非小细胞肺癌CD44途径免疫逃逸机制的初步研究及其临床意义
摘要
目的探讨非小细胞肺癌CD44途径免疫逃逸的机制及其临床意义。方法采用免疫组化EnVison法，检测CD44s、CD44v6以及Fas基因蛋白在60例非小细胞肺癌组织中的表达，分析其相关性。结果1．与癌旁肺组织相比，Fas基因蛋白在非小细胞肺癌组织中的表达减弱，Fas在肺鳞癌和腺癌的表达率为62.5％和46.4％。2．CD44s和CD44v6在癌旁正常肺组织未见表达；CD44s在鳞癌和腺癌的表达率分别为83.3％和54.2％，CD44v6在鳞癌和腺癌的表达率分别为81.0％和39.6％。3．Fas、CD44s和CD44v6的表达均与肿瘤TNM分期、分化程度及淋巴结转移相关(P＜0.01)，TNM分期越晚，分化越低，有淋巴结转移时，Fas和CD44s的表达的强度越弱、阳性率越低，而CD44v6表达的强度越强、阳性率越高。结论1．非小细胞肺癌通过癌细胞表面CD44分子的构型由标准型向变异体改变(CD44s——CD44v6)，降低其Fas的表达，从而逃脱Fas-FasL介导的细胞凋亡，这可能是非小细胞肺癌存在CD44途径免疫逃逸。2非小细胞肺癌CD44s、CD44v6及Fas基因蛋白的检测可能为机体免疫状态、肿瘤进展程度及其预后的判断指标。
Objective To study the mechanism of CD44 way immune escape in non-smallcell lung cancer and its clinical significance. Methods EnVison immunohistochemicalmethod was used to study the expression of Fas, CD44v6 and CD44s in 60 cases ofnon-small lung cancer and adjcent normal lung tissue. Results 1. The expression ofFas in non-small cell lung cancer (NSCIC) weaken campare with adjcent normal lungtissue, and positive expression rates are 100%, 62.5% and 46.4% in adjcent normallung tissue, squamous cell carcinomas and adenocacinomas respectively. 2. NoCD44s and CD44v6 positive expressions is seen in adjcent normal lung tissue.Positive expressions of CD44s is 83.3% and 54.2% in squamous cell carcinomas andadenocacinomas respectively, and positive expressions of CD44v6 is 81.0% and39.6% in squamous cell carcinomas and adenocacinomas respectively. 3. Expressionof Fas, CD44s and CD44v6 are correlated with NSCLC's TNM stages, differentiationand lymphatic metastasis. Expression of Fas and CD44s weaken in late stage, lowerdifferentiation and lymphatic metastasis cases, and their positive expression decrease,however, Expression of CD44v6 is on the contrary. Conclusion 1. The mechanism ofCD44 way immune escape in NSCLC may lie in the transformation of CD44 moleculefrom standard type to variant type, variant type CD44 molecule causes the weaken of Fasexpression, so the cancer cell can escape from the apoptosis mediated by Fas-FasLsystem. 2. Detection of the expression of Fas, CD44s and CD44v6 may show immunestatus, degree of tumor's advancement and prognosis of NSCLC.
Objective To study the mechanism of CD44 way immune escape in non-smallcell lung cancer and its clinical significance. Methods EnVison immunohistochemicalmethod was used to study the expression of Fas, CD44v6 and CD44s in 60 cases ofnon-small lung cancer and adjcent normal lung tissue. Results 1. The expression ofFas in non-small cell lung cancer (NSCIC) weaken campare with adjcent normal lungtissue, and positive expression rates are 100%, 62.5% and 46.4% in adjcent normallung tissue, squamous cell carcinomas and adenocacinomas respectively. 2. NoCD44s and CD44v6 positive expressions is seen in adjcent normal lung tissue.Positive expressions of CD44s is 83.3% and 54.2% in squamous cell carcinomas andadenocacinomas respectively, and positive expressions of CD44v6 is 81.0% and39.6% in squamous cell carcinomas and adenocacinomas respectively. 3. Expressionof Fas, CD44s and CD44v6 are correlated with NSCLC's TNM stages, differentiationand lymphatic metastasis. Expression of Fas and CD44s weaken in late stage, lowerdifferentiation and lymphatic metastasis cases, and their positive expression decrease,however, Expression of CD44v6 is on the contrary. Conclusion 1. The mechanism ofCD44 way immune escape in NSCLC may lie in the transformation of CD44 moleculefrom standard type to variant type, variant type CD44 molecule causes the weaken of Fasexpression, so the cancer cell can escape from the apoptosis mediated by Fas-FasLsystem. 2. Detection of the expression of Fas, CD44s and CD44v6 may show immunestatus, degree of tumor's advancement and prognosis of NSCLC.
