生成拟态和不良预后的意义

摘要/Abstract

摘要： 目的探讨MMP-1，- 2，- 9，- 14表达与胆囊癌患者的预后和有/无血管生成拟态的相关性。方法免疫组化染色(IHC)计算机图像定量分析、高/低免疫反应性截点得分选择和ROC曲线被用来分析基质金属蛋白酶(MMP，2，9，和14)在89例胆囊癌(GBC)表达及其与血管生成拟态(VM)和临床病理特征、预后的相关性。结果 MMP-2与MMP-14(MT1-MMP)表达明显与胆囊癌VM相关(P均＜0.01)，与Nevin分期、分化和无VM组肝转移程度相关(P均＜0.05);此外，MMP-2表达也与浆膜浸润和VM组肝转移相关(P均＜0.05)。在胆囊癌VM患者中，MMP-2表达与临床病理参数如中度分化、Nevin分期(S3-S5)、肝转移、浆膜浸润和淋巴结转移相关(P＜0.05)，MMP-14表达与分化程度(G2和G3)、Nevin分期、淋巴结转移、浆膜侵犯、阴性肝转移和浆膜浸润相关(P均＜0.05)。多变量分析显示，MMP-2与MMP-14为胆囊癌VM阴性或阳性患者总生存和不良预后的独立因素(P均＜0.05)。结论 MMP-2、MMP-14是有/无VM胆囊癌患者的独立的预后因素，在VM形成和GBC进展中可能起重要作用。

关键词: 血管生成拟态, 基质金属蛋白酶, 胆囊肿瘤, 预后

Abstract: Objective To investigate MMP-1,-2,-9,-14 expressions and their correlation with prognosis of the gallbladder carcinoma patients with/without vasculogenic mimicry.Methods Immunohistochemistry (IHC) computer-assisted quantitative image analysis and receiver operating characteristic curve were used to analyze expression of MMPs (MMP-1,-2,-9,and -14) in 89 gallbladder carcinoma (GBC) samples,IHC quantitative analysis and selection of the cut-off score for high or low IHC reactivity.Correlation of MMPs expression with vasculogenic mimicry (VM),clinicopathologic features and prognosis of GBC patients with VM and non-VM was evaluated simultaneously.Reaults Over-expression of MMP-2 and MMP-14 was significantly associated with VM in GBC (both P<0.01).Moreover,the expression of MMP-2 and MMP-14 was correlated with Nevin stage,degree of differentiation and liver metastasis in non-VM group (both P<0.05).In addition,MMP-2 expression was also associated with serosal invasion and liver metastasis in VM group (both P<0.05).Over-expression of MMP-2 in GBC patients was associated with VM in the same subset of clinicopathologic parameters,including moderate degree of differentiation,Nevin stage (S3-S5),positive liver metastasis,serosal invasion and lymph node metastasis (both P<0.05).Moreover,over-expression of MMP-14 in GBC patients was correlated with VM in the same subset of clinicopathologic parameters,including degree of differentiation (G2 and G3),Nevin stage,positive lymph node metastasis and serosal invasion,negative liver metastasis and serosal invasion(both P<0.05).Multivariate analysis showed that MMP-2 and MMP-14 were independent factors for the overall survival (OS) rate and associated with poor prognosis either in VM negative or positive group (both P<0.05).Conclusion MMP-2 and MMP-14 were independent factors,associated with prognosis of the GBC patients with/without VM,might play significant role in VM formation and progression of GBC.

Key words: Vasculogenic mimicry, Matrix metalloproteinases, Matrix metalloproteinase 2, Matrix metalloproteinase 14, Gallbladder neoplasm, Prognosis

中图分类号:

R575.6

孙伟，范跃祖，张文忠，葛春燕. 生成拟态和不良预后的意义[J]. 外科研究与新技术, 2013, 2(2): 73-86.

SUN Wei,FAN Yue-Zu,ZHANG Wen-Zhong,GE Chun-Yan. MMP-2 and MT1-MMP contribute to vasculogenic mimicry and poor prognosis in human primary gallbladder carcinomas[J]. 外科研究与新技术, 2013, 2(2): 73-86.

