Th17、CD40、PCNA在骶骨脊索瘤中作用和意义的临床及实验研究
摘要
目的:探讨Th1、Th2、Treg、Th17在骶骨脊索瘤发生发展中所起的作用,以及与骶骨脊索瘤生物学行为的关系,为骶骨脊索瘤的诊断、预后评测、骶骨脊索瘤免疫学靶向治疗等方面提供理论参考。
方法:收集2002年1月～2008年12月间在我院手术的27例骶骨肿瘤患者的新鲜肿瘤组织,包括骶骨脊索瘤11例,骶骨骨巨细胞瘤9例,骶骨神经鞘瘤7例,进行Real-time PCR研究,检测FoxP3 mRNA、ROR-γt mRNA、T-bet mRNA、GATA-3 mRNA的表达,以各基因的表达量以均数±标准误表示,目的基因表达量的比较采用Wilcoxon秩和检验。以P<0.05判定为有统计学意义。
结果:①FoxP3基因在骶骨脊索瘤、原发骨巨细胞瘤、神经鞘瘤中相对表达量分别为8.5±7.6%、1.6±0.9%、0.7±0.5%,FoxP3基因在骶骨脊索瘤中表达高于骨巨细胞瘤组及神经鞘瘤组。差异有统计学差异(P<0.05)。②T-bet基因在骶骨脊索瘤、原发骨巨细胞瘤、神经鞘瘤中相对表达量分别为0.7±0.3%、1.7±1.2%、1.6±1.3%,T-bet基因在骶骨脊索瘤中表达低于骨巨细胞瘤组及神经鞘瘤组。差异有统计学意义(P<0.05)。③GATA-3基因在骶骨脊索瘤、原发骨巨细胞瘤、神经鞘瘤中相对表达量分别为2.9±2.3%、0.6±0.5%、0.3±0.1%,GATA-3基因在骶骨脊索瘤中表达高于骨巨细胞瘤组及神经鞘瘤组。差异有统计学意义(P<0.05)。④ROR-γt基因在骶骨脊索瘤、原发骨巨细胞瘤、神经鞘瘤中相对表达量分别为4.1±2.9%、1.6±0.8%、0.2±0.1%,RORγt基因在骶骨脊索瘤中表达明显高于骨巨细胞瘤组及神经鞘瘤组。差异有统计学意义(P<0.05)。
结论:原发性骶骨脊索瘤患者肿瘤组织转录因子FoxP3 mRNA、GATA3 mRNA表达增高,T-bet mRNA减低,表明其肿瘤局部组织呈现Th2偏移现象,可能是其发生免疫逃逸的机制之一。ROR-γt mRNA表达增加,提示骶骨脊索瘤患者肿瘤组织存在Th17优势化现象,并可能通过上调肿瘤血管生成因子促进脊索瘤的复发。
目的:探讨Th17细胞因子与患者手术后复发率以及无瘤生存时间、总生存时间的相关性。为今后预防或延缓骶骨脊索瘤术后复发,延长术后无瘤生存期提供参考依据。
方法:对1998年1月～2008年12月间在我院骨外科完成初次手术的28例骶骨脊索瘤患者进行随访,对病理蜡块行免疫组化。另对我院保存在液氮里27例新鲜骶骨肿瘤组织进行免疫研究,采用Kaplan-Meier法作单因素变量分析并绘制CDFS曲线,并用Log-Rank法检验复发率差异。设P<0.05为差异有统计学意义。
结果:①Th17在骶骨脊索瘤组织中阳性表达率为60.7%,而在骨巨细胞瘤组Th17为弱阳性表达,在神经鞘瘤组则不表达。②不同年龄段之间、不同性别之间骶骨脊索瘤Th17表达无统计学差异(P>0.05)。③肿瘤直径≥10cm组Th17阳性表达率为83.33%,直径<10cm组Th17阳性表达率为40.75%,差异有统计学意义(P<0.05)。④肿瘤切缘阳性组Th17阳性表达率为69.23%,高于肿瘤切缘阴性组53.33%,但差异无统计学意义(P>0.05)。⑤术后复发组Th17阳性表达率为78.57%,未复发组为42.86%,两组差异有统计学意义(P<0.05)。其中Th17阳性组5年无复发生存率为(32.4±12.8)%,5年总生存率为(86.9±8.7) %;Th17阴性组5年无复发生存率为(81.8±11.6) %,5年总生存率为100 %,差异有统计学意义(P<0.05)。
结论:Th17在骶骨肿瘤局部复发等生物学行为中发挥重要作用,Th17高表达的患者复发率较高,术后CDFS期较短。Th17高表达是病情进展和复发的一个重要信号,可作为判断骶骨脊索瘤复发的指标之一。
第三部分CD40、PCNA等在骶骨脊索瘤中表达及其与复发的相关性研究
目的:研究骶骨脊索瘤中CD40、PCNA的表达水平及其与脊索瘤复发的相关性,为骶骨脊索瘤的免疫治疗提供一种新的靶点。
方法:取1998年1月～2008年12月我院骨科28例临床及病理资料均完整的骶骨脊索瘤患者手术切除的肿瘤组织腊块,采用免疫组化技术检测其中的CD40和PCNA的表达,另9例正常胚胎脊索组织为对照组,并计数CD31标记的肿瘤组织微血管密度(MVD)。所得数据用均数±标准差表示,两组计量数据之间比较采用t检验或方差分析,两组计数资料率的比较采用Fisher确切概率法。设P<0.05为差异有统计学意义。
结果:①CD40、PCNA在骶骨脊索瘤中的强阳性表达率分别为66.1%、64.3%,明显高于正常胚胎脊索组织。两者之间的差异有统计学意义(P<0.05);骶骨脊索瘤中CD31标记的微血管密度(24.26±18.68)/mm2,正常胚胎脊索组织微血管密度值为(4.63±2.19)/mm2;差异有统计学意义(P<0.05);②28例骶骨脊索瘤,其中复发组14例,非复发组14例,两组间CD40阳性表达率分别为14.29%、85.71%;PCNA阳性表达率分别为92.86%、50.00%;CD31标记的MVD值分别为(30.66±23.75)/mm2、(17.88±8.52)/mm2;均有统计学差异(P<0.05)。③CD40、PCNA表达及CD31标记的MVD值与患者的年龄、性别、肿瘤大小无统计学相关性。④PCNA阳性表达的骶骨脊索瘤组织中MVD值为(28.92±20.27) /mm2,明显高于PCNA阴性组(12.64±3.70) /mm2,差异有统计学意义(P<0.05)。CD40阴性表达的骶骨脊索瘤组织中MVD值为(31.68±22.81) /mm2,明显高于CD40阳性表达组(16.86±9.28) /mm2,差异有统计学意义(P<0.05)。
结论:CD40、PCNA在肿瘤浸润及复发转移等生物学行为中均发挥重要作用,PCNA强表达,CD40弱表达,是骶骨脊索瘤病情进展和复发的重要信号,骶骨脊索瘤中CD40和PCNA表达水平可作为判断病情进展和肿瘤复发的指标之一。
Purpose: To discuss the effect of Th1、Th2、Treg、Th17 in the occurrence and development of sacral chordoma, and the relationship with biological behaviour of sacral chordoma, and provide some theoretical basis for the diagnosis, prognostic evaluation and immunological targeted therapy of sacral chordoma.
Methods: To collect the fresh tumor tissue of 27 patients with sacral tumors who received surgery in our hospital from January 2002 to December 2008. Among them, there were 11 patients with sacral chordoma, 9 with giant cell tumor of the sacrum, 7 with sacral nerve sheath tumor. Using Real-time PCR to detect the expression of FoxP3 mRNA, ROR-γt mRNA、T-bet mRNA and GATA-3 mRNA, using mean±standard error to represent the expression of all genes, and using Wilcoxon rank test to compare the expression of genes. It has statistical significance if P <0.05.