引文
Esposito V, Baldi A, Liuzzi G, et al. Analysis of Fas (Apo-1/CD95) expression in non-small cell lung cancer[J].Anticancer Res. 2003 Nov-Dec;23(6C):4901-4905.
2 rakigawa N, Segawa Y, Mandai K, et al. Serum CD44 levels in patients with non-small cell lung cancer and their relationship with clinicopathological features[J].Lung Cancer, 1997,18(2): 147-157.
3 Yasuda M, Tanaka Y, Fjii K, et al. CD44 stimulation down regulates Fas expression and Fas mediated apotosis of lung cancer cells[J].Int Immunol, 2001,13(10): 1309-1319.
4 Penno MB, Askin FB, Ma H, et al. High CD44 expression on human mesotheliomas mediates association with hyahronan[J].Cancer J Sci Am, 1995, 1 (3): 196-203.
5. N icho las PR, Paul AA, Steven EF et al. Assumptions of the tumor 'escape' hypothesis[J]. Cancer B iol, 2002, 12: 81- 86.
6 Fasano M. Sabatini MW. Wieczorek R. et al. CD44 and its v6 spliced variant in lung tumors: a role in histogenesis[J].Cancer, 1997,80(1): 34-41.
7. A yhan A,Baykal C,A l A, et al. Altered CD44 variat 6 expression in F IGO stage B cervical carcinoma[J]. Gyneco 10 nco 1, 2001, 83 (3): 569- 574.
8 Fujisaki T, Tanaka Y, Fujii K, et al. CD44 stimulation induces integrin-mediated adhesion of colon cancer cell lines to endothelial cells by up-regulation of integrins and c-Met and activation of integrins. Cancer Res, 1999,59 (17): 4427-4434.
9 荆雪宁综述 张玲审校CD44与肿瘤的免疫逃逸国外医学肿瘤学分册2004，31(3)：186-188
10 Yasuda M, Nakano K, Yasumoto K, et al. CD44: functional relevance to inflammation and malignancy[J]. Histol Histopathol, 2002,17(3):945-950.
11 Takanami I, Takeuchi K, Naruke M, et al. Expression and prognostic value of the standard CD44 protein in pulmonary adenocarcinoma[J]. Oncol Rep, 2000,7(5):1065-1067.
12 Takahashi K,Takahashi F,Hirama M, et al. Restoration of CD44sin non-small cell lung cancer cells enhanced their susceptibility to the macrophage cytotoxicity[J]. Lung Cancer,2003,41 (2):145-153.
13 张桂蓉，梅同华．CD44s和CD44V6在非小细胞肺癌组织中的表达[J]．重庆医学，2002, 31 (2):77-78
14 McKallip RJ, Do Y, Fisher MT, et al. Role of CD44 in activation- induced cell death:CD44-deficient nice exhibit enhanced T cell re- sponse to conventional and superantigens. Int Immunol, 2002, 14 (9):101521026.
15 Ferguson TA, Griffith TS. The role of Fas ligand and TNF-related apoptosis-inducing ligand (TRAIL) in the ocular immune response. Chem Immunol Allergy. 2007;92:140-154. Review
16 O'Brien DI, Nally K, Kelly RG, et al. Targeting the Fas/Fas ligand pathway in cancer. Expert Opin Ther Targets. 2005 Oct;9(5):1031-1044. Review.
17 张明刚：曹雪涛(审校)．Fas/FasL系统、杀伤性DC与免疫耐受．国外医学·免疫学分册，2004，27(5)：267-270．
18 Gordon N, Arndt CA, Hawkins DS, et al. Fas expression in lung metastasis from osteosarcoma patients[J]. Pediatr Hematol Oncol. 2005 Nov;27(11):611-615.