参考文献

[1] Miller G,Jarnagin WR.Gallbladder carcinoma[J].EJSO,2008,34(3):306-312.
[2] Hsing AW,Gao YT,Devesa SS,et al.Rising incidence of biliary tract cancers in Shanghai,China[J].Int J Cancer,1998,75(3):368-370.
[3] Zhu AX,Hong TS,Hezel AF,et al.Current management of gallbladder carcinoma[J].Oncologist,2010,15(2):168-181.
[4] Maniotis AJ,Folberg R,Hess A,et al.Vascular channel formation by human melanoma cells in vivo and in vitro:vasculogenic mimicry[J].Am J Pathol,1999,155(3):739-752.
[5] Hendrix MJ,Seftor EA,Hess AR,et al.Vasculogenic mimicry and tumor-cell plasticity:lessons from melanoma[J].Nat Rev Cancer,2003,3(6):411-421.
[6] Lissitzky JC,Parriaux D,Ristorcelli E,et al.Cyclic AMP signaling as a mediator of vasculogenic mimicry in aggressive human melanoma cells in vitro[J].Cancer Res,2009(3),69:802-809.
[7] Vartanian AA,Stepanova EV,Gutorov SL,et al.Prognostic significance of periodic acid-Schiff-positive patterns in clear cell renal cell carcinoma[J].Can J Urol,2009,16(4):4726-4732.
[8] Sood AK,Fletcher MS,Zahn CM,et al.The clinical significance of tumor cell-lined vasculature in ovarian carcinoma:implications for anti-vasculogenic therapy[J].Cancer Biol Ther,2002,1(6):661-664.
[9] Sood AK,Fletcher MS,Coffin JE,et al.Functional role of matrix metalloproteinases in ovarian tumor cell plasticity[J].Am J Obstet Gynecol,2004,190(4):899-909.
[10] Sun B,Zhang S,Zhang D,et al.Vasculogenic mimicry is associated with high tumor grade,invasion and metastasis,and short survival in patients with hepatocellular carcinoma[J].Oncol Rep,2006,16(4):693-698.
[11] Shirakawa K,Wakasugi H,Heike Y,et al.Vasculogenic mimicry and pseudo-comedo formation in breast cancer[J].Int J Cancer,2002,99(6):821-828.
[12] Basu GD,Liang WS,Stephan DA,et al.A novel role for cyclooxygenase-2 in regulating vascular channel formation by human breast cancer cells[J].Breast Cancer Res,2006,8(6):R69.
[13] Robertson FM,Simeone AM,Lucci A,et al.Differential regulation of the aggressive phenotype of inflammatory breast cancer cells by prostanoid receptors EP3 and EP4[J].Cancer,2010,116(11):2806-2814.
[14] Wang W,Lin P,Han C,et al.Vasculogenic mimicry contributes to lymph node metastasis of laryngeal squamous cell carcinoma[J].J Exp Clin Cancer Res,2010,Jun 2;29:60.
[15] El Hallani S,Boisselier B,Peglion F,et al.A new alternative mechanism in glioblastoma vascularization:tubular vasculogenic mimicry[J].Brain,2010,133(Pt 4):973-982.
[16] Li M,Gu Y,Zhang Z,et al.Vasculogenic mimicry:a new prognostic sign of gastric adenocarcinoma[J].Pathol Oncol Res,2010,16(2):259-266.
[17] Baeten CI,Hillen F,Pauwels P,et al.Prognostic role of vasculogenic mimicry in colorectal cancer[J].Dis Colon Rectum,2009,52(12):2028-2035.
[18] Zhao H,Gu XM.Study on vasculogenic mimicry in malignant esophageal stromal tumors[J].World J Gastroenterol,2008,14(15):2430-2433.
[19] Sun B,Qie S,Zhang S,et al.Role and mechanism of vasculogenic mimicry in gastrointestinal stromal tumors[J].Hum Pathol,2008,39(3):444-451.
[20] McCawley LJ,Matrisian LM.Matrix metalloproteinases:multifunctional contributors to tumor progression[J].Mol Med Today,2000,6(4):149-156.
[21] Noel A,Gilles C,Bajou K,et al.Emerging roles for proteinases in cancer[J].Invasion & Metastasis,1997,17(5):221-239.
[22] Stetler-Stevenson WG.Matrix metalloproteinases in angiogenesis:a moving target for therapeutic intervention[J].J Clin Invest,1999,103(9):1237-1241.
[23] Seiki M.Membrane-type matrix metalloproteinases[J].Apmis,1999,107(1):137-143.
[24] Hess AR,Seftor EA,Seftor RE,et al.Phosphoinositide 3-kinase regulates membrane Type 1-matrix metalloproteinase (MMP) and MMP-2 activity during melanoma cell vasculogenic mimicry[J].Cancer Res,2003,63(16):4757-4762.
