膀胱移行细胞癌中COX-2、VEGF表达及临床意义
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摘要
膀胱癌是泌尿系最常见的恶性肿瘤，在西方工业国家占男性肿瘤死亡的第四或第五位。尽管目前的外科手术技术以及围绕手术结合化疗等医疗技术水平有所提高，但浸润性癌患者的预后仍相当差。因此，将来有可能需要通过发展新的化疗药物或更有效治疗方案来提高膀胱癌患者的生存率。近年来，欧美、日本等国家的科研人员对COX-2作了大量的研究，特别是COX-2与肿瘤关系的研究尤为深入，并发现非甾类抗炎药(NSAIDs)能降低结肠癌的发病率，且在小鼠动物模型试验中能抑制小鼠膀胱癌的发生，探其原因很可能与该类药物对COX-2的抑制作用有关。环氧化酶(Cyclooxygenase，COX)是花生四烯酸合成前列腺素过程中的限速酶，有两种异构体，分别称COX-1和COX-2。COX-1为一种结构型酶，在许多组织和器官内持续表达，而且在维持该组织正常生理功能上扮演重要角色。COX-2是诱导型酶，静息时不表达，可被多种诱导剂(如炎症因子、肿瘤因子、一氧化氮等)激活，且在炎症、肿瘤形成和免疫监视中发挥重要作用。大量的证据表明COX-2与肿瘤的形成有关，在异型上皮细胞内有高表达现象，COX-2表达可能与某些肿瘤的浸润、转移等
郑州大学2003年硕士毕业论文
膀胶移行细胞癌中COX一、们泊F表达及临床意义
特性有关，其过表达可通过激活金属蛋白酶给予体外肿瘤细胞一种浸润
能力，金属蛋白酶是肿瘤浸润的前提，而且COX一2的过度表达能够增加
包括血管内皮生长因子(VEGF)在内的多种血管生成因子的表达。大量
文献报导，血管形成与恶性新生物和肿瘤发展密切相关。而V砚F是其中
之一最重要的血管生成因子，而且在血管形成中扮演重要角色，vEGP表
达与肿瘤的浸润和血管形成密切相关。最近的研究表明，coX一2可能通
过其产物前列腺素E:(PGE办刺激肿瘤组织产生VEGF增多，从而促进肿
瘤血管的形成。已有文献报导，在结肠癌、皮肤黑色素肿瘤及胃癌中
coX一2、VEGF表达与微血管密度(淤D)密切相关。尽管已有COX一2及VEGF
在膀肤癌中过表达的报导，但有关膀肤移行细胞癌中COX一2、VEGF共同
表达及微血管计数关系，以及其表达与病人预后关系的报导还相当少。
资料与方法:在这次研究中，我们采用免疫组织化学技术(S一P法)
检测68例原发性膀肤移行细胞癌(其中G:17例、仪29例、G。22例;
Tis一T、36例、毛一T:32例:26例有淋巴结转移:14例有血管浸润)和
10例非癌膀肤手术标本Cox一2、花GF的表达，并对肿瘤微血管进行计数，
探讨其相互关系及临床意义，以及其表达与病人预后的关系。
结果:l，68例膀胧移行细胞癌标本中CQX一2的阳性表达率为
63，2%(43/68)，VEGF阳性表达率为45，6%(31/68)，对照组10例膀胧粘
膜两者表达均为阴性;2，膀肤移行细胞癌中Cox一2、VEGF表达具有相关
性(r挤0，637，xZ=27.566，P<0，01)，且低分化和浸润性癌组织中COX一2、
vEGF阳性表达率及微血管计数〔则C)显著高于高化分和表浅性癌组
(P
郑州大学2佣3年硕士毕业论文膀胧移行细胞癌中COX.2、VEGF表达及临床意义
阴性者(P<0 .05 P<0.01);4.浅表性膀肤移行细胞癌和浸润性膀肤癌生
存时间与淋巴结转移、血管浸润、肌层浸润深度和化疗方案密切相关，
与年龄、分化程度、性别无关。且COX一2、VEGF表达阳性者生存超过5
年者(54.1%/39.3%)明显低于COX一2、VEGF表达阴性者(91.3%/93.8%)
(P<0.01);其共同表达阳性者生存超过5年者(37.070)明显低于非共
同表达阳性者(93.9.6%)(P 浸润性癌组织中VEGF阳性表达及微血管计数(MVC)均相当高，且与临
床分期、病理分级、血管浸润、淋巴结转移有关(P<0 .01)，而Cox一2阳
性表达与临床分期、病理分级、血管浸润有关(P<0 .05)，而与淋巴结是
否转移无显著性差异(P> .05)。
结论:1.COX一2、VEGF表达具有相关性，其表达与微血管计数及膀
肤移行细胞癌的恶性程度密切相关。2.Cox一2、VEGF过分表达，能增加
膀肤移行细胞癌浸润和转移的可能性，预示预后不佳，可能成为预测膀
肤癌生物学行为的预后指标。3.同时检测Cox一2、vEGF的表达水平在判
断膀肤移行细胞癌预后方面有更大的价值。4.COX一2过分表达在判断肌
层浸润程度方面比VEGF意义更大，而VEGF表达在判断淋巴结转移方面
有更大价值。
Bladder cancer is the most common malignancy of the urinary tract, and the fourth or fifth leading cause of cancerrelated death of men in Wester industrialied countries. The prognosis of patients with advanced bladder cancer is still extremely poor despite recent therapeutic advances, such as improved surgical techniques and perioperative combination chemotherapy. Therefore, future improvement in the survival rate of patients with bladder cancer might be possible through the development of novel indicator or therapeutic strstegies.ln recent years, there are ample studies about COX-2 in Euro-American and America and Japan, especially about the relationship with COX-2 and the formation of tumor. Non-steroid anti-inflammatory drugs(NSAIDs) including aspirin and piroxicam, which are candidate chemopreventive agents active against the development of colon cancer, have