Results:①The relative expression of FoxP3 in sacral chordoma, giant cell tumor of the sacrum and nerve sheath tumor were 8.5±7.6%、1.6±0.9%、0.7±0.5%. The expression of FoxP3 in sacral chordoma was higher than that in giant cell tumor of the sacrum and nerve sheath tumor. The difference has statistical significance (P<0.05).②The The relative expression of T-bet in sacral chordoma, giant cell tumor of the sacrum and nerve sheath tumor were 0.7±0.3%、1.7±1.2%、1.6±1.3% . The expression of T-bet in sacral chordoma was lower than that in giant cell tumor of the sacrum and nerve sheath tumor. The difference has statistical significance (P<0.05).③The relative expression of GATA-3 in sacral chordoma, giant cell tumor of the sacrum and nerve sheath tumor were 2.9±2.3%、0.6±0.5%、0.3±0.1%. The expression of GATA-3 in sacral chordoma was higher than that in giant cell tumor of the sacrum and nerve sheath tumor. The difference has statistical significance (P<0.05).④The relative expression ROR-γt of in sacral chordoma, giant cell tumor of the sacrum and nerve sheath tumor were 4.1±2.9%、1.6±0.8%、0.2±0.1%.The expression of ROR-γt in sacral chordoma was obviously higher than that in giant cell tumor of the sacrum and nerve sheath tumor .The difference has statistical significance (P<0.05).
Conclusion: The high-expression of FoxP3 mRNA、GATA3 mRNA and low- expression of T-bet mRNA in the primary sacral chordoma patients indicated that the local tissue of the tumors appeared migration phenomenon of Th2, and it may be one of the reasons for the immunologic escape. The increased expression of ROR-γt mRNA indicated that there was advantage phenomenon of Th17 in the primary sacral chordoma tissue, and it may cause the recurrence of chordoma by upexpressing the angiogenic factors of the tumors.
Part two The study of Th17 and its relationship with prognosis in primary sacral chordoma
Purpose: To discuss the correlation between Th17 and the recurrence after operation, survival time without tumor, overall survival time. And to provide some reference for prevent or delay the recurrence of sacral chordoma after operation, prolong the survival time without tumor after operation in the future.
Methods: To follow up the 28 patients with sacral chordoma who received the first operation in our orthopaedic department from January 1998 to December 2008. Using the immunohistochemisty with the pathology wax. Besides, using the immunity study for the 16 fresh tissue of giant cell tumor of the sacrum and nerve sheath tumor which were stored in the liquid nitrogen. Using Kaplan-Meier to get the single factors analysis of variance and draw the curve of CDFS, and using the Log-Rank to check the difference of recurrence. It has statistical significance if P <0.05.
Results:①The positive expression of Th17 in sacral chordoma was 60.7%,and weakly positive expressed in group of giant cell tumor of the sacrum, no expression in group of nerve sheath tumor.②There were no statistical significance for the expression of Th17 in sacral chordoma between different age and gender (P>0.05).③The positive expression percentage of Th17 in the group of tumor diameter≥10cm was 83.33%,for the group of tumor diameter<10cm was 40.75%,there was statistical significance (P>0.05).④The positive expression percentage of Th17 in the group of positive incisal margin was 69.23%, which was higher than that of negative incisal margin(53.33%), but no statistical significance(P>0.05).⑤The positive expression percentage of Th17 in the group of recurrence was 78.57% and 42.86% in the group of no-recurrence. There was statistical significance (P<0.05). The survival rate of 5-year no recurrence in the group of positive Th17 was (32.4±12.8)%, overall survival rate of 5-year was (86.9±8.7) %. The survival rate of 5-year no recurrence in the group of negative Th17 was (81.8±11.6)%, overall survival rate of 5-year was 100 %. Conclusions: Th17 played an important role in the local recurrence of sacral tumors.The high expression of Th17 indicated the high recurrence and short CDFS after operation. The high expression of TH17 was an important sign for the progress and recurrence,and could be one of the indexs to determine the recurrence of the sacral chordoma.
Purpose: To study the expression level of CD40、PCNA in sacral chordoma and their relationship with recurrence, and to provide a new target for the immunization therapy of sacral chordoma.
Methods: To collect tumor tissue of 28 cases with sacral chordoma who had full information of clinical and pathology for the wax. To detect the expression of CD40 and PCNA by using immunohistochemisty, another 9 cases with normal notochordal tissue were set as control group and count the MVD marked by CD31. All the data was showed by mean±standard error and using T-test to compare two groups. It has statistical significance if P <0.05.
Results:①The strong positive expression of CD40、PCNA in the sacral chordoma were 66.1% and 64.3%, obviously higher than that in normal notochordal tissue. There was statistical significance (P<0.05). The MVD marked by CD31 in sacral chordoma was (24.26±18.68)/mm2 and (4.63±2.19)/mm2 in normal notochordal tissue. There was statistical significance (P<0.05).②Among the 28 sacral chordoma, 14 had recurrence and 14 had no recurrence, the positive expression of CD40 were 14.29% and 85.71%.For the PCNA, the positive expression were 92.86% and 50.55%. MVD marked by CD31 were (30.66±23.75)/mm2 and (17.88±8.52)/mm2. All had statistical significance (P<0.05).③There were no statistical correlation between the expression of CD40、PCNA and the value of MVD with the age, gender and the size of tumor.④The MVD in the group of positive expression of PCNA was (28.92±20.27) /mm2, significantly higher than the negative group (12.64±3.70) /mm2. And there was statistical significance(P<0.05). The MVD in the group of negative expression of CD40 was (31.68±22.81 /mm2, significantly higher than the positive group (16.86±9.28) /mm2. And there was statistical significance (P<0.05).
Conclusions: CD40 and PCNA had vital role in the tumor invasion, recurrence and metastasis. Strong expression of PCNA and weak expression of CD40 was important sign for the progress and recurrence of sacral chordoma. The expression level of CD40 and PCNA in the sacral chordoma was one of the index to determine the progress and recurrence of the tumor.
方法:收集2002年1月～2008年12月间在我院手术的27例骶骨肿瘤患者的新鲜肿瘤组织,包括骶骨脊索瘤11例,骶骨骨巨细胞瘤9例,骶骨神经鞘瘤7例,进行Real-time PCR研究,检测FoxP3 mRNA、ROR-γt mRNA、T-bet mRNA、GATA-3 mRNA的表达,以各基因的表达量以均数±标准误表示,目的基因表达量的比较采用Wilcoxon秩和检验。以P<0.05判定为有统计学意义。
结果:①FoxP3基因在骶骨脊索瘤、原发骨巨细胞瘤、神经鞘瘤中相对表达量分别为8.5±7.6%、1.6±0.9%、0.7±0.5%,FoxP3基因在骶骨脊索瘤中表达高于骨巨细胞瘤组及神经鞘瘤组。差异有统计学差异(P<0.05)。②T-bet基因在骶骨脊索瘤、原发骨巨细胞瘤、神经鞘瘤中相对表达量分别为0.7±0.3%、1.7±1.2%、1.6±1.3%,T-bet基因在骶骨脊索瘤中表达低于骨巨细胞瘤组及神经鞘瘤组。差异有统计学意义(P<0.05)。③GATA-3基因在骶骨脊索瘤、原发骨巨细胞瘤、神经鞘瘤中相对表达量分别为2.9±2.3%、0.6±0.5%、0.3±0.1%,GATA-3基因在骶骨脊索瘤中表达高于骨巨细胞瘤组及神经鞘瘤组。差异有统计学意义(P<0.05)。④ROR-γt基因在骶骨脊索瘤、原发骨巨细胞瘤、神经鞘瘤中相对表达量分别为4.1±2.9%、1.6±0.8%、0.2±0.1%,RORγt基因在骶骨脊索瘤中表达明显高于骨巨细胞瘤组及神经鞘瘤组。差异有统计学意义(P<0.05)。