19 Yasuda M, Tanaka Y, Fujii K, et al. CD44 stimulation down-regulates Fas expression and Fas-mediated apoptosis of lung cancer cells. Int Immunol, 2001, 13 (10):1309-1319.
20 Fujita Y, Kitagawa M, Nakamura S, et al. CD44 signaling through focal adhesion kinase and its anti2apoptotic effect. FEBS Lett,2002,528 (123):1012108
21 Zhang X, Miao X, Sun T, et al. Functional polymorphisms in cell death pathway genes FAS and FASL contribute to risk of lung cancer[J]. MedGenet. 2005 Jun;42(6):479-484.
22 向青，徐波，徐梅．Fas/FasL途径介导的人肺癌细胞免疫逃逸．中国病理生理杂志，2006 22 (1) ：168-171.
23 Takahashi K, Takahashi F,Hirama M, et al. Restoration of CD44s in non-small cell lung cancer cells enhanced their susceptibility to the macrophage cytotoxicity. Lung Cancer,2003,41 (2) ：145-153.
24 Omoteyama K, Inoue S. The variation in Fas localization and the changes in Fas expression level upon stimulation with growth factors[J]. Biochem Biophys Res Commun. 2007, 2, 353(1): 159-163.
1 Aznavoorian S ,Murphy AN , Stetler - Stevenson WG. Cell ,1992 ;69 :11
2 Lafrenie RM,Buchanan MR ,Orr FW. Cell Biophys. 1993 Aug- Dec ;23(1 - 3) :3 - 89
3 N icho las PR, Paul AA, Steven EF, et al. Assumptions of the tumor 'escape' hypothesis [J ]. Cancer B iol, 2002,12: 81- 86.
4 A lan TL , Dagmar FF. Enhanced cytolytic activity of tumor infiltrating lymphocytes (T IL s) derived from an ICAM-1 transfected tumor in a murine model [J].J Surg Res, 1998, 75 (1): 49- 53.
5 Guo J , SiL, W ang Y. A n in situ study on immuno stimulatory molecules in cancer cells with in the cervical carcinoma t issues [J J. Ch in M ed J, 2000, 80 (5): 342- 345.
6 Koutsam iM K, Doussis-A nagno stopoulou I, Papavassiliou A G, et al. Genetic and molecular coo- rdinates of neuroendocrine lung tumors, with emphasis on small-cell lung carcinoma [J J. Mo IM ed, 2002, 8 (8): 419-436.
7 Patel A, Halliday GM , Cooke BE, et al. Evidence that regression in keratoacanthoma is immuno logically mediated: a comparission w ith squamous cell carcinoma [J ]. B r J Dermato 1,1994,131(6) : 789- 798.
8 Wolfram RM , Budinsky AC, B rodow icz T , et al. Defective antigen presentation resulting from impaired expression of co-stimulatory molecules in breast cancer [J ]. Int J Cancer, 2000, 88 (2): 239- 244.
9 Gho YS, Kim PN , L iHC, et al. Stimulation of tumor growth by human soluble intercellular adhesion molecule-1 [J ]. Cancer Res, 2001, 61 (10): 4253 -4257.
10 M iller A , Kraiem Z, Sobel E, et al. Modulation of human leukocyte antigen and intracellular adhesion molecule-1 surface expression in malignant and nonmalignant human thyroid cells by cytok- ines in the context of extracellular matrix [J ]. Thyroid, 2000, 10(11): 945- 950.
11 Ruco L P, De L aat PA, M at teucci C, et al. Exp ression of ICAM 21 and VCAM 21 in human malignantmeso thelioma [J J. J Patho 1,1996,179 (3): 266- 271.
12 DanglesV ,V alidire P,W ertheimer M , et al. Impact of human bladder cancer cell architecture on autogous T -lymphocyte activation [J ]. Int J Cancer, 2002, 98(1): 51- 56.
13 Whiteway A , Corbet t T , A nderson R, et al. Exp ression of co-stimulatory molecules on acute myeloid leukaemia blasts may effect duration of first remission [J ]. B r J Haemato 1, 2003,120(3): 442- 451.