chemo-preventive potential against rat urinary bladder carcinogens induced by N-butyl-N-(4-hydro-xybutyl)nitroamine, The chemo preventive mechanisms of NSAIDs remain to be elucidated in detail, but have been postulated to involve their abilities to inhibit cyclooxy -genase(COX) activity. COX catalyzes the synthesis of prostaglandin's from arachidonic acid. There are two isoforms of COX: one is constitutively expressed (COX-l)and other is inducible (COX-2). COX-1 is a constitutively expressed gene in many tissues, and levels of this protein do not fluctuate in response to stimuli. COX-2 is induced by pathologic stimuli, such as inflammation, various growth factors, and cytokines produced by tumor cells. Multiple lines of evidence suggest that COX-2 is important in carcinogen sis, and COX-2 is up-regulated in transformed cells. COX-2 also may be involved in certain features of tumor aggressiveness such as invasion and metastasis. Over expression of COX-2 confers invasive ability on tumor cells in vitro by activating metal- oproteinase,which is a prerequisite for tumor invasion. Furthermore, over expression of COX-2 increases production of variable proangiogenic factors including vascular endothelial growth factor. Recently, many studies have reported on the relation between the malignant potential of neoplasm and tumor angiogenesis. Vascular endothelial growth factor (VEGF) is one of these angiogenic factors, and is known to play a crucial role in the formation of neovasculature. VEGF expression is correlated significantly with tumor vascularity and a marker for tumor
angiogenesis. The current study indicate that expression of COX-2 contributes to angiogenesis in tumor, This action is probably related to the production of angiogenic factors VEGF modulated by COX-2. Recently cox-2 overexpression has been reported in human colon cancer and colorectal carcinoma and gastric carcinoma. And the over expression of COX-2 and VEGF have also been reported in human transitional cell carcinoma of bladder .However, There are few reports about the expression of COX-2 and VEGF in human transitional cell carcinoma of bladder and its relationship with the formation of microvessels and their clinical significance and the prognosis value in transitional cell carcinoma of bladder.