结论:原发性骶骨脊索瘤患者肿瘤组织转录因子FoxP3 mRNA、GATA3 mRNA表达增高,T-bet mRNA减低,表明其肿瘤局部组织呈现Th2偏移现象,可能是其发生免疫逃逸的机制之一。ROR-γt mRNA表达增加,提示骶骨脊索瘤患者肿瘤组织存在Th17优势化现象,并可能通过上调肿瘤血管生成因子促进脊索瘤的复发。
目的:探讨Th17细胞因子与患者手术后复发率以及无瘤生存时间、总生存时间的相关性。为今后预防或延缓骶骨脊索瘤术后复发,延长术后无瘤生存期提供参考依据。
方法:对1998年1月～2008年12月间在我院骨外科完成初次手术的28例骶骨脊索瘤患者进行随访,对病理蜡块行免疫组化。另对我院保存在液氮里27例新鲜骶骨肿瘤组织进行免疫研究,采用Kaplan-Meier法作单因素变量分析并绘制CDFS曲线,并用Log-Rank法检验复发率差异。设P<0.05为差异有统计学意义。
结果:①Th17在骶骨脊索瘤组织中阳性表达率为60.7%,而在骨巨细胞瘤组Th17为弱阳性表达,在神经鞘瘤组则不表达。②不同年龄段之间、不同性别之间骶骨脊索瘤Th17表达无统计学差异(P>0.05)。③肿瘤直径≥10cm组Th17阳性表达率为83.33%,直径<10cm组Th17阳性表达率为40.75%,差异有统计学意义(P<0.05)。④肿瘤切缘阳性组Th17阳性表达率为69.23%,高于肿瘤切缘阴性组53.33%,但差异无统计学意义(P>0.05)。⑤术后复发组Th17阳性表达率为78.57%,未复发组为42.86%,两组差异有统计学意义(P<0.05)。其中Th17阳性组5年无复发生存率为(32.4±12.8)%,5年总生存率为(86.9±8.7) %;Th17阴性组5年无复发生存率为(81.8±11.6) %,5年总生存率为100 %,差异有统计学意义(P<0.05)。
结论:Th17在骶骨肿瘤局部复发等生物学行为中发挥重要作用,Th17高表达的患者复发率较高,术后CDFS期较短。Th17高表达是病情进展和复发的一个重要信号,可作为判断骶骨脊索瘤复发的指标之一。
第三部分CD40、PCNA等在骶骨脊索瘤中表达及其与复发的相关性研究
目的:研究骶骨脊索瘤中CD40、PCNA的表达水平及其与脊索瘤复发的相关性,为骶骨脊索瘤的免疫治疗提供一种新的靶点。
方法:取1998年1月～2008年12月我院骨科28例临床及病理资料均完整的骶骨脊索瘤患者手术切除的肿瘤组织腊块,采用免疫组化技术检测其中的CD40和PCNA的表达,另9例正常胚胎脊索组织为对照组,并计数CD31标记的肿瘤组织微血管密度(MVD)。所得数据用均数±标准差表示,两组计量数据之间比较采用t检验或方差分析,两组计数资料率的比较采用Fisher确切概率法。设P<0.05为差异有统计学意义。
结果:①CD40、PCNA在骶骨脊索瘤中的强阳性表达率分别为66.1%、64.3%,明显高于正常胚胎脊索组织。两者之间的差异有统计学意义(P<0.05);骶骨脊索瘤中CD31标记的微血管密度(24.26±18.68)/mm2,正常胚胎脊索组织微血管密度值为(4.63±2.19)/mm2;差异有统计学意义(P<0.05);②28例骶骨脊索瘤,其中复发组14例,非复发组14例,两组间CD40阳性表达率分别为14.29%、85.71%;PCNA阳性表达率分别为92.86%、50.00%;CD31标记的MVD值分别为(30.66±23.75)/mm2、(17.88±8.52)/mm2;均有统计学差异(P<0.05)。③CD40、PCNA表达及CD31标记的MVD值与患者的年龄、性别、肿瘤大小无统计学相关性。④PCNA阳性表达的骶骨脊索瘤组织中MVD值为(28.92±20.27) /mm2,明显高于PCNA阴性组(12.64±3.70) /mm2,差异有统计学意义(P<0.05)。CD40阴性表达的骶骨脊索瘤组织中MVD值为(31.68±22.81) /mm2,明显高于CD40阳性表达组(16.86±9.28) /mm2,差异有统计学意义(P<0.05)。
结论:CD40、PCNA在肿瘤浸润及复发转移等生物学行为中均发挥重要作用,PCNA强表达,CD40弱表达,是骶骨脊索瘤病情进展和复发的重要信号,骶骨脊索瘤中CD40和PCNA表达水平可作为判断病情进展和肿瘤复发的指标之一。
Purpose: To discuss the effect of Th1、Th2、Treg、Th17 in the occurrence and development of sacral chordoma, and the relationship with biological behaviour of sacral chordoma, and provide some theoretical basis for the diagnosis, prognostic evaluation and immunological targeted therapy of sacral chordoma.
Methods: To collect the fresh tumor tissue of 27 patients with sacral tumors who received surgery in our hospital from January 2002 to December 2008. Among them, there were 11 patients with sacral chordoma, 9 with giant cell tumor of the sacrum, 7 with sacral nerve sheath tumor. Using Real-time PCR to detect the expression of FoxP3 mRNA, ROR-γt mRNA、T-bet mRNA and GATA-3 mRNA, using mean±standard error to represent the expression of all genes, and using Wilcoxon rank test to compare the expression of genes. It has statistical significance if P <0.05.
Results:①The relative expression of FoxP3 in sacral chordoma, giant cell tumor of the sacrum and nerve sheath tumor were 8.5±7.6%、1.6±0.9%、0.7±0.5%. The expression of FoxP3 in sacral chordoma was higher than that in giant cell tumor of the sacrum and nerve sheath tumor. The difference has statistical significance (P<0.05).②The The relative expression of T-bet in sacral chordoma, giant cell tumor of the sacrum and nerve sheath tumor were 0.7±0.3%、1.7±1.2%、1.6±1.3% . The expression of T-bet in sacral chordoma was lower than that in giant cell tumor of the sacrum and nerve sheath tumor. The difference has statistical significance (P<0.05).③The relative expression of GATA-3 in sacral chordoma, giant cell tumor of the sacrum and nerve sheath tumor were 2.9±2.3%、0.6±0.5%、0.3±0.1%. The expression of GATA-3 in sacral chordoma was higher than that in giant cell tumor of the sacrum and nerve sheath tumor. The difference has statistical significance (P<0.05).④The relative expression ROR-γt of in sacral chordoma, giant cell tumor of the sacrum and nerve sheath tumor were 4.1±2.9%、1.6±0.8%、0.2±0.1%.The expression of ROR-γt in sacral chordoma was obviously higher than that in giant cell tumor of the sacrum and nerve sheath tumor .The difference has statistical significance (P<0.05).
Conclusion: The high-expression of FoxP3 mRNA、GATA3 mRNA and low- expression of T-bet mRNA in the primary sacral chordoma patients indicated that the local tissue of the tumors appeared migration phenomenon of Th2, and it may be one of the reasons for the immunologic escape. The increased expression of ROR-γt mRNA indicated that there was advantage phenomenon of Th17 in the primary sacral chordoma tissue, and it may cause the recurrence of chordoma by upexpressing the angiogenic factors of the tumors.
Part two The study of Th17 and its relationship with prognosis in primary sacral chordoma
Purpose: To discuss the correlation between Th17 and the recurrence after operation, survival time without tumor, overall survival time. And to provide some reference for prevent or delay the recurrence of sacral chordoma after operation, prolong the survival time without tumor after operation in the future.
Methods: To follow up the 28 patients with sacral chordoma who received the first operation in our orthopaedic department from January 1998 to December 2008. Using the immunohistochemisty with the pathology wax. Besides, using the immunity study for the 16 fresh tissue of giant cell tumor of the sacrum and nerve sheath tumor which were stored in the liquid nitrogen. Using Kaplan-Meier to get the single factors analysis of variance and draw the curve of CDFS, and using the Log-Rank to check the difference of recurrence. It has statistical significance if P <0.05.
Results:①The positive expression of Th17 in sacral chordoma was 60.7%,and weakly positive expressed in group of giant cell tumor of the sacrum, no expression in group of nerve sheath tumor.②There were no statistical significance for the expression of Th17 in sacral chordoma between different age and gender (P>0.05).③The positive expression percentage of Th17 in the group of tumor diameter≥10cm was 83.33%,for the group of tumor diameter<10cm was 40.75%,there was statistical significance (P>0.05).④The positive expression percentage of Th17 in the group of positive incisal margin was 69.23%, which was higher than that of negative incisal margin(53.33%), but no statistical significance(P>0.05).⑤The positive expression percentage of Th17 in the group of recurrence was 78.57% and 42.86% in the group of no-recurrence. There was statistical significance (P<0.05). The survival rate of 5-year no recurrence in the group of positive Th17 was (32.4±12.8)%, overall survival rate of 5-year was (86.9±8.7) %. The survival rate of 5-year no recurrence in the group of negative Th17 was (81.8±11.6)%, overall survival rate of 5-year was 100 %. Conclusions: Th17 played an important role in the local recurrence of sacral tumors.The high expression of Th17 indicated the high recurrence and short CDFS after operation. The high expression of TH17 was an important sign for the progress and recurrence,and could be one of the indexs to determine the recurrence of the sacral chordoma.