14 Boussiotis VA , F reeman GJ , Griffin JD, et al. CD is involved in maintenance and reversal of human alloantigen-specific clonal anergy [ J ]. J Exp M ed,1994, 180 (5) : 1665-1673.
15 Gro senbach DW , Sch lom J , GritzL , et al. A recombinant vector expressing transgenes for four T -cell co-stimulatory molecules (OX4OL, B721, ICAM 21,L FA 23) induces sustained CD4+ and CD8+ T-cell activation, protection from apoptosis, and enhanced cytokine production [ J ]. Cell Immuno 1, 2003, 222(1): 45- 57.
16 Sellar GC, W at t KP, Rabiasz GJ , et al. Opcm 1 atllq25 is epigenetically inactivated and has tumor suppressor function in epithelial ovarian cancer [J ].N at Genet, 2003, 34 (3): 337- 343.
17 Van der Flier A ,Sonnenberg A. Function and interaction of integrins.Cell Tissue Res ,2001,305 :285-298.
18 Timpl R. Macromolecular organization of basement membranes. CurrOpin Cell Biol ,1996 ,8 :618-624.
19 Schlaepfer DD , Signal through FAK. Prog Biophys Mol Biol ,1999 ,71:435-478.
20 Hood JD ,Cheresh DA. Role of integrins in cell invasion and migration.Nat review/ cancer ,2002, 2:91-100.
21 Klemke RL ,Richard LK. Regulation of cell motility by mitogen - acti2vated protein kinase. J Cell Biol ,1997,137 :481-492.
22 Margaret CF, Valerie GB. Advances in Rho - dependent actin regulationand oncogenic transformation. Curr Opin Genet Rev ,2002 ,12 :36-43.
23 Genda T ,Sakamoto M,Ichida T ,et al . Cell motility mediated by rho andrho - associated protein kinase plays a critical role in intrahepatic metastasis of human hepatocellular carcinoma. Hepatology ,1999 , 30 :1027—1036
24 Datta M. Akt phosphorylation of BAD couples survival signals to the cell- intrinsic death machinery. Cell ,1997 , 91:231—241.
25 Cardone MH ,Asakura H. Regulation of cell death protease Caspase - 9 by phosphorylation. Science ,1998 ,282 :1318-1321.
26 Keely PJ ,Westwick JK,Whitehead IP ,et al. Cdc42 and Rac 1 induceintegrin - mediated cell motility and invasiveness through PI3K. Nature ,1997 , 390 :632-636.
27 Kansas GS. Selectins and their ligands :current concepts ad controversies. Blood ,1996 ,88(9) :3259-3287.
28 Zak I , Lewandowska E , Gnyp W. Selectin glycoprotein ligands. ActaBiochim Pol , 2000 ,47 (2) :393-412.
29 Gray KA , Mrachko GT , Squires CH , et al . Biodesulfurization of fossilfuels. Curr Opin Microbiol, 2003 ,6 :229-235.
30 Ugorski M, Laskowska A. Sialyl lewis (a) : a tumor-associated carbohydrate antigen involved in adhesion and metastatic potential of cancer cells. Acta Biochim Pol, 2002 ,49 (2) :303-311.
31 Greenberg AW, Brunk DK, Hammer DA. Cell2free rolling mediated by L-selectin and sialyl-lewis(x) reveals the shear threshold effect .Biophysical J 2000 ,79 (5) :2391-2402.
32 Tu LL, Poe JC. , Kadono T , et al . A functional role for circulating mouse L-selectin in regulating leukocyte Pendothelial cell interactions in vivo. JImmunol , 2002 ,169 :2034-2043.
33 Bernimoulin MP , Zeng XL , Abbal C , et al . Molecular basis of leukocyte rolling on PSGL-1. Predominant role of core 2 O-glycans and of tyrosinesulfate residue 51. J Biol Chem, 2003 ,278 (1) :37-47.
34 Rodgers SD , Camphausen RT , Hammer DA. Tyrosine sulfation enhances but is not required for PSGL-1 rolling adhesion on P2selectin. Biophysical, 2001,81(4) :2201-2209.