Materials and Methods: In the current study, expression of COX-2 ,VEGF and MVC were detected by immunohistochemical method(S-p method) in 68 specimens of transitional cell carcinoma of bladder(Histologic grades were classified into there groups,Grades1,2and Grade3,Local invasion was classified into two groups, pTis~T1 and pT2-4, 26 including metastatic lymph nodes, 14 including vascular invasion) and in 10 normal bladder mucosa as control, the relationship among the expression of COX-2, VEGF and microvessel count (MVC) were studied and their clinical significance in transitional cell carcinoma of bladder were evaluated
Results: 1. COX-2 was positive in 43 specimens(63.2%)while was negative in all controls and VEGF was positive in 31 specimens(45.6%) while was negative in all controls . 2. The expression of COX-2 and VEGF is
correlated (rs=0. 637, x2=27. 566, P<0. 01). And the positive rates
郑州大学2003年硕士毕业论文
膀胶移行细胞癌中COX一、们泊F表达及临床意义
特性有关，其过表达可通过激活金属蛋白酶给予体外肿瘤细胞一种浸润
能力，金属蛋白酶是肿瘤浸润的前提，而且COX一2的过度表达能够增加
包括血管内皮生长因子(VEGF)在内的多种血管生成因子的表达。大量
文献报导，血管形成与恶性新生物和肿瘤发展密切相关。而V砚F是其中
之一最重要的血管生成因子，而且在血管形成中扮演重要角色，vEGP表
达与肿瘤的浸润和血管形成密切相关。最近的研究表明，coX一2可能通
过其产物前列腺素E:(PGE办刺激肿瘤组织产生VEGF增多，从而促进肿
瘤血管的形成。已有文献报导，在结肠癌、皮肤黑色素肿瘤及胃癌中
coX一2、VEGF表达与微血管密度(淤D)密切相关。尽管已有COX一2及VEGF
在膀肤癌中过表达的报导，但有关膀肤移行细胞癌中COX一2、VEGF共同
表达及微血管计数关系，以及其表达与病人预后关系的报导还相当少。
资料与方法:在这次研究中，我们采用免疫组织化学技术(S一P法)
检测68例原发性膀肤移行细胞癌(其中G:17例、仪29例、G。22例;
Tis一T、36例、毛一T:32例:26例有淋巴结转移:14例有血管浸润)和
10例非癌膀肤手术标本Cox一2、花GF的表达，并对肿瘤微血管进行计数，
探讨其相互关系及临床意义，以及其表达与病人预后的关系。
结果:l，68例膀胧移行细胞癌标本中CQX一2的阳性表达率为
63，2%(43/68)，VEGF阳性表达率为45，6%(31/68)，对照组10例膀胧粘
膜两者表达均为阴性;2，膀肤移行细胞癌中Cox一2、VEGF表达具有相关
性(r挤0，637，xZ=27.566，P<0，01)，且低分化和浸润性癌组织中COX一2、
vEGF阳性表达率及微血管计数〔则C)显著高于高化分和表浅性癌组
(P
郑州大学2佣3年硕士毕业论文膀胧移行细胞癌中COX.2、VEGF表达及临床意义
阴性者(P<0 .05 P<0.01);4.浅表性膀肤移行细胞癌和浸润性膀肤癌生
存时间与淋巴结转移、血管浸润、肌层浸润深度和化疗方案密切相关，
与年龄、分化程度、性别无关。且COX一2、VEGF表达阳性者生存超过5
年者(54.1%/39.3%)明显低于COX一2、VEGF表达阴性者(91.3%/93.8%)
(P<0.01);其共同表达阳性者生存超过5年者(37.070)明显低于非共
同表达阳性者(93.9.6%)(P
床分期、病理分级、血管浸润、淋巴结转移有关(P<0 .01)，而Cox一2阳
性表达与临床分期、病理分级、血管浸润有关(P<0 .05)，而与淋巴结是
否转移无显著性差异(P> .05)。
结论:1.COX一2、VEGF表达具有相关性，其表达与微血管计数及膀
肤移行细胞癌的恶性程度密切相关。2.Cox一2、VEGF过分表达，能增加
膀肤移行细胞癌浸润和转移的可能性，预示预后不佳，可能成为预测膀
肤癌生物学行为的预后指标。3.同时检测Cox一2、vEGF的表达水平在判
断膀肤移行细胞癌预后方面有更大的价值。4.COX一2过分表达在判断肌
层浸润程度方面比VEGF意义更大，而VEGF表达在判断淋巴结转移方面
有更大价值。
Bladder cancer is the most common malignancy of the urinary tract, and the fourth or fifth leading cause of cancerrelated death of men in Wester industrialied countries. The prognosis of patients with advanced bladder cancer is still extremely poor despite recent therapeutic advances, such as improved surgical techniques and perioperative combination chemotherapy. Therefore, future improvement in the survival rate of patients with bladder cancer might be