Purpose: To study the expression level of CD40、PCNA in sacral chordoma and their relationship with recurrence, and to provide a new target for the immunization therapy of sacral chordoma.
Methods: To collect tumor tissue of 28 cases with sacral chordoma who had full information of clinical and pathology for the wax. To detect the expression of CD40 and PCNA by using immunohistochemisty, another 9 cases with normal notochordal tissue were set as control group and count the MVD marked by CD31. All the data was showed by mean±standard error and using T-test to compare two groups. It has statistical significance if P <0.05.
Results:①The strong positive expression of CD40、PCNA in the sacral chordoma were 66.1% and 64.3%, obviously higher than that in normal notochordal tissue. There was statistical significance (P<0.05). The MVD marked by CD31 in sacral chordoma was (24.26±18.68)/mm2 and (4.63±2.19)/mm2 in normal notochordal tissue. There was statistical significance (P<0.05).②Among the 28 sacral chordoma, 14 had recurrence and 14 had no recurrence, the positive expression of CD40 were 14.29% and 85.71%.For the PCNA, the positive expression were 92.86% and 50.55%. MVD marked by CD31 were (30.66±23.75)/mm2 and (17.88±8.52)/mm2. All had statistical significance (P<0.05).③There were no statistical correlation between the expression of CD40、PCNA and the value of MVD with the age, gender and the size of tumor.④The MVD in the group of positive expression of PCNA was (28.92±20.27) /mm2, significantly higher than the negative group (12.64±3.70) /mm2. And there was statistical significance(P<0.05). The MVD in the group of negative expression of CD40 was (31.68±22.81 /mm2, significantly higher than the positive group (16.86±9.28) /mm2. And there was statistical significance (P<0.05).
Conclusions: CD40 and PCNA had vital role in the tumor invasion, recurrence and metastasis. Strong expression of PCNA and weak expression of CD40 was important sign for the progress and recurrence of sacral chordoma. The expression level of CD40 and PCNA in the sacral chordoma was one of the index to determine the progress and recurrence of the tumor.
引文
1. Sallusto F, Lanzavecchia A, Heterogeneity of CD4+ memory T cell: functional modules for tailored immunity. Eur J Immunol, 2009, 39: 2076-2082
2. Dong C. Th17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008, 8: 337-348.
3. Numasaki M, Watanabe M, Suzuki T, et al. IL-17 enhances the net angiogenic activity and in vivo growth of human nonsmall cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. Immunol, 2005, 175(9): 6177-6189
4. Kom T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009, 27: 485-517
5. Woo EY, Yeh H, Chu CS, et a. Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J immunol, 2002, 168(9): 4272-4276
6. Curiel TJ, Coukos G, Zou L, et a1. Specific recruitment of regulatory T cells in ovarian carcinomafosters immune privilege and predicts reduced survival. Nat Med, 2004, 10(9): 942-949
7. Liyanade UK, MooreT T, Joo HG, et a1. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol, 2002, 169(5): 2756-2761
8. Kohno M, Tsutsumi A, Matsui H, et al. Interleukin-17 gene expression in patients with rheumatoid arthritis. Mod Rheumatol, 2008, 18: 15-22.
9. Asquith DL, Mclnnes IB. Emerging cytokine tarets in rheumatoid arthritis. Curr Opin Rheumatol. 2007, 19: 246-251.
10. Nistala K, Moncrieffe H, Newton KR, et al. Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum, 2008, 58: 875-887.
11. Agarwal S, Misra R, Aggarwal A. Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produce proinflammatory cytokines and matrix metalloproteinases. J Rheumatol, 2008, 35: 515-519.
12. Bullens DM, Truyen E, Coteur L, et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir Res, 2006,7:135.
13. Wong CK, Lit LC, Tam LS, et al. Hyperproduction of IL-23 and IL-17 in patients with sysmetic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol. 2008, 127: 385-393.
14. Zaba LC, Fuentes-Duculan J, Eungdamrong NJ, et al. Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cell. J Invest Dermatol. 2009, 129: 79-88.
15. Blauvelt A. T=helper 17 cells in psoriatic plaques and additional genetic links between IL-23 and psoriasis. J Invest Dermatol, 2008, 128: 1064-1067.
16. Fransson ME, Liljenfeldt LS, Fagius J, et al. The T-cell pool is anergized in patients with multiple sclerosis in remission. Immunology, 2009, 126: 92-101.
17. Maloy KJ. The Interleukin-23/ Interleukin-17 axis in intestinal inflammation. J Intern Med, 2008, 263: 584-590.
18. Alex W Tong, Marvin J Stone. Prospect for CD40-directed experimental therapy of human cancer. Cancer Gene Therapy. 2003, 10: 1-3
19. Banchereau J, de Paoli P, Valle A, et al. Long-term human B cell lines dependenton interleukin 4 and antibody to CD40. Science. 1991, 251: 70-83
20. Hollenbaugh D, Grosmair LS, Kullas CD, et al. The human T antigen gp39, amember of the TNFαGene family, is a ligand for the CD40 receptor: expression of asoluble from of gp 39 with B cell co-stimulatory activity. EMBOJ. 1992, 11: 4313
21. Spriggs MK, Armitage RJ, Strockbine L, et al. Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. J Exp Med. 1992, 176: 1543
22. Seran C.Hill, Sarah J. Youde, Stephen M, et al. Activation of CD40 in cervical carcinoma cell facilitates CTL responses and augments chemotherapy-induced apoptosis. J. Immunol. 2005, 168: 41-46
23. Biancone L, Cantaluppi V, Camussi G. CD40-CD40L interaction in experimental and human disease. Int J Mol Med. 1999; 3: 343-353
24. Kabayashi I ,Matsuo K , Ishibashi Y, et al. Proliferative activity in dysplasia and carcinoma in situ of theuterine cervix analyzed by PCNA immunostaining and AgNOR staining. Hum Pathol, 1994 ;25 :198
25.夏书月,姜彦多,何安光等。肺鳞癌发生过程中p 53蛋白和增殖细胞核抗原的表达.。中国肿瘤临床,1995;22(11): 772～5。
26.吴名耀,郑瑞明,沈健等。食管癌增殖细胞核抗原的免疫组化研究。中华病理学杂志,1993;22(4): 239～40。
27. Woods AL, Hall PA, Shepherd NA, et al. The assessment of proliferating cell nuclear antigen (PCNA) immunostaining in primary gastro-intestinal lymphomas and its relationship to histological grade, S+G2+M, phase fraction (flowcytometric analysis) and prognosis. Histopathology, 1991; 19: 21～7.
28.阮幼冰,武忠弼,Ivankovic S。增殖细胞核抗原及表皮生长因子受体在大鼠肝癌与胃癌中的表达。中华病理学杂志,1994;23(5): 274～7。
29. Pich A, Ponti R, Chiusa L, et al. MIB-1, Ki67, and PCNA scores and DNA flow cytometry in intermediate grade malignant lymphomas. J Clin Pat hol, 1994; 47: 18～22.
1 Chandawarkar RY. Sacrococcygeal chordoma: review of 50 consecutive patients. World J Surg, 1996, 20(6): 717-719.
2 Bergh P, Kindblom LG, Gunterberg B, et a1. Prognostic factors in chordoma of the sacrum and mobile spine: a study of 39 patients. Cancer, 2000, 88(9): 2122-2134.
3 Ribbert H. Uber die ecchondrsis physalifora spheno-occipitallis nach untersuchungen von Herman. Zbl Allg Pathol Pathol anat, 1894, 5: 457-461.
4 Fuchs B, Dickey ID, Yaszemski MJ, et al. Operative management of sacral chordoma. J Bone Joint Surg Am, 2005, 87: 2211-2216.
5 Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol, 2005, 6(11): 1123-1132.
6 Fontenot J D, Gavin M A, Rudensky A Y, et al. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol, 2003; 4(4):330-6.
7 Maggie E, Biswar R, Pnete GD, et a1. Accumulation of Th2 like helper T cells in the conjunctiva of patients with vernal conjunctivitis. J Immunol, 1991, 146(4): 1169-1174.
8 Lighvani AA, Frucht DM, Jankovic D, et al. T-bet is rapidly induced by interferon- gamma in lymphoid and myeloid cells. Proc Natl Acad Sci, 2001, 98(26): 15137-15142.
9 Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell, 1997, 89(4): 587-596.
