宫颈癌组织中Fas、FasL及Caspase-8的表达及其临床意义
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摘要
目的：本文旨在研究Fas、Fas配体(FasL)及半胱天冬氨酸酶-8(caspase-8)蛋白在正常宫颈上皮、宫颈上皮内瘤样病变组织(CIN)、宫颈癌组织中的表达，了解Fas、FasL、caspase-8与宫颈癌临床病理关系，探讨Fas系统在宫颈肿瘤细胞免疫逃避中的作用。
方法：采用免疫组化法检测52例宫颈癌、18例宫颈上皮内瘤样病变组织(CIN)及其肿瘤浸润淋巴细胞(TIL)，10例正常宫颈上皮Fas、FasL和caspase-8蛋白表达情况。
结果：Fas及FasL在CIN及宫颈癌组织中的表达与在正常组织中表达比较有显著性差异(pFas＜0.05，PFasL＜0.01)，宫颈鳞癌明显高于宫颈腺癌(p_(Fas)＜0.05，P_(FasL)＜0.01)。Fas阳性表达率随着组织学分级的升高而降低，FasL则增高(p＜0.01)；有淋巴结转移者FasL阳性表达率高于无淋巴结转移者(p＜0.01)；Fas及FasL表达与患者的年龄，临床分期无关(p＞0.05)。宫颈癌TIL的Fas及FasL表达明显高于CIN(p＜0.01)；caspase-8在宫颈癌组织中的表达明显低于正常宫颈上皮(p＜0.01)，caspase-8表达与宫颈癌患者的年龄，临床分期，组织学类别无关(p＞0.05)，有淋巴结转移者明显低于无淋巴结转移者(p＜0.05)，随着组织学分化的降低，caspase-8表达亦明显降低，但无显著性差异。
结论：宫颈癌能通过Fas，caspase-8低表达及FasL高表达逃避机体免疫监视以促使肿瘤发生发展及转移。
Objective: To investigate factor associated suicide (Fas), Fas ligand (FasL) and caspase-8 expressions and their clinical significance in cervical carcinoma and explore the mechanism of tumor immune evasion.
Methods: Immunohistochemical method was used to detect the expressions of Fas ,FasL and caspase-8 in 52 samples of cervical carcinoma,and18samples of cervical intraepithelial neoplasia(CIN),together with 10 samples of normal cervical tissues.
Results: Fas and FasL expression were significantly different between cervical carcinoma and normal cervix (pFas<0.05, ppasL<0.01),The expressions of Fas and FasL of squamous cell carcinoma were significantly higher than that of adenocarcinoma (pFas<0.05,FasL<0.01),There was a significant difference between Fas, FasL expressions and histologic grades(p<0.01),the higher expression rate of FasL and the lower expression of Fas were found in those poorer differentiated tumors. FasL not Fas correlated with lymphnode metastasis.There was no significant difference between Fas,FasL expression and age of patient as well as clinical stage.The expressions of Fas and FasL on TIL around cervical carcinoma were higher than that around CIN(p<0.01).There was no correlation between caspase-8 expression and histological type ,age of patient as well as clinical stage.Caspase-8 expression rate in cervical carcinoma was lower than that in normal cervix(p<0.01),The expression of caspase-8 in positive lymphnode metastasis cervical carcinoma was higher than that in negative metastasis cervical carcinoma.Furthermore in highly differented tissues expression of caspase-8 was higher than that in lowly differented tissues,but without statistical difference.
Conclusion: Down-regulation of Fas and caspase-8 expressions but up-regulation of FasL expression may take part in carcinogenesis and development of cervical carcinoma,and this may be a mechanism by which the tumor cells evade the host immune surveillance.