possible through the development of novel indicator or therapeutic strstegies.ln recent years, there are ample studies about COX-2 in Euro-American and America and Japan, especially about the relationship with COX-2 and the formation of tumor. Non-steroid anti-inflammatory drugs(NSAIDs) including aspirin and piroxicam, which are candidate chemopreventive agents active against the development of colon cancer, have
chemo-preventive potential against rat urinary bladder carcinogens induced by N-butyl-N-(4-hydro-xybutyl)nitroamine, The chemo preventive mechanisms of NSAIDs remain to be elucidated in detail, but have been postulated to involve their abilities to inhibit cyclooxy -genase(COX) activity. COX catalyzes the synthesis of prostaglandin's from arachidonic acid. There are two isoforms of COX: one is constitutively expressed (COX-l)and other is inducible (COX-2). COX-1 is a constitutively expressed gene in many tissues, and levels of this protein do not fluctuate in response to stimuli. COX-2 is induced by pathologic stimuli, such as inflammation, various growth factors, and cytokines produced by tumor cells. Multiple lines of evidence suggest that COX-2 is important in carcinogen sis, and COX-2 is up-regulated in transformed cells. COX-2 also may be involved in certain features of tumor aggressiveness such as invasion and metastasis. Over expression of COX-2 confers invasive ability on tumor cells in vitro by activating metal- oproteinase,which is a prerequisite for tumor invasion. Furthermore, over expression of COX-2 increases production of variable proangiogenic factors including vascular endothelial growth factor. Recently, many studies have reported on the relation between the malignant potential of neoplasm and tumor angiogenesis. Vascular endothelial growth factor (VEGF) is one of these angiogenic factors, and is known to play a crucial role in the formation of neovasculature. VEGF expression is correlated significantly with tumor vascularity and a marker for tumor
angiogenesis. The current study indicate that expression of COX-2 contributes to angiogenesis in tumor, This action is probably related to the production of angiogenic factors VEGF modulated by COX-2. Recently cox-2 overexpression has been reported in human colon cancer and colorectal carcinoma and gastric carcinoma. And the over expression of COX-2 and VEGF have also been reported in human transitional cell carcinoma of bladder .However, There are few reports about the expression of COX-2 and VEGF in human transitional cell carcinoma of bladder and its relationship with the formation of microvessels and their clinical significance and the prognosis value in transitional cell carcinoma of bladder.