10 Yamamura M, Modlin RL, Ohmen JD, et al. Local expression of anti- inflammatory cytokines in cancer. J Clin Invest, 1993, 91(3): 1005-1010.
11 Kharkeviteh DD, Seito D, Balch GC, et a1. Characterization of auto1ogous tumor specific T-helper 2 cells in tumor infiltrating lymphocytes from a patient with metastatic melanoma. J Cancer, 1994, 58(3): 317-323.
12 Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alphachain (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol, 1995; 155(3):1151-64.
13 Thornton A M, Shevach E M, et al. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol, 2000; 164(1):183-90.
14 Hori S, Nomura T, Sakaguchi S, et al. Control of regulatory T cell development by the transcription factor Foxp3. Science, 2003; 299 (5609): 1057-61.
15 Gambineri E, Torgerson T R, Ochs H D, et al. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol, 2003; 15(4):430-5.
16 Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+ CD25- naive T cells toCD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med, 2003; 198(12): 1875-86.
17 Zhang JP, Yan J, Xu J, et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol, 2009, 50( 5 ): 980-989.
18 Tosolini M, Kirilovsky A, Mlecnik B, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011, 15; 71(4):1263-1271.
19 Wrobel T, Mazur G, Jazwiec B, et al. Interleukin-17 in acute myeloid leukemia. Cell Mol Med, 2003, 7(4): 472-474.
20 Numasaki M, Watanabe M, Suzuki T, et al. IL-17 enhances the net angiogenic activity and in vivo growth of human nonsmall cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. Immunol, 2005, 175(9): 6177-6189.
1 York JE, Kaczaraj A, Abi-Said D, et al. Sacral chordoma: 40-year experience at a major cancer center. Neurosurgery, 1999, 44: 74-79.
2 Hulen CA, Temple HT, Fox WP, et al. Oncologic and functional outcome following sacrectomy for sacral chordoma. J Bone and Joint Surg Am, 2006, 88(7): 1532-1539.
3 Fuchs B, Dickey ID, Yaszemski MJ, et al. Operative management of sacral chordoma. J Bone Joint Surg Am, 2005, 87: 2211-2216.
4 Akmal S, Ole SN, Anne GJ, et a1. A retrospective clinicopathological study of 37 patients with chordoma: a Danish national series. Sarcoma, 1997, 1: 161-165.
5杨惠林,倪才方,唐天驷等。靶血管栓塞后手术治疗骶骨肿瘤。中华骨科杂志, 1998,18(11): 646-648。
6 Mattern J, Koomagi R, Volm K. Association of vascular endothelial growth factor expression with intratumoral microvessel density and tumor cell proliferation in human epidermoid lung cancer. Br J Cancer, 1996, 73: 931-934.
7 Simpson AH, Porter A, Davis A, et a1. Cephalad sacral resection with a combined extended ilioinguinal and posterior approach. J Bone and Joint Surg Am, 1995, 77(3): 405-411.
8 Cheng EY, Ozerdemoglu RA, Transfeldt EE, et al. Lumbosacral chordoma: Prognostic factors and treatment. Spine, 1999, 24: 1639-1645.
9 Yonemoto T, Tatezaki SJ, Ishii T, et a1. The surgical management of sacrococcygeal chordoma. Cancer, 1999, 85(4): 878-883.
10 Hanna SA, Aston WJS, Briggs TWR, et al. Sacral Chordoma: can local recurrence after sacrectomy be predicted? Clin Orth Rela Res, 2008, 466: 2217-2223.
11 Lin Wang, Tangsheng Yi, Wang Zhang,et al IL-17 Enhances Tumor Development in Carcinogen-Induced Skin Cancer. Cancer Res., Dec 2010; 70: 10112 - 10120.
12 Afzali B, Lombardi G, Lechler RI, et al The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol. 2007 Apr;148(1):32-46.
13 Dong C. Th17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008 May;8(5):337-348.
14 Miossec P. Interleukin-17 in rheumatoid arthritis: if T cells were to contribute to inflammation and destruction through synergy. Arthritis Rheum, 2003, 48 ( 3) : 594-601.
15 Nistala K, Moncrieffe H, Newtonk R, et al. Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum, 2008, 58(3): 875-887.
16 Bullens DM, Truyen E, Coteur L, et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflamm at ionandgranulocyic influx? Respir Res, 2006, 7 (1): 135-139.
17 Mok MY, Wu HJ, Lo Y, et al. The relation of interleukin 17 (IL-17) and IL-23 to Th1/Th2cytokines and disease activity in systemic lupus erythematosus. J Rheumatol. 2010, 37(10): 2046-2052.
18 Fransson ME, Liljenfeldt LS, Fagius J, et al. The T-cell pool is anergized in patients with multiple sclerosis in remission. Immunology, 2009, 126(1): 92-101.
19 Kuang DM, Peng C, Zhao QY, et al Tumor-Activated Monocytes Promote Expansion of IL-17–Producing CD8+ T Cells in Hepatocellular Carcinoma Patients. J. Immunol, Aug 2010; 185: 1544 - 1549.
20 Numasaki M, Watanabe M, Suzuki T, et al IL-17 Enhances the Net Angiogenic Activity and In Vivo Growth of Human Non-Small Cell Lung Cancer in SCID Mice through Promoting CXCR-2-Dependent Angiogenesis. J. Immunol, Nov 2005; 175: 6177 - 6189.
21 Cailin MW, Ilona Kryczek, Shuang Wei, et al Th17 Cells in Cancer: Help or Hindrance? Carcinogenesis, Feb 2011; 10.1093.
22 Gopal Murugaiyan and Bhaskar Saha Protumor vs Antitumor Functions of IL-17. J. Immunol, Oct 2009; 183: 4169 - 4175.
23 Iida T, Iwahashi M, Katsuda M, et al. Tumor-infiltrating CD4+ Th17 cells produce IL-17 in tumor microenvironment and promote tumor progression in human gastric cancer. Oncol Rep. 2011 Mar 1.
24 Carmi Y, Rinott G, Dotan S, et al Microenvironment-Derived IL-1 and IL-17 Interact in the Control of Lung Metastasis. J Immunol. 2011 Mar 15;186(6):3462-71.
25 Miyahara Y, Odunsi K , Chen W, et al Generation and regulation of human CD4+ IL-17- producing T cells in ovarian cancer. PNAS, Oct 2008; 105: 15505 - 15510.
26 Wang L, Yi TS, Kortylewski M, et al IL-17 can promote tumor growth through an IL-6–Stat3 signaling pathway. J. Exp. Med., Jul 2009; 206: 1457 - 1464.
1. Ferraresi V, Nuzzo C, Zoccali C, et al. Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients. BMC Cancer. 2010 Jan 28; 10: 22.
2. Watkins L,Khudados ES,Kaleoglu M,et a1. Skull base chordomas: A review of 38 patients,1958～1988. Br J Neurosurg, 1993, 7: 241-248.
3. Hulen CA, Temple HT, Fox WP, et al. Oncologic and functional outcome following sacrectomy for sacral chordoma. J Bone and Joint Surg Am, 2006, 7: 1532-1539.
4. York JE, Kaczaraj A, Abi- Said D, et al. Sacral chordoma: 40-year experience at a major cancer center. Neurosurgery, 1999, 44: 74-79.
5.陈康武,杨惠林,王根林等,骶骨脊索瘤术后复发的相关因素分析,中国矫形外科杂志,2009,17(21):1613-1616。
6. Quezada SA , Jarvinen LZ , Lind EF , et a l. CD40/CD154 Interactions at the interface oftolerance and immunity. Annu Rev Immunol, 2004, 22: 307-328.
7. Sabel MS, Yamada M, Kawaguchi Y, et al. CD40 expression on human lung cancer correlates with metastatic spread. Cancer Immunol Immunother, 2000, 49: 101-108.
8. Weidner N, Semple JP, Welch WR, et al. Tumor angiogenesis and metastasis correlation in invasive breast carcinoma. Cancer, 2000, 89: 1102-1110.
9. Yang H, Zhu L, Ebraheim NA, et al. Analysis of risk factors for recurrence after the resection of sacral chordoma combined with embolization. Spine J. 2009 Dec; 9(12): 972-80.
10. Bergh P, Kindblom LG, Gunterberg B, et al. Prognostic factors in chordoma of the sacrum and mobile spine: a study of 39 patients. Cancer, 2000, 9: 2122-2134.
