. Ai Zheng, 2002, 21(6): 696-700.
    61. Foster RR, Satchell SC, Seckley J, et al. VEGF-C promotes survival in podocytes. Am J Physiol Renal Physiol, 2006, 291(1): F196-207.
    62. Vlahakis NE, Young BA, Atakilit A, et al. The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin alpha9betal. J Biol Chem, 2005, 280(6): 4544-4552.
    63. Hillman NJ, Whittles CE, Pocock TM, et al. Differential effects of vascular endothelial growth factor-C and placental growth factor-1 on the hydraulic conductivity of frog mesenteric capillaries. J Vasc Res, 2001, 38(2): 176-186.
    64. Marconcini L, Marchio S, Morbidelli L, et al. c-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro. Proc Natl Acad Sci USA, 1999, 96(17): 9671-9676.
    65. McColl BK, Paavonen K, Karnezis T, et al. Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2. FASEB J, 2007,21(4): 1088-1098.
    66. Dixelius J, Makinen T, Wirzenius M, et al. Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites. J Biol Chem, 2003, 278(42): 40973-40979.
    67. Zhang X, Groopman JE, Wang JF. Extracellular matrix regulates endothelial functions through interaction of VEGFR-3 and integrin alpha5betal. J Cell Physiol, 2005, 202(1): 205-214.
    68. Lu ZQ, Li HG, Xie DR, et al. Expression and clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in non-small cell lung carcinoma. Ai Zheng, 2005, 24(9): 1132-1135.
    69. Takizawa H, Kondo K, Fujino H, et al. The balance of VEGF-C and VEGFR-3 mRNA is a predictor of lymph node metastasis in non-small cell lung cancer. Br J Cancer, 2006, 95(1): 75-79.
    70. Ochi N, Matsuo Y, Sawai H, et al. Vascular endothelial growth factor-C secreted by pancreatic cancer cell line promotes lymphatic endothelial cell migration in an in vitro model of tumor lymphangiogenesis. Pancreas, 2007, 34(4): 444-451.
    71. Ding MX, Lin XQ, Fu XY, et al. Expression of vascular endothelial growth factor-C and angiogenesis in esophageal squamous cell carcinoma. World J Gastroenterol, 2006, 12(28): 4582-4585.
    72. Matsumura S, Oue N, Mitani Y, et al. DNA demethylation of vascular endothelial growth factor-C is associated with gene expression and its possible involvement of lymphangiogenesis in gastric cancer. Int J Cancer, 2007, 120(8): 1689-1695.
    73. Mohammed RA, Green A, Shikh S, et al. Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis. Br J Cancer, 2007, 96(7): 1092-1100.
    74. Trappen PO, Steele D, Lowe DG, et al. Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. J Pathol, 2003, 201(4): 544-554.
    75. Fujimoto J, Toyoki H, Sato E, et al. Clinical implication of expression of vascular endothelial growth factor-C in metastatic lymph nodes of uterine cervical cancers. Br J Cancer, 2004, 91(3): 466-4669.
    76. Furudoi A, Tanaka S, Haruma K, et al. Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma. Oncology, 2002, 62(2): 157-166.
    77. Munoz GF, Marazuela EG, Martin VE, et al. Prognostic significance of intratumoral lymphangiogenesis in squamous cell carcinoma of the oral cavity. Cancer, 2004, 100(3): 553-560.
    78. Mandriota SJ, Jussila L, Jeltsch M, et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J, 2001, 20(4): 672-682.
    79. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med, 2001, 7(2): 192-198.
    80. Krishnan J, Kirkin V, Steffen A, et al. Differential in vivo and in vitro expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in tumors and its relationship to lymphatic metastasis in immunocompetent rats. Cancer Res, 2003, 63(3): 713-722.
    81. Mattila MM, Ruohola JK, Karpanen T, et al. VEGF-C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF-7 tumors. Int J Cancer, 2002, 98(6): 946-951.
    82. Ishikawa M, Kitayama J, Kazama S, et al. The expression pattern of vascular endothelial growth factor C and D in human esophageal normal mucosa, dysplasia and neoplasia. Hepatogastroenterology, 2004, 51(59): 1319-1322.
    83. Nakamura Y, Yasuoka H, Tsujimoto M, et al. Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis. Clin Cancer Res, 2006, 12(4): 1201-1207.
    84. Stearns M, Tran J, Francis MK, et al. Activated Ras enhances insulin-like growth factor I induction of vascular endothelial growth factor in prostate epithelial cells. Cancer Res, 2005, 65(6): 2085-2088.
    85. Bando H, Brokelmann M, Toi M, et al. Immunodetection and quantification of vascular endothelial growth factor receptor-3 in human malignant tumor tissues. Int J Cancer, 2004, 111(2): 184-191.
    86. Neid M, Datta K, Stephan S, et al. Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells. J Biol Chem, 2004, 279(6): 3941-3948.
    87. Achen MG, Roufail S, Domagala T, et al. Monoclonal antibodies to vascular endothelial growth factor-D block its interactions with both VEGF receptor-2 and VEGF receptor-3. Eur J Biochem, 2000, 267(9): 2505-2515.
    88. Nakazato T, Shingaki S, Kitamura N, et al. Expression level of vascular endothelial growth factor-C and -A in cultured human oral squamous cell carcinoma correlates respectively with lymphatic metastasis and angiogenesis when transplanted into nude mouse oral cavity. Oncol Rep, 2006, 15(4): 825-830.
    89. Laakkonen P, Waltari M, Holopainen T, et al. Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res, 2007, 67(2): 593-599.
    90. Liang QC, Wei QY, Fan SQ. Expression of VEGF-C and angiogenesis, and lymphangiogenesis in papillary thyroid carcinoma. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2006,31(3): 414-6, 419.