Materials and Methods: In the current study, expression of COX-2 ,VEGF and MVC were detected by immunohistochemical method(S-p method) in 68 specimens of transitional cell carcinoma of bladder(Histologic grades were classified into there groups,Grades1,2and Grade3,Local invasion was classified into two groups, pTis~T1 and pT2-4, 26 including metastatic lymph nodes, 14 including vascular invasion) and in 10 normal bladder mucosa as control, the relationship among the expression of COX-2, VEGF and microvessel count (MVC) were studied and their clinical significance in transitional cell carcinoma of bladder were evaluated
Results: 1. COX-2 was positive in 43 specimens(63.2%)while was negative in all controls and VEGF was positive in 31 specimens(45.6%) while was negative in all controls . 2. The expression of COX-2 and VEGF is
correlated (rs=0. 637, x2=27. 566, P<0. 01). And the positive rates
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40. Song ZJ, Gong P, Wu YE. Relationship between the expression of iNOS, VEGF, tumor angiogenesis and gastric cancer. World J Gastroentero12002; 8:591-595
41. Lnoue K, Kamda M, Slaton JM.et el.The prognostic value of angiogenesis and metastasis-related genes for progression of transitional cell carcinoma of the renal pelvis and ureter. Clin Cancer Res.2002 Jun;8(6); 1863-70
42. Grew TPO Brien T, Bradburu M,et el.Vascular endothelial growth factor is a predictor of relapse and stage progression in superficial bladder cancer .Cancer Res. 1997;57(23):5281-5
43. Liu X H,Kirschenbaum A,Yao S,et al .Upregulation of vascular endothelial, growth factor by cobalt ehloridesimulated hypoxia is mediatde by persistent induction of cyclooxygenase-2 in a metastatic human pristate cancer cell line.Clin Exp Metastasis 1999, 17-687-694
44. Tsujii M, Kawano S,Tsuji S, et el. Cyclooxygenase regulates angiogenesis induced by colon cancer cells.Cell 1998;93;705-16
45. Fosslien E. Molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis. Ann Clin Lab Sci 2001; 31:325-348
46. Li G, Yang T, Yan J.et al.Cyclooxygenase-2 increased the angiogenic and metastatic potential of tumor cetls.Biochem Biophys Res Commun 2002 20;299(5):886-90
47. Majima M, Haya Shiz, Muramatsn M, et al.Cyclooxygenase-2 enhances bacsic fibroblast groowth thetor-indueed angiogenesis through induction of vascular endothelial growth factor in rat sponge implants .Br J Pharmacol,2000; 130(3):641-9
48. Catelys.The contributions-of Cyclooxygenase-2 to tumor angiogenesis. Cancer Metastasis Rev,2000; 19(1-2): 19-27
49. Masferrer J.Approach to angiogenesis inhibition based on Cyclooxygenase-2. Cancer J,2001 Nov-Del;7 suppl 3:s144-50.Review
50. Leahy KM, Orabtrg RL, Wang Y, et al. Cyctooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogentic endothelial cells in vivo.Cancer Res ,2002 ;62(3):625-31
51. Maeda K, Chung YS, Ogawa Y, Takatsuka S, Kang SM, Ogawa M, Sawada T, Sowa M. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer 1996; 77:858-863
52. Maeda K, Kang SM, Onoda N, Ogawa M, Kato Y, Sawada T, Chung KH. Vascular endothelial growth factor expression in preoperative biopsy specimens correlate with disease recturrence in patients with early gastric
carcinoma. Cancer 1999; 86:566-57
53. Sato K, Sasaki R, Ogura ,et al.Expression of vascular endothelial growth factor gene and its receptor(fit-1) gene in urinary bladder cancer. Tchoku J Exp Med, 1998,158:173-184
54. Offersen BV, Knup MM,Marcussen N,et al.Intense inflammation in bladder earcinorna is associated with angiogenesis and indicates good prognesis. Br J Cancer.2002 Dec 2;87(12); 1422-30
55. Chaudhary R,Bromley M, Clarke NW, et al. Prognostic relevance of micro-vessel density in cancer of the urinary bladder .Anticancer Res. 1999 Jul-Aug; 19(4c);3479-84
56. Offersen BV, Borre M, Overgoard J,et al.Quantification of angi0-genesis as a prognositie marker in human eareinomas:a erieical evaluation of histopathological methods for estimation of vascular density.Eur J.Cancer. 2003 may;39(7):881-90