11. Fuchs B, Dickey ID, Yaszemski M J, et al. Operative management of sacral chordoma. J Bone Joint Surg Am, 2005, 87: 2211-2216.
12. Hanna SA, Aston W JS, Briggs T WR, et al. Sacral chordoma: can local recurrence after sacrectomy be predicted. Clin Orth Rela Res, 2008, 466: 2217-2223.
13. Van Kooten C,Banchereau J. CD40-CD40 1igand. Leukocyte Biol, 2000, 67(1): 2-17.
14. Tong AW, Stone MJ. Prospects for CD40-directed experimental therapy of human cancer. Cancer Gene Ther. 2003 Jan; 10(1):1-13. Review.
15. Seran C.Hill, Sarah J. Youde, Stephen Man, et al. Activation of CD40 in cervical carcinoma cell facilitates CTL responses and augments chemotherapy-induced apoptosis. J. Immunol. 2005, 168: 41-46
16. Voorzanger-Rousselot N, Alberti L, Blay JY. CD40L induces multidrug resistance to apoptosis in breast carcinoma and lymphoma cells through caspase independent and dependent pathways. BMC Cancer, 2006, 186: 75.
17. Dangerfield J,Larbik Y,Huang MT,et a1. PECAM-1 (CD31) homophilic interaetion upregulated d 6 B 1 on transmigrated neutrophils in vivo and plays a functional role in d1e ability of 6 integrinsto mediate leukoeyte migration through the perivaseular basementmembrane.J Exp Med, 2002, 196(9): 1201-1211.
18. Sumpio BE,Yun S,Cordova AC,et a1. MAP Kinases(ERK1/2,p38) and AKT can be phosphorylated by shear stress independently of PECAM一1(CD31)in vascular endothelial cells. J Biol Chem, 2005, 280(12): 11185-11191.
19. Weidner N.The relationship of tumor an giogenesis and metastasis with emphasis on invasive breast carcinoma. Advances in pathology and laboratory medicine edited by RS Weinstein. Chicago: Mosby Year Book. 1992:111-121。
20.李家谋,钟延丰,蔡钦林。脊索瘤中增殖细胞核抗原表达与细胞凋亡检测的临床意义.中国脊柱脊髓杂志, 2001,11: 210-212 .
21. Schattner EJ, Mascarenhas J, Bishop J, et al. CD4+ T-cell induction of Fas-mediated apoptosis in Burkitt’s lymphoma B cell. Blood, 1996, 88: 1375-1382.
22. Hill SC, Youde SJ, Man S, et al. Activation of CD40 in cervical carcinoma cells facilitates CTL responses and augments chemotherapy-induced apoptosis. Immunol, 2005, 174(1): 41-50
23.王东,陈俐,高奉浔.骨肉瘤血管内皮生长因子表达与肿瘤血管生成及预后的关系。癌症,1998,17(4): 264-256.
24. Holling HC, Kohn EC, Steinberg SM, et al. Tumor angiogenesis in advanced stage ovarian carcinoma. Am J Pathol, 1995, 147:33.
25. Narita M, Nakao K, Ogino N, et al. Independent prognostic factors in breast cancer patient. Am J Surg, 1998, 177: 73.
1. Korn T, Bettelli E, Oukka M, et al. IL-17 and Th17 cells. Annu Rev Immunol, 2009, 27 (1): 485-517.
2. Afzali B, Lombardi G, Lechler RI, et al. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol, 2007, 148(1):32-46.
3. Dong C. Th17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol, 2008, 8 (5): 337-348.
4. Laan M, Lotvall J, Chung KF, et a1. IL-17-induced cytokine release in human bronchi epithelial cells in vitrn: role of mitogen-activated protein(MAP) kinases. Pharmacol, 2001, 133(1): 200-206.
5. GranB,.Zhang GX, Yu S, et al. IL-12p35-defcient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. Immunol, 2002, 169(12): 7104-7110.
6. Cua DJ, Sherlock J, Chen Y, et al. Interleukin 23 rather than interleukin 12 is the critical cytokine for autoimmune inflammation of the brain. Nature, 2003, 421 (6924): 744-748.
7. Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med, 2005, 201(2): 233-240.
8. Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effect or T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol, 2005, 6(11): 1123-1132.
9. Brentano F, Ospelt C, Stanczyk J, et al. Abundantexpression of the interleukin ( IL) 23 subunit p19, but lowlevels of bioactive IL23 in the rheumatoid synovium: differential expression and Toll like receptor ( TLR ) dependent regulation of the IL23 subunits, p19 and p40, in rheumatoid arthritis. Ann Rheum Dis, 2008, 68 (1): 143-150.
10. Bettelli E, Carrier Y, Gao W, et al. Reciprocal development l pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature, 2006, 441 ( 7091) :
11. Kimura A, Naka T, Kishimoto T. IL-6 dependent and independent pathways in the developmen to finterleukin17-producing T helper cells. Proc Natl Acad Sci USA, 2007, 104 (29): 12099-12104.
12. Chen Z, O’Shea JJ. Regulation of IL-17 production in human lymphocytes. Cytokine, 2008; 41(2): 71-78.
13. Chen Z, Tato CM, Muul L. Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum, 2007; 56(9): 2936-2946.
14. Wilson NJ, Boniface K, Chan JR, et al. Development cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol, 2007; 8(9): 950-957.
15. Yang XO, Panopoulos AD, Nurieva R, et al. STAT3 regulates cytokine mediated generation of inflammato ryhelper T cells. J Biol Chem, 2007, 282 (13): 9358-9363.
16. Napolitani G, Acosta-Rodriguez EV, Lanzavecchia A,et al. Prostaglandin E2 enhances Th17 responses via modulation of IL-17 and IFN-gamma production by memory CD4+ T cells. Eur J Immunol. 2009, 39(5):1301-1312.
17. Stumhofer JS, Laurence A, Wilson EH, et al. Interleukin 27 negatively regulates the development of interleukin 17 producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol, 2006, 7(9): 937-945.
18. Batten M, Li J, Yi S, et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleuk in 17 producing T cells. Nat.Immunol, 2006, 7 (9): 929-936.
19. Moisan J, Grenningloh R, Bettelli E, et al. Ets1 is anegative regulator of Th17 differentiation. J ExpMed, 2007, 204(12): 28256-28235.
20. Bozza S, Zelante T, Moretti S, et al. Lack of Toll IL-1R8 exacerbates Th17 ce ll responses in funga l infection. J Immunol, 2008, 180(6) : 4022-4031.
21. Liang SC, Nickerson-Nutter C, Pittman DD, et al. IL-22 induces an acute-phase response. J Immunol. 2010, 185(9): 5531-5538.
22. Aujla SJ, Chan YR, Zheng M, et al. IL-22 mediatesmucosa l host defense against G ram-negative bacterialpneumonia. NatMed, 2008, 14 ( 3): 275-281.
23. OuyangW, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity, 2008, 28( 4) : 454-467.
24. Wilson N J, Boniface K, Chan JR, et al. Development cytokine profile and function of human interleuk in 17–producing helper T cell[ J]. Nat Immunol, 2007, 8(9): 950-957.
25. Dambacher J, Beigel F, Zitzmann K, et al. The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut, 2008, 15. [ Epub ahead of print] .
26. Miossec P. Interleukin-17 in rheumatoid arthritis: if T cells were to contribute to inflammation and destruction through synergy. Arthritis Rheum, 2003, 48 ( 3) : 594-601.
27. Nistala K, Moncrieffe H, Newtonk R, et al. Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum, 2008, 58(3): 875-887.
28. Bullens DM, Truyen E, Coteur L, et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflamm at ionandgranulocyic influx? Respir Res, 2006, 7 (1): 135-139.
29. Mok MY, Wu HJ, Lo Y, et al. The relation of interleukin 17 (IL-17) and IL-23 to Th1/Th2 cytokines and disease activity in systemic lupus erythematosus. J Rheumatol. 2010, 37(10): 2046-2052.
30. Fransson ME, Liljenfeldt LS, Fagius J, et al. The T-cell pool is anergized in patients with multiple sclerosis in remission. Immunology, 2009, 126(1): 92-101.