35 Snapp KR , Heitzig CE , Ellies LG, et al . Differential requirements for the O-linked branching enzyme core 2 betal-6-N-glucosaminyl transferase in biosynthesis of ligands for E-selectin and P-selectin. Blood , 2001,97(12) :3806-3811.
36 Furie B , Furie BC. Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends in Molecular Medicine , 2004 ,10(4) ,171-178.
37 Rabenstein DL. Heparin and heparan sulfate : structure and function. Nat Prod Rep , 2002 ,19(3),312-331.
38 Wei M, Tai GH , Gao YG, et al . Modified heparin inhibit P-selectin-mediated cell adhesion of human colon carcinoma cells to immobilized platelets under dynamic flow conditions. J Biol Chem 2004 , 279 : 29202-29210.
39 Luo J , Kato M, Wang H , et al . Heparan sulfate and chondroitin sulfate proteoglycans inhibit E-selectin binding to endothelial cells. J Cell Biochem, 2001,80(4) :522-531.
40 Ohmori K, Kanda K, Mitsuoka C , et al. P-and E-selectins recognize sialyl 6-sulfolewis X, the recently identified L-selectin ligand. Biochem Biophys Res , 2000 ,278 :90-96.
41 Rops AL, van der Vlag J , Lensen JF , et al. Heparan sulfate proteoglycansin glomerular inflammation. Kidney International, 2004 ,65(3) :768-785.
42 L iu S, Calderwood DA , GinsbergMH, et al. Integrin cytoplasmic domain-binding proteins [J ]. J CellSci, 2000,113(20) : 3563- 3571.
43 von Bernstorff W, Voss M , Freichel S ,et al. Systemic and local immunosuppression in pancreatic cancer patients. Clin Cancer Res ,2001,7 (3 Suppl) :925s2932s.
44 Sheu BC , Lin RH , Lien HC , et al. Predominant Th2/ Tc2 polarityof tumor2infiltrating lymphocytes in human cervical cancer. J Immunol , 2001 ,167 (5) :297222978.
45 Sheu BC , Hsu SM , Ho HN , et al. A novel role of metallopro2teinase in cancer2mediated immunosuppression. Cancer Res , 2001,61 (1) :2372242.
46 Finke J H , Rayman P , George R , et al. Tumor2induced sensitivity to apoptosis in T cells from patients with renal cell carcinoma : role of nuclear factor2kappa B suppression. Clin Cancer Res , 2001, 7(3Suppl) :940s2946s.
2 rakigawa N, Segawa Y, Mandai K, et al. Serum CD44 levels in patients with non-small cell lung cancer and their relationship with clinicopathological features[J].Lung Cancer, 1997,18(2): 147-157.
3 Yasuda M, Tanaka Y, Fjii K, et al. CD44 stimulation down regulates Fas expression and Fas mediated apotosis of lung cancer cells[J].Int Immunol, 2001,13(10): 1309-1319.
4 Penno MB, Askin FB, Ma H, et al. High CD44 expression on human mesotheliomas mediates association with hyahronan[J].Cancer J Sci Am, 1995, 1 (3): 196-203.
5. N icho las PR, Paul AA, Steven EF et al. Assumptions of the tumor 'escape' hypothesis[J]. Cancer B iol, 2002, 12: 81- 86.
6 Fasano M. Sabatini MW. Wieczorek R. et al. CD44 and its v6 spliced variant in lung tumors: a role in histogenesis[J].Cancer, 1997,80(1): 34-41.
7. A yhan A,Baykal C,A l A, et al. Altered CD44 variat 6 expression in F IGO stage B cervical carcinoma[J]. Gyneco 10 nco 1, 2001, 83 (3): 569- 574.
8 Fujisaki T, Tanaka Y, Fujii K, et al. CD44 stimulation induces integrin-mediated adhesion of colon cancer cell lines to endothelial cells by up-regulation of integrins and c-Met and activation of integrins. Cancer Res, 1999,59 (17): 4427-4434.
9 荆雪宁综述 张玲审校CD44与肿瘤的免疫逃逸国外医学肿瘤学分册2004，31(3)：186-188
10 Yasuda M, Nakano K, Yasumoto K, et al. CD44: functional relevance to inflammation and malignancy[J]. Histol Histopathol, 2002,17(3):945-950.