    91. Tille JC, Wang X, Lipson KE, et al. Vascular endothelial growth factor (VEGF) receptor-2 signaling mediates VEGF-C(deltaNdeltaC)- and VEGF-A-induced angiogenesis in vitro. Exp Cell Res, 2003, 285(2): 286-298.
    92. Marchio S, Primo L, Pagano M, et al. Vascular endothelial growth factor-C stimulates the migration and proliferation of Kaposi's sarcoma cells. J Biol Chem, 1999, 274(39): 27617-27622.
    93. Zeng Y, Opeskin K, Baldwin ME, et al. Expression of vascular endothelial growth factor receptor-3 by lymphatic endothelial cells is associated with lymph node metastasis in prostate cancer. Clin Cancer Res, 2004, 10(15): 5137-5144.
    94. Patila T, Ikonen T, Rutanen J, et al. Vascular endothelial growth factor C-induced collateral formation in a model of myocardial ischemia. J Heart Lung Transplant, 2006, 25(2): 206-213.
    95. Shimizu K, Kubo H, Yamaguchi K, et al. Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer. Cancer Sci, 2004, 95(4): 328-333.
    1. Pereira A, Magrina JF, Rey V, et al. Pelvic and aortic lymph node metastasis in epithelial ovarian cancer. Gynecol Oncol, 2007, 105(3): 604-608.
    2. Markman M. The dangers of "cross-trial" and "cross-retrospective experience" comparisons: examples employing data in the peer-reviewed ovarian cancer literature. Cancer, 2007, 109(10): 1929-1932.
    3. Olsen CM, Green AC, Whiteman DC, et al. Obesity and the risk of epithelial ovarian cancer: a systematic review and meta-analysis. Eur J Cancer, 2007, 43(4): 690-709.
    4. Muggia FM. New and emerging intraperitoneal (IP) drugs for ovarian cancer treatment. Semin Oncol, 2006, 33(6S): S18-24.
    5. Goff BA, Matthews BJ, Larson EH, et al. Predictors of comprehensive surgical treatment in patients with ovarian cancer. Cancer, 2007, 109(10): 2031-2042.
    6. Neal RD, Allgar VL, Ali N, et al. Stage, survival and delays in lung, colorectal, prostate and ovarian cancer: comparison between diagnostic routes. Br J Gen Pract, 2007, 57(536): 212-219.
    7. Li J, Wood WH, Becker KG, et al. Gene expression response to cisplatin treatment in drug-sensitive and drug-resistant ovarian cancer cells. Oncogene, 2007, 26(20): 2860-2872.
    8. Malamou MV, Crikoni O, Timotheadou E, Prognostic significance of HER-2, p53 and Bcl-2 in patients with epithelial ovarian cancer. Anticancer Res, 2007, 27(2): 1157-1165.
    9. Materna V, Surowiak P, Markwitz E, et al. Expression of factors involved in regulation of DNA mismatch repair- and apoptosis pathways in ovarian cancer patients. Oncol Rep, 2007, 17(3): 505-516.
    10. Scoles DR, Pavelka J, Cass I, et al. Characterization of CSOC 882, a novel immortalized ovarian cancer cell line expressing EGFR, HER2, and activated AKT. Gynecol Oncol, 2007, 104(1): 120-128.
    11. Beiner ME, Niv H, Haklai R, et al.Ras antagonist inhibits growth and chemosensitizes human epithelial ovarian cancer cells. Int J Gynecol Cancer, 2006, 16(S1): 200-206.
    12. Fabjani G, Kriegshaeuser G, Schuetz A, et al. Biochip for K-ras mutation screening in ovarian cancer. Clin Chem, 2005, 51(4): 784-787.
    13. Li H, Ye X, Mahanivong C, et al. Signaling mechanisms responsible for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells. J Biol Chem, 2005,280(11): 10564-10571.
    14. Dinulescu DM, Ince TA, Quade BJ, et al. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med, 2005, 11(1): 63-70.
    15. Pieretti M, Hopenhayn RC, Khattar NH, et al. Heterogeneity of ovarian cancer: relationships among histological group, stage of disease, tumor markers, patient characteristics, and survival. Cancer Invest, 2002, 20(1): 11-23.
    16. Parrella P, Zangen R, Sidransky D, et al. Molecular analysis of peritoneal fluid in ovarian cancer patients. Mod Pathol, 2003, 16(7): 636-640.
    17. Tammela J, Odunsi K. Gene expression and prognostic significance in ovarian cancer. Minerva Ginecol, 2004, 56(6): 495-502.
    18. Puputti M, Sihto H, Isola J, et al. Allelic imbalance of HER2 variant in sporadic breast and ovarian cancer. Cancer Genet Cytogenet, 2006, 167(1): 32-38.
    19. Nielsen JS, Jakobsen E, Holund B, et al. Prognostic significance of p53, Her-2, and EGFR overexpression in borderline and epithelial ovarian cancer. Int J Gynecol Cancer, 2004, 14(6): 1086-1096.
    20. Surowiak P, Materna V, Kaplenko I, et al. Topoisomerase 1A, HER/2neu and Ki67 expression in paired primary and relapse ovarian cancer tissue samples. Histol Histopathol, 2006,21(7): 713-20.
    21. Heinrich JK, Bottcher LF, Andrade LL, et al. HER-2 and cancer antigen 125 evaluation in ovarian borderline tumors by immunohistochemistry and fluorescence in situ hybridization. Int J Gynecol Cancer, 2004, 14(6): 1078-1085.
    22. McNeil CM, Sergio CM, Anderson LR, et al. c-Myc overexpression and endocrine resistance in breast cancer. J Steroid Biochem Mol Biol, 2006, 102(1-5): 147-155.
    23. Baldwin RL, Tran H, Karlan BY. Loss of c-myc repression coincides with ovarian cancer resistance to transforming growth factor beta growth arrest independent of transforming growth factor beta/Smad signaling. Cancer Res, 2003, 63(6): 1413-1419.