31. Hwang SY, Kim HY. Expression of IL-17 homologs and their receptors in the synovial cells of rheumatoid arthritis patients. Mol Cells, 2005, 19(2): 180-184
32. Joosten LA, Abdollahi Roodsaz S, HeuvelmansJacobs M, et al. T cell dependence of chronic destructivemurine arthritis induced by repeated local activation of Toll-like receptor-drivenpathways: crucial role of both interleukin-1beta and interleukin-17. Arthritis Rheum, 2008, 58 ( 1): 98-108.
33. Ohsugi Y. Recent advances in immunopathophysiology of interleukin-6: an innovative therapeutic drug, tocilizumab (recombinant humanized anti-human interleukin-6 receptor antibody), unveils the mysterious etiology of immune-mediated inflammatory diseases. Biol. Pharm. Bull, 2007, 30(11): 2001-2006。
34. Wong CK, Lit LC, Tam LS, et al. Hyperproduction of IL-23 and IL-17 in patients with systemic lupuse rythematosus: implications for Th17-mediated inflammation in autoimmunity. Clin Immunol, 2008, 127( 3): 385-393.
35. Kebir H, Kreymborg K, Ifergan I, et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007, 13(10):1173-1175.
36. Jain R, Tartar DM, Gregg RK, et al. Innocuous IFN gamm a induced by adjuvant free antigen restoresnormoglycemia in NOD mice through inhibition of IL-17 production. J ExpMed, 2008, 205(1): 207-218.
37. Kato T, Furumoto H, Ogura T, et al. Express ion of IL-17 mRNA inovarian cancer. B iochem BiophysRes Commun, 2001, 282( 3) : 735- 738.
38. Kryczek I, Banerjee M, Cheng P, et al. Phenotype, distribution, generation, functional and clinical relevance of Th17 cells in the human tumor environments. Blood, 2009, 114( 6 ) : 1141 - 1149.
39. Miyahara Y, Odunsi K, ChenW, et al. Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer. Proc Nat l Acad Sci USA, 2008, 105 ( 40) : 15505- 15510.
40. Zhang B, Rong G, Wei H, et al. The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun, 2008, 374( 3 ) : 533 - 537.
41. Zhang JP, Yan J, Xu J, et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol, 2009, 50( 5 ): 980-989.
42. Kryczek I, Wei S, Zou L, et al. Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immuno,l 2007, 178 ( 11) : 6730- 6733.
43. Sfanos KS, Bruno TC, Maris CH, et al. Phenotypic analysis of prostate infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res, 2008, 14( 11) : 3254- 3261.
44. Tosolini M, Kirilovsky A, Mlecnik B, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011, 15; 71(4):1263-1271.
45. Le GS, Bastuji-Garin S, Aloulou N, et al. High prevalence of Foxp3 and IL-17 inMMR-proficient colorectal carcinomas. Gut, 2008, 57( 6) : 772- 779.
46. Krycak I, Wei S, Szeliga W, et al. Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood, 2009 [ 2009-04-13 ] . h ttp: / /blood journal hematology library. org/cgi/ content / abstract /blood, 2008, 09, 177360v1.
47. Wrobel T, Mazur G, Jazwiec B, et al. Interleukin-17 in acute myeloid leukemia. Cell Mol Med, 2003, 7(4): 472-474
48. Horlock C, Stott B, Dyson PJ, et al. The effects of trastuzumabon the CD4+ CD25+ FoxP3+ and CD4+ IL17A+ T-cell axis in patients with breast cancer. Br J Cancer, 2009, 100 ( 7 ): 1061-1067.
49. Benchetrit F, Circe A, Vires V, et al. Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood, 2002, 99( 6 ): 2114-2 l21.
50. Muranski P, Boni A, Antony PA, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood, 2008, 112( 2 ) : 362-373.
2. Dong C. Th17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008, 8: 337-348.
3. Numasaki M, Watanabe M, Suzuki T, et al. IL-17 enhances the net angiogenic activity and in vivo growth of human nonsmall cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. Immunol, 2005, 175(9): 6177-6189
4. Kom T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009, 27: 485-517
5. Woo EY, Yeh H, Chu CS, et a. Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J immunol, 2002, 168(9): 4272-4276
6. Curiel TJ, Coukos G, Zou L, et a1. Specific recruitment of regulatory T cells in ovarian carcinomafosters immune privilege and predicts reduced survival. Nat Med, 2004, 10(9): 942-949
7. Liyanade UK, MooreT T, Joo HG, et a1. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol, 2002, 169(5): 2756-2761
8. Kohno M, Tsutsumi A, Matsui H, et al. Interleukin-17 gene expression in patients with rheumatoid arthritis. Mod Rheumatol, 2008, 18: 15-22.
9. Asquith DL, Mclnnes IB. Emerging cytokine tarets in rheumatoid arthritis. Curr Opin Rheumatol. 2007, 19: 246-251.
10. Nistala K, Moncrieffe H, Newton KR, et al. Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum, 2008, 58: 875-887.
11. Agarwal S, Misra R, Aggarwal A. Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produce proinflammatory cytokines and matrix metalloproteinases. J Rheumatol, 2008, 35: 515-519.
12. Bullens DM, Truyen E, Coteur L, et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir Res, 2006,7:135.
13. Wong CK, Lit LC, Tam LS, et al. Hyperproduction of IL-23 and IL-17 in patients with sysmetic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol. 2008, 127: 385-393.
14. Zaba LC, Fuentes-Duculan J, Eungdamrong NJ, et al. Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cell. J Invest Dermatol. 2009, 129: 79-88.
15. Blauvelt A. T=helper 17 cells in psoriatic plaques and additional genetic links between IL-23 and psoriasis. J Invest Dermatol, 2008, 128: 1064-1067.
16. Fransson ME, Liljenfeldt LS, Fagius J, et al. The T-cell pool is anergized in patients with multiple sclerosis in remission. Immunology, 2009, 126: 92-101.
17. Maloy KJ. The Interleukin-23/ Interleukin-17 axis in intestinal inflammation. J Intern Med, 2008, 263: 584-590.
18. Alex W Tong, Marvin J Stone. Prospect for CD40-directed experimental therapy of human cancer. Cancer Gene Therapy. 2003, 10: 1-3
19. Banchereau J, de Paoli P, Valle A, et al. Long-term human B cell lines dependenton interleukin 4 and antibody to CD40. Science. 1991, 251: 70-83
20. Hollenbaugh D, Grosmair LS, Kullas CD, et al. The human T antigen gp39, amember of the TNFαGene family, is a ligand for the CD40 receptor: expression of asoluble from of gp 39 with B cell co-stimulatory activity. EMBOJ. 1992, 11: 4313
21. Spriggs MK, Armitage RJ, Strockbine L, et al. Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. J Exp Med. 1992, 176: 1543
22. Seran C.Hill, Sarah J. Youde, Stephen M, et al. Activation of CD40 in cervical carcinoma cell facilitates CTL responses and augments chemotherapy-induced apoptosis. J. Immunol. 2005, 168: 41-46
23. Biancone L, Cantaluppi V, Camussi G. CD40-CD40L interaction in experimental and human disease. Int J Mol Med. 1999; 3: 343-353
24. Kabayashi I ,Matsuo K , Ishibashi Y, et al. Proliferative activity in dysplasia and carcinoma in situ of theuterine cervix analyzed by PCNA immunostaining and AgNOR staining. Hum Pathol, 1994 ;25 :198
25.夏书月,姜彦多,何安光等。肺鳞癌发生过程中p 53蛋白和增殖细胞核抗原的表达.。中国肿瘤临床,1995;22(11): 772～5。
26.吴名耀,郑瑞明,沈健等。食管癌增殖细胞核抗原的免疫组化研究。中华病理学杂志,1993;22(4): 239～40。
27. Woods AL, Hall PA, Shepherd NA, et al. The assessment of proliferating cell nuclear antigen (PCNA) immunostaining in primary gastro-intestinal lymphomas and its relationship to histological grade, S+G2+M, phase fraction (flowcytometric analysis) and prognosis. Histopathology, 1991; 19: 21～7.
28.阮幼冰,武忠弼,Ivankovic S。增殖细胞核抗原及表皮生长因子受体在大鼠肝癌与胃癌中的表达。中华病理学杂志,1994;23(5): 274～7。
29. Pich A, Ponti R, Chiusa L, et al. MIB-1, Ki67, and PCNA scores and DNA flow cytometry in intermediate grade malignant lymphomas. J Clin Pat hol, 1994; 47: 18～22.