11 Takanami I, Takeuchi K, Naruke M, et al. Expression and prognostic value of the standard CD44 protein in pulmonary adenocarcinoma[J]. Oncol Rep, 2000,7(5):1065-1067.
12 Takahashi K,Takahashi F,Hirama M, et al. Restoration of CD44sin non-small cell lung cancer cells enhanced their susceptibility to the macrophage cytotoxicity[J]. Lung Cancer,2003,41 (2):145-153.
13 张桂蓉，梅同华．CD44s和CD44V6在非小细胞肺癌组织中的表达[J]．重庆医学，2002, 31 (2):77-78
14 McKallip RJ, Do Y, Fisher MT, et al. Role of CD44 in activation- induced cell death:CD44-deficient nice exhibit enhanced T cell re- sponse to conventional and superantigens. Int Immunol, 2002, 14 (9):101521026.
15 Ferguson TA, Griffith TS. The role of Fas ligand and TNF-related apoptosis-inducing ligand (TRAIL) in the ocular immune response. Chem Immunol Allergy. 2007;92:140-154. Review
16 O'Brien DI, Nally K, Kelly RG, et al. Targeting the Fas/Fas ligand pathway in cancer. Expert Opin Ther Targets. 2005 Oct;9(5):1031-1044. Review.
17 张明刚：曹雪涛(审校)．Fas/FasL系统、杀伤性DC与免疫耐受．国外医学·免疫学分册，2004，27(5)：267-270．
18 Gordon N, Arndt CA, Hawkins DS, et al. Fas expression in lung metastasis from osteosarcoma patients[J]. Pediatr Hematol Oncol. 2005 Nov;27(11):611-615.
19 Yasuda M, Tanaka Y, Fujii K, et al. CD44 stimulation down-regulates Fas expression and Fas-mediated apoptosis of lung cancer cells. Int Immunol, 2001, 13 (10):1309-1319.
20 Fujita Y, Kitagawa M, Nakamura S, et al. CD44 signaling through focal adhesion kinase and its anti2apoptotic effect. FEBS Lett,2002,528 (123):1012108
21 Zhang X, Miao X, Sun T, et al. Functional polymorphisms in cell death pathway genes FAS and FASL contribute to risk of lung cancer[J]. MedGenet. 2005 Jun;42(6):479-484.
22 向青，徐波，徐梅．Fas/FasL途径介导的人肺癌细胞免疫逃逸．中国病理生理杂志，2006 22 (1) ：168-171.
23 Takahashi K, Takahashi F,Hirama M, et al. Restoration of CD44s in non-small cell lung cancer cells enhanced their susceptibility to the macrophage cytotoxicity. Lung Cancer,2003,41 (2) ：145-153.
24 Omoteyama K, Inoue S. The variation in Fas localization and the changes in Fas expression level upon stimulation with growth factors[J]. Biochem Biophys Res Commun. 2007, 2, 353(1): 159-163.
1 Aznavoorian S ,Murphy AN , Stetler - Stevenson WG. Cell ,1992 ;69 :11
2 Lafrenie RM,Buchanan MR ,Orr FW. Cell Biophys. 1993 Aug- Dec ;23(1 - 3) :3 - 89
3 N icho las PR, Paul AA, Steven EF, et al. Assumptions of the tumor 'escape' hypothesis [J ]. Cancer B iol, 2002,12: 81- 86.
4 A lan TL , Dagmar FF. Enhanced cytolytic activity of tumor infiltrating lymphocytes (T IL s) derived from an ICAM-1 transfected tumor in a murine model [J].J Surg Res, 1998, 75 (1): 49- 53.
5 Guo J , SiL, W ang Y. A n in situ study on immuno stimulatory molecules in cancer cells with in the cervical carcinoma t issues [J J. Ch in M ed J, 2000, 80 (5): 342- 345.
6 Koutsam iM K, Doussis-A nagno stopoulou I, Papavassiliou A G, et al. Genetic and molecular coo- rdinates of neuroendocrine lung tumors, with emphasis on small-cell lung carcinoma [J J. Mo IM ed, 2002, 8 (8): 419-436.