    24. Chen CH, Shen J, Lee WJ, et al. Overexpression of cyclin D1 and c-Myc gene products in human primary epithelial ovarian cancer. Int J Gynecol Cancer, 2005, 15(5): 878-883.
    25. Wang ZR, Liu W, Smith ST, et al. c-myc and chromosome 8 centromere studies of ovarian cancer by interphase FISH. Exp Mol Pathol, 1999, 66(2): 140-148.
    26. Iba T, Kigawa J, Kanamori Y, et al. Expression of the c-myc gene as a predictor of chemotherapy response and a prognostic factor in patients with ovarian cancer. Cancer Sci, 2004, 95(5): 418-423.
    27. Armaou S, Konstantopoulou I, Anagnostopoulos T, et al. Novel genomic rearrangements in the BRCA1 gene detected in Greek breast/ovarian cancer patients. Eur J Cancer, 2007, 43(2): 443-453.
    28. Simard J, Dumont M, Moisan AM, et al. Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer. J Med Genet, 2007,44(2): 107-121.
    29. Buekers TE, Lallas TA, Buller RE. Xp22.2-3 loss of heterozygosity is associated with germline BRCA1 mutation in ovarian cancer. Gynecol Oncol, 2000, 76(3): 418-422.
    30. Rose SL, Buller RE. The role of p53 mutation in BRCA1-associated ovarian cancer. Minerva Ginecol, 2002, 54(3): 20-29.
    31. Metzinger DS, Taylor DD, Gercel TC. Induction of p53 and drug resistance following treatment with cisplatin or paclitaxel in ovarian cancer cell lines. Cancer Lett, 2006, 236(2): 302-308.
    32. Buchynska LG, Nesina IP, Yurchenko NP, et al. Expression of p53, p21WAF1/CIP1, p16INK4A and Ki-67 proteins in serous ovarian tumors. Exp Oncol, 2007, 29(1): 49-53.
    33. Strano S, Dell S, Mongiovi AM, et al. Mutant p53 proteins: between loss and gain of function. Head Neck, 2007, 29(5): 488-496.
    34. Lopez CE, Bibeau F, Thezenas S, et al. p53 status and response to radiotherapy in rectal cancer: a prospective multilevel analysis. Br J Cancer, 2005, 92(12): 2114-2121.
    35. Yang X, Fraser M, Moll UM, et al.Akt-mediated cisplatin resistance in ovarian cancer: modulation of p53 action on caspase-dependent mitochondrial death pathway. Cancer Res, 2006,66(6): 3126-3136.
    36. Graeff P, Hall J, Crijns AP, et al. Factors influencing p53 expression in ovarian cancer as a biomarker of clinical outcome in multicentre studies. Br J Cancer, 2006, 95(5): 627-633.
    37. Song YC, Kim SH, Juhnn YS, et al. Apoptotic effect of Celecoxib dependent upon p53 status in human ovarian cancer cells. Ann N Y Acad Sci, 2007, 1095: 26-34.
    38. Bruchim I, Fishman A, Friedman E, et al. Analyses of p53 expression pattern and BRCA mutations in patients with double primary breast and ovarian cancer. Int J Gynecol Cancer, 2004, 14(2): 251-258.
    39. Lubet R, Wang Y, Zhang Z, et al. Mouse models incorporating alterations in the major tumor suppressor genes P53 and P16: their use in screening for potential carcinogens, developing further relevant mouse models, and screening for potential chemopreventive and chemotherapetutic agents. Exp Lung Res, 2005, 31(1): 117-133.
    40. Dray M, Russell P, Dalrymple C, et al. p16 (INK4a) as a complementary marker of high-grade intraepithelial lesions of the uterine cervix. I: Experience with squamous lesions in 189 consecutive cervical biopsies. Pathology, 2005, 37(2): 112-124.
    41. Bian Y, Matsubayashi H, Li CP, et al. Detecting low-abundance pl6 and p53 mutations in pancreatic juice using a novel assay: heteroduplex analysis of limiting dilution PCRs. Cancer Biol Ther, 2006, 5(10): 1392-1399.
    42. Schmider RA, Pirsig O, Gottschalk E, et al. Cyclin-dependent kinase inhibitors CIP1 (p21) and KIP1 (p27) in ovarian cancer. J Cancer Res Clin Oncol, 2006, 132(3): 163-170.
    43. Rosen DG, Yang G, Cai KQ, et al. Subcellular localization of p27kipl expression predicts poor prognosis in human ovarian cancer. Clin Cancer Res, 2005, 11(2 Pt 1): 632-637.
    44. Psyrri A, Bamias A, Yu Z, et al. Subcellular localization and protein levels of cyclin-dependent kinase inhibitor p27 independently predict for survival in epithelial ovarian cancer. Clin Cancer Res, 2005, 11(23): 8384-8390.
    45. Li P, Li C, Zhao X, et al. p27(Kip1) stabilization and G(1) arrest by 1,25-dihydroxyvitamin D(3) in ovarian cancer cells mediated through down-regulation of Cyclin E/cyclin-dependent kinase 2 and Skpl-Cullin-F-box protein/Skp2 ubiquitin ligase. J Biol Chem, 2004,279(24): 25260-25267.
    46. Zhou J, Obrate A, Zelnak A, et al. Survivin deregulation in beta-tubulin mutant ovarian cancer cells underlies their compromised mitotic response to taxol. Cancer Res, 2004, 64(23): 8708-8714.
    47. Romagnoli M, Trichet V, David C, et al. Significant impact of Survivin on myeloma cell growth. Leukemia, 2007, 21(5): 1070-1078.
    48. Zaffaroni N, Pennati M, Colella G, et al. Expression of the anti-apoptotic gene Survivin correlates with taxol resistance in human ovarian cancer. Cell Mol Life Sci, 2002, 59(8): 1406-1412.