方法：采用免疫组化法检测52例宫颈癌、18例宫颈上皮内瘤样病变组织(CIN)及其肿瘤浸润淋巴细胞(TIL)，10例正常宫颈上皮Fas、FasL和caspase-8蛋白表达情况。
结果：Fas及FasL在CIN及宫颈癌组织中的表达与在正常组织中表达比较有显著性差异(pFas＜0.05，PFasL＜0.01)，宫颈鳞癌明显高于宫颈腺癌(p_(Fas)＜0.05，P_(FasL)＜0.01)。Fas阳性表达率随着组织学分级的升高而降低，FasL则增高(p＜0.01)；有淋巴结转移者FasL阳性表达率高于无淋巴结转移者(p＜0.01)；Fas及FasL表达与患者的年龄，临床分期无关(p＞0.05)。宫颈癌TIL的Fas及FasL表达明显高于CIN(p＜0.01)；caspase-8在宫颈癌组织中的表达明显低于正常宫颈上皮(p＜0.01)，caspase-8表达与宫颈癌患者的年龄，临床分期，组织学类别无关(p＞0.05)，有淋巴结转移者明显低于无淋巴结转移者(p＜0.05)，随着组织学分化的降低，caspase-8表达亦明显降低，但无显著性差异。
结论：宫颈癌能通过Fas，caspase-8低表达及FasL高表达逃避机体免疫监视以促使肿瘤发生发展及转移。
Objective: To investigate factor associated suicide (Fas), Fas ligand (FasL) and caspase-8 expressions and their clinical significance in cervical carcinoma and explore the mechanism of tumor immune evasion.
Methods: Immunohistochemical method was used to detect the expressions of Fas ,FasL and caspase-8 in 52 samples of cervical carcinoma,and18samples of cervical intraepithelial neoplasia(CIN),together with 10 samples of normal cervical tissues.
Results: Fas and FasL expression were significantly different between cervical carcinoma and normal cervix (pFas<0.05, ppasL<0.01),The expressions of Fas and FasL of squamous cell carcinoma were significantly higher than that of adenocarcinoma (pFas<0.05,FasL<0.01),There was a significant difference between Fas, FasL expressions and histologic grades(p<0.01),the higher expression rate of FasL and the lower expression of Fas were found in those poorer differentiated tumors. FasL not Fas correlated with lymphnode metastasis.There was no significant difference between Fas,FasL expression and age of patient as well as clinical stage.The expressions of Fas and FasL on TIL around cervical carcinoma were higher than that around CIN(p<0.01).There was no correlation between caspase-8 expression and histological type ,age of patient as well as clinical stage.Caspase-8 expression rate in cervical carcinoma was lower than that in normal cervix(p<0.01),The expression of caspase-8 in positive lymphnode metastasis cervical carcinoma was higher than that in negative metastasis cervical carcinoma.Furthermore in highly differented tissues expression of caspase-8 was higher than that in lowly differented tissues,but without statistical difference.
Conclusion: Down-regulation of Fas and caspase-8 expressions but up-regulation of FasL expression may take part in carcinogenesis and development of cervical carcinoma,and this may be a mechanism by which the tumor cells evade the host immune surveillance.
引文
1. Jamila KA, Bharti O, Kanti DB. Immune responses in cancer[J]. Pharmacology & Therapeutics ,2003, 99: 113- 132
2. Jakóbisiak M,Jakub Goab,WL.Natural mechanisms protecting against cancer[J]. Immunology Letters, 2003, 90:103-122
3. Dunn GP, Bruce AT, Ikeda H,et al. Cancer immunoediting: from immunosurveillance to tumor escape[J]. Nature immunology, 2002, 3(11):991-998
4. Wajant H, PfizenmaierK, Scheurich P. Non-apoptotic Fas signaling[J]. Cytokine & Growth Factor Reviews.2003, 14:53-66
5．杨文武，刘元姣，张蔚．MHC-Ⅰ类抗原加工途径异常与肿瘤关系的研究进展．中国肿瘤，2003，12(3)：160-163
6. Gastman BR, Atarashi Y, Reichert TE,et al.Fas Ligand is expressed on human squhmous cell carcinomas of the head and neck,and it promotes apoptosis of T lymphocytes [J]. Cancer-Res. 1999,59(20):5356-5364
7. Walker PR, Saas P, Dietrich PY.Tumor expression of Fas Ligand (CD95L) and the consequence [J]. Current opinion in Immunology, 1998,16(12):564-572
8. Okada K,Komuta K,Hashimoto S. Frequency of apoptosis of tumor infiltrating lymphocytes induced by fas counterattack in human colorectal carcinoma and its correlation with prognosis[J]. Clinical cancer research. 2000, 6(9):3560-3564
9. Ashkenazi A,Dixit VM.Death receptors:signaling and modulation [J]. Science. 1998, 281 (8): 1305-1308