7 Patel A, Halliday GM , Cooke BE, et al. Evidence that regression in keratoacanthoma is immuno logically mediated: a comparission w ith squamous cell carcinoma [J ]. B r J Dermato 1,1994,131(6) : 789- 798.
8 Wolfram RM , Budinsky AC, B rodow icz T , et al. Defective antigen presentation resulting from impaired expression of co-stimulatory molecules in breast cancer [J ]. Int J Cancer, 2000, 88 (2): 239- 244.
9 Gho YS, Kim PN , L iHC, et al. Stimulation of tumor growth by human soluble intercellular adhesion molecule-1 [J ]. Cancer Res, 2001, 61 (10): 4253 -4257.
10 M iller A , Kraiem Z, Sobel E, et al. Modulation of human leukocyte antigen and intracellular adhesion molecule-1 surface expression in malignant and nonmalignant human thyroid cells by cytok- ines in the context of extracellular matrix [J ]. Thyroid, 2000, 10(11): 945- 950.
11 Ruco L P, De L aat PA, M at teucci C, et al. Exp ression of ICAM 21 and VCAM 21 in human malignantmeso thelioma [J J. J Patho 1,1996,179 (3): 266- 271.
12 DanglesV ,V alidire P,W ertheimer M , et al. Impact of human bladder cancer cell architecture on autogous T -lymphocyte activation [J ]. Int J Cancer, 2002, 98(1): 51- 56.
13 Whiteway A , Corbet t T , A nderson R, et al. Exp ression of co-stimulatory molecules on acute myeloid leukaemia blasts may effect duration of first remission [J ]. B r J Haemato 1, 2003,120(3): 442- 451.
14 Boussiotis VA , F reeman GJ , Griffin JD, et al. CD is involved in maintenance and reversal of human alloantigen-specific clonal anergy [ J ]. J Exp M ed,1994, 180 (5) : 1665-1673.
15 Gro senbach DW , Sch lom J , GritzL , et al. A recombinant vector expressing transgenes for four T -cell co-stimulatory molecules (OX4OL, B721, ICAM 21,L FA 23) induces sustained CD4+ and CD8+ T-cell activation, protection from apoptosis, and enhanced cytokine production [ J ]. Cell Immuno 1, 2003, 222(1): 45- 57.
16 Sellar GC, W at t KP, Rabiasz GJ , et al. Opcm 1 atllq25 is epigenetically inactivated and has tumor suppressor function in epithelial ovarian cancer [J ].N at Genet, 2003, 34 (3): 337- 343.
17 Van der Flier A ,Sonnenberg A. Function and interaction of integrins.Cell Tissue Res ,2001,305 :285-298.
18 Timpl R. Macromolecular organization of basement membranes. CurrOpin Cell Biol ,1996 ,8 :618-624.
19 Schlaepfer DD , Signal through FAK. Prog Biophys Mol Biol ,1999 ,71:435-478.
20 Hood JD ,Cheresh DA. Role of integrins in cell invasion and migration.Nat review/ cancer ,2002, 2:91-100.
21 Klemke RL ,Richard LK. Regulation of cell motility by mitogen - acti2vated protein kinase. J Cell Biol ,1997,137 :481-492.
22 Margaret CF, Valerie GB. Advances in Rho - dependent actin regulationand oncogenic transformation. Curr Opin Genet Rev ,2002 ,12 :36-43.
23 Genda T ,Sakamoto M,Ichida T ,et al . Cell motility mediated by rho andrho - associated protein kinase plays a critical role in intrahepatic metastasis of human hepatocellular carcinoma. Hepatology ,1999 , 30 :1027—1036
24 Datta M. Akt phosphorylation of BAD couples survival signals to the cell- intrinsic death machinery. Cell ,1997 , 91:231—241.
25 Cardone MH ,Asakura H. Regulation of cell death protease Caspase - 9 by phosphorylation. Science ,1998 ,282 :1318-1321.
26 Keely PJ ,Westwick JK,Whitehead IP ,et al. Cdc42 and Rac 1 induceintegrin - mediated cell motility and invasiveness through PI3K. Nature ,1997 , 390 :632-636.