    49. Eder AM, Sui X, Rosen DG, et al. Atypical PKCiota contributes to poor prognosis through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer. Proc Natl Acad Sci USA, 2005, 102(35): 12519-12524.
    50. Ferrandina G, Legge F, Martinelli E, et al. Survivin expression in ovarian cancer and its correlation with clinico-pathological, surgical and apoptosis-related parameters. Br J Cancer, 2005, 92(2): 271-277.
    51. Vikhanskaya F, Bani MR, Borsotti P, et al. p73 Overexpression increases VEGF and reduces thrombospondin-1 production: implications for tumor angiogenesis. Oncogene, 2001, 20(50): 7293-7300.
    52. Concin N, Hofstetter G, Berger A, et al. Clinical relevance of dominant-negative p73 isoforms for responsiveness to chemotherapy and survival in ovarian cancer: evidence for a crucial p53-p73 cross-talk in vivo. Clin Cancer Res, 2005,11(23): 8372-8383.
    53. Vikhanskaya F, Dincalci M, Broggini M. p73 competes with p53 and attenuates its response in a human ovarian cancer cell line. Nucleic Acids Res, 2000, 28(2): 513-519.
    54. Matsunaga T, Kotamraju S, Kalivendi SV, et al. Ceramide-induced intracellular oxidant formation, iron signaling, and apoptosis in endothelial cells: protective role of endogenous nitric oxide. J Biol Chem, 2004, 279(27): 28614-28624.
    55. Broderick KE, Singh V, Zhuang S, et al. Nitric oxide scavenging by the cobalamin precursor cobinamide. J Biol Chem, 2005, 280(10): 8678-8685.
    56. Musiek ES, Gao L, Milne GL, et al. Cyclopentenone isoprostanes inhibit the inflammatory response in macrophages. J Biol Chem, 2005, 280(42): 35562-35570.
    57. Tedeschi E, Menegazzi M, Yao Y, et al. Green tea inhibits human inducible nitric-oxide synthase expression by down-regulating signal transducer and activator of transcription-1alpha activation. Mol Pharmacol, 2004, 65(1): 111-120.
    58. Florio S, Pagnini U, Crispino A, et al. GnRH and steroids in cancer. Front Biosci, 2002, 7: dl590- 1608.
    59. Leis H, Sanchis A, Perez P. Deletion of the N-terminus of IKKgamma induces apoptosis in keratinocytes and impairs the AKT/PTEN signaling pathway. Exp Cell Res, 2007, 313(4): 742-752.
    60. Lee S, Choi EJ, Jin C, et al. Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol, 2005, 97(1): 26-34.
    61. Saga Y, Mizukami H, Suzuki M, et al. Overexpression of PTEN increases sensitivity to SN-38, an active metabolite of the topoisomerase I inhibitor irinotecan, in ovarian cancer cells. Clin Cancer Res, 2002, 8(5): 1248-1252.
    62. Ramirez PT, Gershenson DM, Tortolero LG, et al. Expression of cell-cycle mediators in ovarian cancer cells after transfection with p16(INK4a), p21(WAF1/Cip-1), and p53. Gynecol Oncol, 2001, 83(3): 543-548.
    63. Guan XY, Fung JM, Ma NF, et al. Oncogenic role of eIF-5A2 in the development of ovarian cancer. Cancer Res, 2004, 64(12): 4197-4200.
    64. Ouellet V, Guyot MC, Page C, et al. Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer. Int J Cancer, 2006, 119(3): 599-607.
    65. Indraccolo S, Tisato V, Agata S, et al. Establishment and characterization of xenografts and cancer cell cultures derived from BRCA1 -/- epithelial ovarian cancers. Eur J Cancer, 2006,42(10): 1475-1483.
    66. Caserta D, Marci R, Porzio G, et al. Pelvic relapses in ovarian cancer. Role of CA-125, transvaginal ultrasound and color Doppler. Eur J Gynaecol Oncol, 2003, 24(3-4): 269-270.
    67. Kupesic S, Plavsic BM. Early ovarian cancer: 3-D power Doppler. Abdom Imaging, 2006,31(5): 613-619.
    68. Lee TS, Kim JW, Park NH, et al. Assessing clinical performance of gynecology residents: sonographic evaluation of adnexal masses based on morphological scoring systems. Ultrasound Obstet Gynecol, 2005, 26(7): 776-779.
    69. Li AJ, Lerner DL, Gapuzan ME, et al. AIB1 polymorphisms predict aggressive ovarian cancer phenotype. Cancer Epidemiol Biomarkers Prev, 2005, 14(12): 2919-2922.
    70. Munkarah A, Chatterjee M, Tainsky MA. Update on ovarian cancer screening. Curr Opin Obstet Gynecol, 2007, 19(1): 22-26.
    71. Kurjak A, Prka M, Arenas JM, et al. Three-dimensional ultrasonography and power Doppler in ovarian cancer screening of asymptomatic peri- and postmenopausal women. Croat Med J, 2005, 46(5): 757-764.
    72. Kurjak A, Kupesic S, Sparac V, et al. The detection of stage I ovarian cancer by three-dimensional sonography and power Doppler. Gynecol Oncol, 2003, 90(2): 258-264.
    73. Takekuma M, Maeda M, Ozawa T, et al. Positron emission tomography with 18F-fluoro-2-deoxyglucose for the detection of recurrent ovarian cancer. Int J Clin Oncol, 2005, 10(3): 177-181.
    74. Nanni C, Rubello D, Farsad M, et al. (18)F-FDG PET/CT in the evaluation of recurrent ovarian cancer: a prospective study on forty-one patients. Eur J Surg Oncol, 2005, 31(7): 792-797.
    75. Risum S, Hogdall C, Loft A, et al. The diagnostic value of PET/CT for primary ovarian cancer—a prospective study. Gynecol Oncol, 2007, 105(1): 145-149.