10. Shimonishi T, Isse K,Shibata F, et al.Up-regulation of fas ligand at early stages and down-regulation of Fas at progressed stages of introhepatic cholangiocarcinoma reflect evasion from immune surveillance[J].Hepatology.2000,32(4pt 1): 761-769
11. Shibalita M,Tachibana M,Dhar DK,et al.Prognostic significance of Fas and Fas ligand expressions in human esophageal cancer[J]. Clin-Cancer-Res, 1999, 5(9): 2464-2469
12. Kase H,Aoki Y, Tanaka K et al. Fas ligand expression in cervical adenocarcinoma: relevance to lymph node metastasis and tumor progression[J].Gynecologic oncollogy, 2003,90(1):70-74
13. Okada K,Komuta K,Hashimoto S. Frequency of apoptosis of tumor infiltrating lymphocytes induced by fas counterattack in human colorectal carcinoma and its correlation with prognosis[J]. Clinical cancer research. 2000, 6(9):3560-3564
14. Thornberry NA,Lazebnik Y.Caspases: Enemies within[J]. Science. 1998.281 (8): 1312-1316
15. O'connell J,Bennett MW, O'Sullivan GC,et al.The Fas counterattack:cancer as a site of immune privilege[J]. Immunology Today, 1999, 20(1):46
16. Real LM, Jimenez P, Kirkin A,et al. Multiple mechanisms of immune evasion can coexist in melanoma tumor cell lines derived from the same patient[J]. Cancer immunology, 2001, 49(11):621-628
2. Jakóbisiak M,Jakub Goab,WL.Natural mechanisms protecting against cancer[J]. Immunology Letters, 2003, 90:103-122
3. Dunn GP, Bruce AT, Ikeda H,et al. Cancer immunoediting: from immunosurveillance to tumor escape[J]. Nature immunology, 2002, 3(11):991-998
4. Wajant H, PfizenmaierK, Scheurich P. Non-apoptotic Fas signaling[J]. Cytokine & Growth Factor Reviews.2003, 14:53-66
5．杨文武，刘元姣，张蔚．MHC-Ⅰ类抗原加工途径异常与肿瘤关系的研究进展．中国肿瘤，2003，12(3)：160-163
6. Gastman BR, Atarashi Y, Reichert TE,et al.Fas Ligand is expressed on human squhmous cell carcinomas of the head and neck,and it promotes apoptosis of T lymphocytes [J]. Cancer-Res. 1999,59(20):5356-5364
7. Walker PR, Saas P, Dietrich PY.Tumor expression of Fas Ligand (CD95L) and the consequence [J]. Current opinion in Immunology, 1998,16(12):564-572
8. Okada K,Komuta K,Hashimoto S. Frequency of apoptosis of tumor infiltrating lymphocytes induced by fas counterattack in human colorectal carcinoma and its correlation with prognosis[J]. Clinical cancer research. 2000, 6(9):3560-3564
9. Ashkenazi A,Dixit VM.Death receptors:signaling and modulation [J]. Science. 1998, 281 (8): 1305-1308
10. Shimonishi T, Isse K,Shibata F, et al.Up-regulation of fas ligand at early stages and down-regulation of Fas at progressed stages of introhepatic cholangiocarcinoma reflect evasion from immune surveillance[J].Hepatology.2000,32(4pt 1): 761-769
11. Shibalita M,Tachibana M,Dhar DK,et al.Prognostic significance of Fas and Fas ligand expressions in human esophageal cancer[J]. Clin-Cancer-Res, 1999, 5(9): 2464-2469
12. Kase H,Aoki Y, Tanaka K et al. Fas ligand expression in cervical adenocarcinoma: relevance to lymph node metastasis and tumor progression[J].Gynecologic oncollogy, 2003,90(1):70-74
13. Okada K,Komuta K,Hashimoto S. Frequency of apoptosis of tumor infiltrating lymphocytes induced by fas counterattack in human colorectal carcinoma and its correlation with prognosis[J]. Clinical cancer research. 2000, 6(9):3560-3564
14. Thornberry NA,Lazebnik Y.Caspases: Enemies within[J]. Science. 1998.281 (8): 1312-1316
15. O'connell J,Bennett MW, O'Sullivan GC,et al.The Fas counterattack:cancer as a site of immune privilege[J]. Immunology Today, 1999, 20(1):46
16. Real LM, Jimenez P, Kirkin A,et al. Multiple mechanisms of immune evasion can coexist in melanoma tumor cell lines derived from the same patient[J]. Cancer immunology, 2001, 49(11):621-628
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