[25] Hendrix MJ,Seftor EA,Kirschmann DA,et al.Remodeling of the microenvironment by aggressive melanoma tumor cells[J].Ann N Y Acad Sci,2003,May,995:151-161.
[26] Seftor RE,Seftor EA,Kirschmann DA,et al.Targeting the tumor microenvironment with chemically modified tetracyclines:inhibition of laminin 5 gamma 2 chain promigratory fragments and vasculogenic mimicry[J].Mol Cancer Ther,2002,1:1173-1179.
[27] Seftor RE,Seftor EA,Koshikawa N,et al.Cooperative interactions of laminin 5 gamma2 chain,matrix metalloproteinase-2,and membrane type-1-matrix/ metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma[J].Cancer Res,2001,61(17):6322-6327.
[28] Sun B,Zhang D,Zhang S,et al.Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma[J].Cancer Lett,2007,249(2):188-197.
[29] van der Schaft DW,Seftor RE,Seftor EA,et al.Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells[J].J Natl Cancer Inst,2004,96(19):1473-1477.
[30] Fan YZ,Sun W,Zhang WZ,et al.Vasculogenic mimicry in human primary gallbladder carcinoma and clinical significance thereof[J].Zhonghua Yi Xue Za Zhi,2007,87(3):145-149.
[31] Wang CJ,Zhou ZG,Holmqvist A,et al.Survivin Expression Quantified by Image Pro-plus Compared With Visual Assessment[J].Appl Immunohistochem Mol Morphol,2009,17(6):530-535.
[32] Xavier LL,Viola GG,Ferraz AC,et al.A simple and fast densitometric method for the analysis of tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta and in the ventral tegmental area[J].Brain Res Protoc,2005,16(1-3):58-64.
[33] Situ DR,Hu Y,Zhu ZH,et al.Prognostic relevance of beta-catenin expression in T2-3N0M0 esophageal squamous cell carcinoma[J].World J Gastroenterol,2010,16(41):5195-5202.
[34] Zlobec I,Steele R,Terracciano L,et al.Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer[J].J Clin Pathol,2007,60(10):1112-1116.
[35] Karadag N,Kirimlioglu H,Isik B,et al.Expression of matrix metalloproteinases in gallbladder carcinoma and their significance in carcinogenesis[J].Appl Immunohistochem Mol Morphol,2008,16(2):148-152.
[36] Fan YZ,Zhang JT,Yang HC,et al.Expression of MMP-2,TIMP-2 protein and the ratio of MMP-2/TIMP-2 in gallbladder carcinoma and their significance[J].World J Gastroenterol,2002,8(6):1138-1143.
[37] Zhang S,Zhang D,Sun B.Vasculogenic mimicry:current status and future prospects[J].Cancer Lett,2007,254(2):157-164.
[38] Williams TM,Medina F,Badano I,et al.Caveolin-1 gene disruption promotes mammary tumorigenesis and dramatically enhances lung metastasis in vivo.Role of Cav-1 in cell invasiveness and matrix metalloproteinase (MMP-2/9) secretion[J].J Biol Chem,2004,279(49):51630-51646.
[39] Miyamori H,Takino T,Kobayashi Y,et al.Claudin promotes activation of pro-matrix metalloproteinase-2 mediated by membrane-type matrix metalloproteinases[J].J Biol Chem,2001,276(30):28204-28211.
[40] Nelson AR,Fingleton B,Rothenberg ML,et al.Matrix metalloproteinases:Biologic activity and clinical implications[J].J Clin Oncol,2000,18(5):1135-1149.
[41] Zucker S,Drews M,Conner C,et al.Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor,membrane type 1 matrix metalloproteinase 1 (MT1-MMP)[J].J Biol Chem,1998,273(2):1216-1222.
[42] Lafleur MA,Handsley MM,Knauper V,et al.Endothelial tubulogenesis within fibrin gels specifically requires the activity of membrane-type-matrix metalloproteinases (MT-MMPs)[J].J Cell Sci,2002,115(17):3427-3438.
[43] Koike T,Vernon RB,Hamner MA,et al.MT1-MMP,but not secreted MMPs,influences the migration of human microvascular endothelial cells in 3-dimensional collagen gels[J].J Cell Biochem,2002,86(4):748-758.
[44] Haas TL,Davis SJ,Madri JA.Three-dimensional type I collagen lattices induce coordinate expression of matrix metalloproteinases MT1-MMP and MMP-2 in microvascular endothelial cells[J].J Biol Chem,1998,273:3604-3610.