27 Kansas GS. Selectins and their ligands :current concepts ad controversies. Blood ,1996 ,88(9) :3259-3287.
28 Zak I , Lewandowska E , Gnyp W. Selectin glycoprotein ligands. ActaBiochim Pol , 2000 ,47 (2) :393-412.
29 Gray KA , Mrachko GT , Squires CH , et al . Biodesulfurization of fossilfuels. Curr Opin Microbiol, 2003 ,6 :229-235.
30 Ugorski M, Laskowska A. Sialyl lewis (a) : a tumor-associated carbohydrate antigen involved in adhesion and metastatic potential of cancer cells. Acta Biochim Pol, 2002 ,49 (2) :303-311.
31 Greenberg AW, Brunk DK, Hammer DA. Cell2free rolling mediated by L-selectin and sialyl-lewis(x) reveals the shear threshold effect .Biophysical J 2000 ,79 (5) :2391-2402.
32 Tu LL, Poe JC. , Kadono T , et al . A functional role for circulating mouse L-selectin in regulating leukocyte Pendothelial cell interactions in vivo. JImmunol , 2002 ,169 :2034-2043.
33 Bernimoulin MP , Zeng XL , Abbal C , et al . Molecular basis of leukocyte rolling on PSGL-1. Predominant role of core 2 O-glycans and of tyrosinesulfate residue 51. J Biol Chem, 2003 ,278 (1) :37-47.
34 Rodgers SD , Camphausen RT , Hammer DA. Tyrosine sulfation enhances but is not required for PSGL-1 rolling adhesion on P2selectin. Biophysical, 2001,81(4) :2201-2209.
35 Snapp KR , Heitzig CE , Ellies LG, et al . Differential requirements for the O-linked branching enzyme core 2 betal-6-N-glucosaminyl transferase in biosynthesis of ligands for E-selectin and P-selectin. Blood , 2001,97(12) :3806-3811.
36 Furie B , Furie BC. Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends in Molecular Medicine , 2004 ,10(4) ,171-178.
37 Rabenstein DL. Heparin and heparan sulfate : structure and function. Nat Prod Rep , 2002 ,19(3),312-331.
38 Wei M, Tai GH , Gao YG, et al . Modified heparin inhibit P-selectin-mediated cell adhesion of human colon carcinoma cells to immobilized platelets under dynamic flow conditions. J Biol Chem 2004 , 279 : 29202-29210.
39 Luo J , Kato M, Wang H , et al . Heparan sulfate and chondroitin sulfate proteoglycans inhibit E-selectin binding to endothelial cells. J Cell Biochem, 2001,80(4) :522-531.
40 Ohmori K, Kanda K, Mitsuoka C , et al. P-and E-selectins recognize sialyl 6-sulfolewis X, the recently identified L-selectin ligand. Biochem Biophys Res , 2000 ,278 :90-96.
41 Rops AL, van der Vlag J , Lensen JF , et al. Heparan sulfate proteoglycansin glomerular inflammation. Kidney International, 2004 ,65(3) :768-785.
42 L iu S, Calderwood DA , GinsbergMH, et al. Integrin cytoplasmic domain-binding proteins [J ]. J CellSci, 2000,113(20) : 3563- 3571.
43 von Bernstorff W, Voss M , Freichel S ,et al. Systemic and local immunosuppression in pancreatic cancer patients. Clin Cancer Res ,2001,7 (3 Suppl) :925s2932s.
44 Sheu BC , Lin RH , Lien HC , et al. Predominant Th2/ Tc2 polarityof tumor2infiltrating lymphocytes in human cervical cancer. J Immunol , 2001 ,167 (5) :297222978.
45 Sheu BC , Hsu SM , Ho HN , et al. A novel role of metallopro2teinase in cancer2mediated immunosuppression. Cancer Res , 2001,61 (1) :2372242.
46 Finke J H , Rayman P , George R , et al. Tumor2induced sensitivity to apoptosis in T cells from patients with renal cell carcinoma : role of nuclear factor2kappa B suppression. Clin Cancer Res , 2001, 7(3Suppl) :940s2946s.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |