摘要
目的：探讨膀胱移行细胞癌(TCCB)中肿瘤血管生成与凝血酶敏感蛋白-1(TSP-1)和转化生长因子α(TGF-α)表达的意义及其与肿瘤微血管密度(MVD)的关系。
方法：收集兰州大学第二医院2007年9月～2009年5月经开放性膀胱肿瘤全切或部分切除标本及经尿道膀胱肿瘤电切手术标本,术后经病理证实为移行细胞癌的石蜡标本85例,排除腺癌、鳞癌、乳头状瘤。另取32例正常膀胱组织作对照,应用免疫组织化学方法检测标本中TSP-1,TGF-α的表达,同时采用CD34标记微血管进行肿瘤MVD计数,并分析其与临床病理参数的关系。
结果：膀胱移行细胞癌和正常膀胱黏膜组织中TSP-1阳性表达率分别为30.6%(26／85)和65.6%(21／32),两者有显著性差异(P<0.01),且与TCCB病理分级、临床分期及肿瘤转移呈负相关表达；TGF-α在膀胱移行细胞癌和正常膀胱组织中阳性表达率分别为74.1%(63／85)和21.9%(7／32)(P<0.01),与膀胱移行细胞癌的病理分级和临床分期及肿瘤转移无明显相关性；膀胱移行细胞癌组织中MVD定量[(66.54±16.19)／mm2],明显高于正常组织[(43.56±11.62)／mm2](P<0.01)。
结论：TSP-1在膀胱移行细胞癌组织和正常膀胱组织相比较表达下调且与病理分级、临床分期及肿瘤转移呈负相关。而TGF-α在膀胱移行细胞癌中的表达却增强。MVD值均高于正常膀胱组织。它们的异常表达提示TSP-1和TGF-α分别是膀胱移行细胞癌血管生成的重要抑制剂和促进剂,是参与调节肿瘤血管形成的密切相关因子。二者共同参与调节了肿瘤的发生发展并有望成为评估膀胱移行细胞癌恶性程度和治疗的新靶点。
Objective:To investigate the expression and significance of thrombospondin-1 (TSP-1), transforming growth factor alpha (TGF-α) in transitional cell carcinoma of bladder and its relationship with microvessel density (MVD) to the tumor angiogenesis.
Methods:The expression of TSP-1 and TGF-αwas detected in 85 transitional cell carcinoma of bladder tissues had been confirmed by pathology, and 32 normal in control cases in paraffin embedded slices by immunohistochemical method, all from the patients underwent surgical radical or partial cystectomy and transurethral resection of bladder tumor in the Second Hospital of Lanzhou University bewteen Sept 2007 to May 2009, adenocarcinoma, squamous cell carcinoma and papillary epithelioma were excluded, meanwhile used CD34 as marker to count MVD. and its correlations of clinicopathologic features were analyzed.
Results:The positive rates of TSP-1 expression in transitional cell carcinoma of bladder and normal bladder mucosa specimens were 30.6%(26/85) and 65.6%(21/32) (P<0.01), respectively. There was close inverse correlation to tumor grade, clinical stage and tumor metastasis. The positive rates of TGF-a expression in bladder transitional cell carcinoma and normal bladder mucosa specimens were 74.1%(63/85) and 21.9%(7/32) (P<0.01), respectively. There was no obvious correlation to tumor grade, clinical stage and tumor metastasis. The mean value of MVD was (66.54±16.19)/mm2 in transitional cell carcinoma of bladder tissues, which were significantly higher than those in the normal bladder mucosa tissues [(43.56±11.62)/mm2] (P<0.01).
Conclusions:The expression of TSP-1 was down-regulated in bladder transitional cell carcinoma compared with normal bladder mucosa specimens and there was close inverse correlation to tumor grade, clinical stage and tumor metastasis. Whereas the expression of TGF-αwas increased, the mean value of MVD was simultaneous higher than in the normal bladder mucosa tissues. The abnormal expression of which suggested that TSP-1 and TGF-αwas a significant suppressor and promoter respectively, were intimate correlation factors to participate in accommodate transitional cell carcinoma of bladder neovascularization and perhaps in tumorigenesis, is expected to be potentially useful for assessing tumor malignany and a novel target for therapeutic intervention against TCCB.
引文
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1 Baenziger N. L, Brodie G. N, Majerus P. W. A thrombin-sensitive protein of human platelet membranes[J]. Proc Natl Acad Sci U S A.1971,68(1):240-243.
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3 Dawson D. W, Pearce S. F, Zhong R, et al. CD36 mediates the In vitro inhibitory effects of thrombospondin-1 on endothelial cells[J]. J Cell Biol.1997,138(3):707-717.
4 Lawler J, Weinstein R., Hynes R. O. Cell attachment to thrombospondin:the role of ARG-GLY-ASP, calcium, and integrin receptors[J]. J Cell Biol.1988,107(6 Pt 1):2351-2361.
5 Kosfeld M. D, Pavlopoulos T. V, Frazier W. A. Cell attachment activity of the carboxyl-terminal domain of human thrombospondin expressed in Escherichia coli[J].J Biol Chem. 1991,266(36):24257-24259.
6 Jimenez B, Volpert O. V, Crawford S. E, et al. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1[J]. Nat Med.2000,6(1):41-48.
7 Guo N, Krutzsch H. C, Inman J. K, et al. Thrombospondin 1 and type Ⅰ repeat peptides of thrombospondin 1 specifically induce apoptosis of endothelial cells[J].Cancer Res.1997, 57(9):1735-1742.
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9 Yu H., Tyrrell D, Cashel J, et al. Specificities of heparin-binding sites from the amino-terminus and type 1 repeats of thrombospondin-1[J]. Arch Biochem Biophys.2000 374(1):13-23.
10 Bagavandoss P, Wilks J. W. Specific inhibition of endothelial cell proliferation by thrombospondin[J]. Biochem Biophys Res Commun.1990,170(2):867-872.
11 Li K, Yang M, Yuen P. M,et al.Thrombospondin-1 induces apoptosis in primary leukemia and cell lines mediated by CD36 and Caspase-3[J] Int J Mol Med.2003,12(6):995-1001.
12 Volm M, Mattern J, Koomagi R. Angiostatin expression in non-small cell lung cancer[J]. Clin Cancer Res.2000,6(8):3236-3240.
13 Sheibani N, Frazier W. A. Thrombospondin 1 expression in transformed endothelial cells restores a normal phenotype and suppresses their tumorigenesis[J]. Proc Natl Acad Sci U S A.1995,92(15):6788-6792.
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