    76. Thrall MM, DeLoia JA, Gallion H, et al. Clinical use of combined positron emission tomography and computed tomography (FDG-PET/CT) in recurrent ovarian cancer. Gynecol Oncol, 2007, 105(1): 17-22.
    77. Kalofonos HP, Karamouzis MV, Epenetos AA. Radioimmunoscintigraphy in patients with ovarian cancer. Acta Oncol, 2001, 40(5): 549-557.
    78. Sorak M, Arsenijevic S, Lukic G, et al. Relationship of serum levels of tumor markers with tissue expression of gene products in ovarian carcinoma. J BUON, 2007, 12(1): 99-104.
    79. Gilani MM, Karimi ZM, Ghaemmaghami F, et al. A study to evaluate the utility of presurgical CA125 to predict optimal tumor cytoreduction of epithelial ovarian cancer. Gynecol-Oncol. 2007, 105(3): 780-783.
    80. Hogdall EV, Christensen L, Kjaer SK, et al. CA125 expression pattern, prognosis and correlation with serum CA125 in ovarian tumor patients. From The Danish "MALOVA" Ovarian Cancer Study. Gynecol Oncol, 2007, 104(3): 508-515.
    81. Coleman RL, Gordon A, Barter J, et al. Early changes in CA125 after treatment with pegylated liposomal doxorubicin or topotecan do not always reflect best response in recurrent ovarian cancer patients. Oncologist, 2007, 12(1): 72-78.
    82. Do TV, Symowicz JC, Berman DM, et al. Lysophosphatidic acid down-regulates stress fibers and up-regulates pro-matrix metalloproteinase-2 activation in ovarian cancer cells. Mol Cancer Res, 2007, 5(2): 121-131.
    83. Erickson JR, Hasegawa Y, Fang X, et al. Lysophosphatidic acid and ovarian cancer: a paradigm for tumorogenesis and patient management. Prostaglandins Other Lipid Mediat, 2001, 64(1-4): 63-81.
    84. Ren J, Xiao YJ, Singh LS, et al. Lysophosphatidic acid is constitutively produced by human peritoneal mesothelial cells and enhances adhesion, migration, and invasion of ovarian cancer cells. Cancer Res, 2006, 66(6): 3006-3014.
    85. Ugrinska A, Bombardieri E, Stokkel MP, et al. Circulating tumor markers and nuclear medicine imaging modalities: breast, prostate and ovarian cancer. Q J Nucl Med, 2002, 46(2): 88-104.
    86. Mandai M, Konishi I, Kuroda H, et al. LH/hCG action and development of ovarian cancer—a short review on biological and clinical/epidemiological aspects. Mol Cell Endocrinol, 2007, 269(1-2): 61-64.
    87. Bast RC, Brewer M, Zou C, et al. Prevention and early detection of ovarian cancer: mission impossible?. Recent Results Cancer Res, 2007, 174: 91-100.
    88. Zhang A, Meng L, Wang Q, et al. Enhanced in vitro invasiveness of ovarian cancer cells through up-regulation of VEGF and induction of MMP-2. Oncol Rep, 2006, 15(4): 831-836.
    89. Yeh LS, Hung YC, Kao A, et al. Tissue polypeptide specific antigen (TPS) and carbohydrate antigen 125 (CA-125) in the early prediction of recurrent ovarian cancer. Anticancer Res, 2002, 22(6B): 3669-3671.
    90. Saitoh E, Aoki D, Susumu N, et al. Galactosyltransferase associated with tumor in patients with ovarian cancer: factors involved in elevation of serum galactosyltransferase. Int J Oncol, 2003, 23(2): 303-310.
    91. Nanjundan M, Nakayama Y, Cheng KW, et al. Amplification of MDS1/EVI1 and EVI1, located in the 3q26.2 amplicon, is associated with favorable patient prognosis in ovarian cancer. Cancer Res, 2007, 67(7): 3074-3084.
    92. Lokshin AE, Winans M, Landsittel D, et al. Circulating IL-8 and anti-IL-8 autoantibody in patients with ovarian cancer. Gynecol Oncol, 2006, 102(2): 244-251.
    93. Chatterjee M, Mohapatra S, Ionan A, et al. Diagnostic markers of ovarian cancer by high-throughput antigen cloning and detection on arrays. Cancer Res, 2006, 66(2): 1181-1190.
    94. Kong F, Nicole WC, Xiao X, et al. using proteomic approaches to identify new biomarkers for detection and monitoring of ovarian cancer. Gynecol Oncol, 2006, 100(2): 247-253.
    95. Franchi M, Ghezzi F, Beretta P, et al. Microlaparoscopy: a new approach to the reassessment of ovarian cancer patients. Acta Obstet Gynecol Scand, 2000, 79(5): 427-430.
    96. Takeshima N, Hirai Y, UmayaharaK, et al. Lymph node metastasis in ovarian cancer: difference between serous and non-serous primary tumors. Gynecol Oncol, 2005, 99(2): 427-431.
    97. Benedetti PP, Vivo A, Bellati F, et al. Secondary cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer. Ann Surg Oncol, 2007, 14(3): 1136-1142.
    98. Murakami M, Miyamoto T, Iida T, et al. Whole-body positron emission tomography and tumor marker CA125 for detection of recurrence in epithelial ovarian cancer. Int J Gynecol Cancer, 2006, 16(S1): 99-107.
    99. Rose PG. Pegylated liposomal doxorubicin: optimizing the dosing schedule in ovarian cancer. Oncologist, 2005, 10(3): 205-214.
    100. Ghezzi F, Cromi A, Uccella S, et al. Laparoscopy versus laparotomy for the surgical management of apparent early stage ovarian cancer. Gynecol Oncol, 2007, 105(2): 409-413.
    101. Ryerson AB, Eheman C, Burton J, et al. Symptoms, diagnoses, and time to key diagnostic procedures among older U.S. women with ovarian cancer. Obstet Gynecol, 2007, 109(5): 1053-1061.
    102. Hassan R, Remaley AT, Sampson ML, et al. Detection and quantitation of serum mesothelin, a tumor marker for patients with mesothelioma and ovarian cancer. Clin Cancer Res,2006, 12(2): 447-453.
    103. Bardella C, Dettori D, Olivero M, et al. The therapeutic potential of hepatocyte growth factor to sensitize ovarian cancer cells to cisplatin and paclitaxel in vivo. Clin Cancer Res, 2007, 13(7): 2191-2198.
    104. Leiser AL, Maluf FC, Chi DS, et al. A phase I study evaluating the safety and pharmacokinetics of weekly paclitaxel and carboplatin in relapsed ovarian cancer. Int J Gynecol Cancer, 2007, 17(2): 379-386.
    105. Vergote I. Role of surgery in ovarian cancer: an update. Acta Chir Belg, 2004, 104(3): 246-256.
    106. Mahdavi A, Pejovic T, Nezhat F. Induction of ovulation and ovarian cancer: a critical review of the literature. Fertil Steril, 2006, 85(4): 819-826.
    107. Fanning J, Pruett A, Flora RF. Feasibility of the Maylard transverse incision for ovarian cancer cytoreductive surgery. J Minim Invasive Gynecol, 2007, 14(3): 352-355.
    108. Memarzadeh S, Berek JS. Advances in the management of epithelial ovarian cancer. J Reprod Med, 2001, 46(7): 621-629.
    109. Rahaman J, Dottino P, Jennings TS, et al. The second-look operation improves survival in suboptimally debulked stage III ovarian cancer patients. Int J Gynecol Cancer, 2005, 15(1): 19-25.
    110. Harnett P, Buck M, Beale P, et al. Phase II study of gemcitabine and oxaliplatin in patients with recurrent ovarian cancer: an Australian and New Zealand Gynaecological Oncology Group study. Int J Gynecol Cancer, 2007, 17(2): 359-366.
    111. Pecorelli S, Pasinetti B, Tisi G, et al. Optimizing gemcitabine regimens in ovarian cancer. Semin Oncol, 2006, 33(2S6): S17-25.
    112. Tournigand C. Intraperitoneal chemotherapy in ovarian cancer: who and when?. Curr Opin Obstet Gynecol, 2005, 17(1): 83-86.
    113.Kushner DM, Connor JP, Sanchez F, et al. Weekly docetaxel and carboplatin for recurrent ovarian and peritoneal cancer: a phase II trial. Gynecol Oncol, 2007, 105(2): 358-364.
    114. Garsa AA, Andrade RS, Heron DE, et al. Four-dimensional computed tomography-based respiratory-gated whole-abdominal intensity-modulated radiation therapy for ovarian cancer: a feasibility study. Int J Gynecol Cancer, 2007, 17(1): 55-60.
    115. Beral V, Bull D, Green J, et al. Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet, 2007, 369(9574): 1703-1710.
    116. Bristow RE, Eisenhauer EL, Santillan A, et al. Delaying the primary surgical effort for advanced ovarian cancer: a systematic review of neoadjuvant chemotherapy and interval cytoreduction. Gynecol Oncol, 2007, 104(2): 480-490.
    1. Pereira A, Magrina JF, Rey V, et al. Pelvic and aortic lymph node metastasis in epithelial ovarian cancer. Gynecol Oncol, 2007, 105(3): 604-608.
    2. Jin Y, Pan LY, Huang HF, et al. Treatment options for patients with recurrent ovarian cancer: a review of 54 cases. Chin Med Sci J, 2006, 21(1): 11-15.
    3. Cohen I, Maly B, Simon I, et al. Tamoxifen induces heparanase expression in estrogen receptor-positive breast cancer.Clin Cancer Res, 2007, 13(14):4069-4077.
    4. Vlodavsky I, Ilan N, Naggi A, et al.Heparanase: structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate. Curr Pharm Des, 2007, 13(20):2057-2073.
    5. Lee MH, Atkinson S, Murphy G. Identification of the extracellular matrix (ECM) binding motifs of tissue inhibitor of metalloproteinases (TIMP)-3 and effective transfer to TIMP-1.J Biol Chem,2007, 282(9): 6887-6898.
    6. Fan J,Guan S, Cheng CF,et al. PKCdelta clustering at the leading edge and mediating growth factor-enhanced, but not ecminitiated, dermal fibroblast migration. J Invest Dermatol,2006, 126(6): 1233-1243.
    7. Gao J,Su L,Qin R,et al. Transfection of antisense oligodeoxynucleotide inhibits heparanase gene expression and invasive ability of human pancreatic cancer cell in vitro. J Huazhong Univ Sci Technolog Med Sci, 2006,26(1):72-74.
    8. Moretti M,Sinnappah ND,Toller M,et al.HPSE-1 expression and functionality in differentiating neural cells.J Neurosci Res, 2006,83(4):694-701.
    9. Roy M, Reiland J, Murry BP,et al.Antisense-mediated suppression of Heparanase gene inhibits melanoma cell invasion.Neoplasia, 2005,7(3):253-262.
    10. Vlodavsky I,Elkin M,Pappo O,et al. Mammalian heparanase as mediator of tumor metastasis and angiogenesis.Isr Med Assoc J, 2000,2 Suppl:37-45.
    11. Dong J, Kukula AK, Toyoshima M,et al. Genomic organization and chromosome localization of the newly identified human heparanase gene. Gene, 2000, 253(2):171-178.
    12. Nasser NJ,Avivi A,Shushy M,et al. Cloning, expression, and characterization of an alternatively spliced variant of human heparanase. Biochem Biophys Res Commun, 2007,354(1):33-38.
    13. Levy AF, Miao HQ, Heinrikson RL,et al.Heterodimer formation is essential for heparanase enzymatic activity.Biochem Biophys Res Commun, 2003,308(4):885-891.
    14. Vlodavsky I,Goldshmidt O, Zcharia E,et al.Molecular properties and involvement of heparanase in cancer progression and normal development. Biochimie, 2001, 83(8): 831-839.
    15. Naomoto Y,Takaoka M, Okawa T,et al.The role of heparanase in gastrointestinal cancer (Review).Oncol Rep, 2005,14(1): 3-8.
    16. Goldshmidt O, Yeikilis R,Mawasi N,et al.Heparanase expression during normal liver development and following partial hepatectomy. J Pathol, 2004, 203(1 ):594-602.
    17. Nadav L, Eldor A, Yacoby ZO,et al. Activation, processing and trafficking of extracellular heparanase by primary human fibroblasts. J Cell Sci, 2002, 115(Pt 10): 2179-2187.
    18. Hulett MD, Hornby JR, Ohms SJ,et al. Identification of active-site residues of the pro-metastatic endoglycosidase heparanase. Biochemistry, 2000, 39(51): 15659-15667.
    19. Nardella C,Lahm A,Pallaoro M,et al. Mechanism of activation of human heparanase investigated by protein engineering. Biochemistry, 2004, 43(7): 1862-1873.
    20. Kosir MA, Wang W,Zukowski KL,et al. Degradation of basement membrane by prostate tumor heparanase. J Surg Res, 1999,81(1):42-47.
    21. Keren H, Burkhoff D, Squara P.Evaluation of a noninvasive continuous cardiac output monitoring system based on thoracic bioreactance. Am J Physiol Heart Circ Physiol, 2007, 293(1): H583-589.
    22. Ihrcke NS, Parker W, Reissner KJ, et al. Regulation of platelet heparanase during inflammation: role of pH and proteinases. J Cell Physiol, 1998, 175(3):255-267.
    23. Sanderson RD,Yang Y,Kelly T,et al.Enzymatic remodeling of heparan sulfate proteoglycans within the tumor microenvironment: growth regulation and the prospect of new cancer therapies. J Cell Biochem, 2005,96(5): 897-905.
    24. Segev A, Nili N, Strauss BH.The role of perlecan in arterial injury and angiogenesis. Cardiovasc Res, 2004,63(4): 603-610.
    25. Beerens AM, Hadithy AF, Rots MG, et al.Protein transduction domains and their utility in gene therapy. Curr Gene Ther, 2003, 3(5):486-494.
    26. Ancsin JB.Amyloidogenesis: historical and modern observations point to heparan sulfate proteoglycans as a major culprit. Amyloid,2003,10(2):67-79.
    27. Haimov KR,Prus D,Zcharia E,et al.Spatiotemporal expression of heparanase during human and rodent ovarian folliculogenesis. Biol Reprod, 2005,73(1):20-28.
    28. Han J, Woytowich AE, Mandal AK, et al. Heparanase upregulation in high glucose-treated endothelial cells is prevented by insulin and heparin. Exp Biol Med (Maywood), 2007, 232(7):927-934.
    29. Marchetti D, Nicolson GL.Human melanoma cell invasion: selected neurotrophin enhancement of invasion and heparanase activity.J Investig Dermatol Symp Proc, 1997,2(1):99-105.
    30. Marchetti D, Nicolson GL.Neurotrophin stimulation of human melanoma cell invasion: selected enhancement of heparanase activity and heparanase degradation of specific heparan sulfate subpopulations. Adv Enzyme Regul, 1997, 37:111-134.
    31. Walch ET, Albino AP, Marchetti D. Correlation of overexpression of the low-affinity p75 neurotrophin receptor with augmented invasion and heparanase production in human malignant melanoma cells. Int J Cancer, 1999, 82(1): 112-120.
    32. Santiago B, Baleux F, Palao G,et al.CXCL12 is displayed by rheumatoid endothelial cells through its basic amino-terminal motif on heparan sulfate proteoglycans. Arthritis Res Ther, 2006, 8(2):R43.
    33. Kisilevsky R, Szarek WA, Ancsin J, et al.Novel glycosaminoglycan precursors as anti-amyloid agents, part III. J Mol Neurosci, 2003, 20(3):291-297.
    34. Kawashima H,Watanabe N,Hirose M,et al. Collagen XVIII, a basement membrane heparan sulfate proteoglycan, interacts with L-selectin and monocyte chemoattractant protein-1. J Biol Chem, 2003,278(15):13069-13076.
    35. Ghesquiere SA, Hofker M H, Winther MP.The role of phospholipases in lipid modification and atherosclerosis. Cardiovasc Toxicol, 2005,5(2): 161-182.
    36. Chang XZ,Wang ZM,Yu JM,et al.Isolation of a human gallbladder cancer cell clone with high invasive phenotype in vitro and metastatic potential in orthotopic model and inhibition of its invasiveness by heparanase antisense oligodeoxynucleotides. Clin Exp Metastasis, 2007,24(1):25-38.
    37. Doviner V, Maly B, Kaplan V, et al. Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence. Mod Pathol, 2006,19(6): 878- 888
    38. Nadir Y, Brenner B, Zetser A, et al.Heparanase induces tissue factor expression in vascular endothelial and cancer cells. J Thromb Haemost, 2006, 4(11): 2443-2451.
    39. Shafat I, Vlodavsky I, Ilan N.Characterization of mechanisms involved in secretion of active heparanase. J Biol Chem, 2006, 281(33):23804-23811.
    40. Kelly T,Suva LJ,Huang Y,et al. Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases.Cancer Res, 2005,65(13):5778-5784.
    41. Nobuhisa T, Naomoto Y, Ohkawa T, et al.Heparanase expression correlates with malignant potential in human colon cancer. J Cancer Res Clin Oncol, 2005, 131(4): 229-237.
    42. Cao HJ,Fang Y,Zhang X,Chen WJ,et al. Tumor metastasis and the reciprocal regulation of heparanase gene expression by nuclear factor kappa B in human gastric carcinoma tissue. World J Gastroenterol, 2005, 11(6):903-907.
    43. Ohkawa T, Naomoto Y, Takaoka M, et al. Localization of heparanase in esophageal cancer cells: respective roles in prognosis and differentiation.Lab Invest, 2004, 84(10):1289-1304.
    44. Xu X, Quiros RM, Maxhimer JB, et al. Inverse correlation between heparan sulfate composition and heparanase-1 gene expression in thyroid papillary carcinomas: a potential role in tumor metastasis. Clin Cancer Res, 2003, 9(16 Pt 1):5968-5979.
    45. Yang YJ, Zhang YL, Li X,et al. Contribution of eIF-4E inhibition to the expression and activity of heparanase in human colon adenocarcinoma cell line: LS-174T. World J Gastroenterol, 2003, 9(8):1707-1712.
    46. Okada Y,Yamada S,Toyoshima M,et al. Structural recognition by recombinant human heparanase that plays critical roles in tumor metastasis. Hierarchical sulfate groups with different effects and the essential target disulfated trisaccharide sequence. J Biol Chem, 2002,277(45):42488-42495.
    47. Walch ET, Marchetti D.Role of neurotrophins and neurotrophins receptors in the in vitro invasion and heparanase production of human prostate cancer cells. Clin Exp Metastasis, 1999,17(4):307-314.
    48. Parish CR, Freeman C, Brown KJ, et al. Identification of sulfated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity. Cancer Res, 1999,59(14):3433-3441.
    49. Takaoka M, Naomoto Y, Ohkawa T, et al. Heparanase expression correlates with invasion and poor prognosis in gastric cancers. Lab Invest, 2003,83(5): 613-622.
    50. Doviner V,Maly B,Kaplan V,et al. Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence. Mod Pathol, 2006,19 (6):878-888.
    51. Mestre AM, Rao S, Hornby JR, et al. Early growth response gene 1 (EGR1) regulates heparanase gene transcription in tumor cells. J Biol Chem, 2005, 280(42): 35136-35147.
    52. Ikeguchi M, Kaibara N. Detection of circulating cancer cells after a gastrectomy for gastric cancer. Surg Today, 2005, 35(6):436-441.
    53. Ikeguchi M, Hirooka Y. Interleukin-2 gene expression is a new biological prognostic marker in hepatocellular carcinomas. Onkologie, 2005, 28(5):255-259.
    54. Rohloff J,Zinke J,Schoppmeyer K,Tannapfel A. Heparanase expression is a prognostic indicator for postoperative survival in pancreatic adenocarcinoma. Br J Cancer, 2002, 86(8): 1270-1275.
    55. Bitan M, Polliack A, Zecchina G, et al. Heparanase expression in human leukemias is restricted to acute myeloid leukemias. Exp Hematol, 2002, 30(1):34-41.
    56. Sommerfeldt N, Beckhove P, Ge Y, et al. Heparanase: a new metastasis-associated antigen recognized in breast cancer patients by spontaneously induced memory T lymphocytes. Cancer Res, 2006, 66(15):7716-7723.
    57. Sotnikov I, Hershkoviz R, Grabovsky V, et al.Enzymatically quiescent heparanase augments T cell interactions with VCAM-1 and extracellular matrix components under versatile dynamic contexts. J Immunol, 2004, 172(9):5185-5193.
    58. Rechter M,Lider O,Cahalon L,et al.A cellulose-binding domain-fused recombinant human T cell connective tissue-activating peptide-III manifests heparanase activity. Biochem Biophys Res Commun, 1999,255(3):657-662.
    59. Hershkoviz R, Marikovsky M, Gilat D, et al.Keratinocytes-associated chemokines and enzymatically quiescent heparanase induce the binding of resting CD4+ T cells. J Invest Dermatol, 1996,106(2):243-248.
    60. Marchetti D, Mrak RE, Paulsen DD, et al.Neurotrophin receptors and heparanase: a functional axis in human medulloblastoma invasion. J Exp Clin Cancer Res, 2007, 26(1):5-23.
    61. Parish CR, Freeman C, Brown KJ, et al. Identification of sulfated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity. Cancer Res, 1999, 59(14):3433-3441.
    62. Shteper PJ, Zcharia E, Role of promoter methylation in regulation of the mammalian heparanase gene. Oncogene, 2003, 22(49): 7737-7749.
    63. Miao HQ, Liu H, Navarro E. Development of heparanase inhibitors for anti-cancer therapy. Curr Med Chem, 2006, 13(18):2101-2111.
    64. Benezra M, Ishai MR. Structure-activity relationships of heparin-mimicking compounds in induction of bFGF release from extracellular matrix and inhibition of smooth muscle cell proliferation and heparanase activity. J Cell Physiol, 2002, 192(3): 276-285.
    65. Sommerfeldt N, Beckhove P, Ge Y, et al.Heparanase: a new metastasis-associated antigen recognized in breast cancer patients by spontaneously induced memory T lymphocytes. Cancer Res, 2006, 66(15):7716-7723.
    66. Sotnikov I, Hershkoviz R, Grabovsky V, et al.Enzymatically quiescent heparanase augments T cell interactions with VCAM-1 and extracellular matrix components under versatile dynamic contexts. J Immunol, 2004, 172(9): 5185-5193.
    67. Rechter M,Lider O,Cahalon L,et al.A cellulose-binding domain-fused recombinant human T cell connective tissue-activating peptide-III manifests heparanase activity. Biochem Biophys Res Commun, 1999, 255(3):657-662.