1 Chandawarkar RY. Sacrococcygeal chordoma: review of 50 consecutive patients. World J Surg, 1996, 20(6): 717-719.
2 Bergh P, Kindblom LG, Gunterberg B, et a1. Prognostic factors in chordoma of the sacrum and mobile spine: a study of 39 patients. Cancer, 2000, 88(9): 2122-2134.
3 Ribbert H. Uber die ecchondrsis physalifora spheno-occipitallis nach untersuchungen von Herman. Zbl Allg Pathol Pathol anat, 1894, 5: 457-461.
4 Fuchs B, Dickey ID, Yaszemski MJ, et al. Operative management of sacral chordoma. J Bone Joint Surg Am, 2005, 87: 2211-2216.
5 Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol, 2005, 6(11): 1123-1132.
6 Fontenot J D, Gavin M A, Rudensky A Y, et al. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol, 2003; 4(4):330-6.
7 Maggie E, Biswar R, Pnete GD, et a1. Accumulation of Th2 like helper T cells in the conjunctiva of patients with vernal conjunctivitis. J Immunol, 1991, 146(4): 1169-1174.
8 Lighvani AA, Frucht DM, Jankovic D, et al. T-bet is rapidly induced by interferon- gamma in lymphoid and myeloid cells. Proc Natl Acad Sci, 2001, 98(26): 15137-15142.
9 Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell, 1997, 89(4): 587-596.
10 Yamamura M, Modlin RL, Ohmen JD, et al. Local expression of anti- inflammatory cytokines in cancer. J Clin Invest, 1993, 91(3): 1005-1010.
11 Kharkeviteh DD, Seito D, Balch GC, et a1. Characterization of auto1ogous tumor specific T-helper 2 cells in tumor infiltrating lymphocytes from a patient with metastatic melanoma. J Cancer, 1994, 58(3): 317-323.
12 Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alphachain (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol, 1995; 155(3):1151-64.
13 Thornton A M, Shevach E M, et al. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol, 2000; 164(1):183-90.
14 Hori S, Nomura T, Sakaguchi S, et al. Control of regulatory T cell development by the transcription factor Foxp3. Science, 2003; 299 (5609): 1057-61.
15 Gambineri E, Torgerson T R, Ochs H D, et al. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol, 2003; 15(4):430-5.
16 Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+ CD25- naive T cells toCD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med, 2003; 198(12): 1875-86.
17 Zhang JP, Yan J, Xu J, et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol, 2009, 50( 5 ): 980-989.
18 Tosolini M, Kirilovsky A, Mlecnik B, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011, 15; 71(4):1263-1271.
19 Wrobel T, Mazur G, Jazwiec B, et al. Interleukin-17 in acute myeloid leukemia. Cell Mol Med, 2003, 7(4): 472-474.
20 Numasaki M, Watanabe M, Suzuki T, et al. IL-17 enhances the net angiogenic activity and in vivo growth of human nonsmall cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. Immunol, 2005, 175(9): 6177-6189.
1 York JE, Kaczaraj A, Abi-Said D, et al. Sacral chordoma: 40-year experience at a major cancer center. Neurosurgery, 1999, 44: 74-79.
2 Hulen CA, Temple HT, Fox WP, et al. Oncologic and functional outcome following sacrectomy for sacral chordoma. J Bone and Joint Surg Am, 2006, 88(7): 1532-1539.
3 Fuchs B, Dickey ID, Yaszemski MJ, et al. Operative management of sacral chordoma. J Bone Joint Surg Am, 2005, 87: 2211-2216.
4 Akmal S, Ole SN, Anne GJ, et a1. A retrospective clinicopathological study of 37 patients with chordoma: a Danish national series. Sarcoma, 1997, 1: 161-165.
5杨惠林,倪才方,唐天驷等。靶血管栓塞后手术治疗骶骨肿瘤。中华骨科杂志, 1998,18(11): 646-648。
6 Mattern J, Koomagi R, Volm K. Association of vascular endothelial growth factor expression with intratumoral microvessel density and tumor cell proliferation in human epidermoid lung cancer. Br J Cancer, 1996, 73: 931-934.
7 Simpson AH, Porter A, Davis A, et a1. Cephalad sacral resection with a combined extended ilioinguinal and posterior approach. J Bone and Joint Surg Am, 1995, 77(3): 405-411.
8 Cheng EY, Ozerdemoglu RA, Transfeldt EE, et al. Lumbosacral chordoma: Prognostic factors and treatment. Spine, 1999, 24: 1639-1645.
9 Yonemoto T, Tatezaki SJ, Ishii T, et a1. The surgical management of sacrococcygeal chordoma. Cancer, 1999, 85(4): 878-883.
10 Hanna SA, Aston WJS, Briggs TWR, et al. Sacral Chordoma: can local recurrence after sacrectomy be predicted? Clin Orth Rela Res, 2008, 466: 2217-2223.
11 Lin Wang, Tangsheng Yi, Wang Zhang,et al IL-17 Enhances Tumor Development in Carcinogen-Induced Skin Cancer. Cancer Res., Dec 2010; 70: 10112 - 10120.
12 Afzali B, Lombardi G, Lechler RI, et al The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol. 2007 Apr;148(1):32-46.
13 Dong C. Th17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008 May;8(5):337-348.
14 Miossec P. Interleukin-17 in rheumatoid arthritis: if T cells were to contribute to inflammation and destruction through synergy. Arthritis Rheum, 2003, 48 ( 3) : 594-601.
15 Nistala K, Moncrieffe H, Newtonk R, et al. Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum, 2008, 58(3): 875-887.
16 Bullens DM, Truyen E, Coteur L, et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflamm at ionandgranulocyic influx? Respir Res, 2006, 7 (1): 135-139.
17 Mok MY, Wu HJ, Lo Y, et al. The relation of interleukin 17 (IL-17) and IL-23 to Th1/Th2cytokines and disease activity in systemic lupus erythematosus. J Rheumatol. 2010, 37(10): 2046-2052.
18 Fransson ME, Liljenfeldt LS, Fagius J, et al. The T-cell pool is anergized in patients with multiple sclerosis in remission. Immunology, 2009, 126(1): 92-101.
19 Kuang DM, Peng C, Zhao QY, et al Tumor-Activated Monocytes Promote Expansion of IL-17–Producing CD8+ T Cells in Hepatocellular Carcinoma Patients. J. Immunol, Aug 2010; 185: 1544 - 1549.
20 Numasaki M, Watanabe M, Suzuki T, et al IL-17 Enhances the Net Angiogenic Activity and In Vivo Growth of Human Non-Small Cell Lung Cancer in SCID Mice through Promoting CXCR-2-Dependent Angiogenesis. J. Immunol, Nov 2005; 175: 6177 - 6189.
21 Cailin MW, Ilona Kryczek, Shuang Wei, et al Th17 Cells in Cancer: Help or Hindrance? Carcinogenesis, Feb 2011; 10.1093.
22 Gopal Murugaiyan and Bhaskar Saha Protumor vs Antitumor Functions of IL-17. J. Immunol, Oct 2009; 183: 4169 - 4175.
23 Iida T, Iwahashi M, Katsuda M, et al. Tumor-infiltrating CD4+ Th17 cells produce IL-17 in tumor microenvironment and promote tumor progression in human gastric cancer. Oncol Rep. 2011 Mar 1.
24 Carmi Y, Rinott G, Dotan S, et al Microenvironment-Derived IL-1 and IL-17 Interact in the Control of Lung Metastasis. J Immunol. 2011 Mar 15;186(6):3462-71.
25 Miyahara Y, Odunsi K , Chen W, et al Generation and regulation of human CD4+ IL-17- producing T cells in ovarian cancer. PNAS, Oct 2008; 105: 15505 - 15510.
26 Wang L, Yi TS, Kortylewski M, et al IL-17 can promote tumor growth through an IL-6–Stat3 signaling pathway. J. Exp. Med., Jul 2009; 206: 1457 - 1464.
1. Ferraresi V, Nuzzo C, Zoccali C, et al. Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients. BMC Cancer. 2010 Jan 28; 10: 22.
2. Watkins L,Khudados ES,Kaleoglu M,et a1. Skull base chordomas: A review of 38 patients,1958～1988. Br J Neurosurg, 1993, 7: 241-248.
3. Hulen CA, Temple HT, Fox WP, et al. Oncologic and functional outcome following sacrectomy for sacral chordoma. J Bone and Joint Surg Am, 2006, 7: 1532-1539.
4. York JE, Kaczaraj A, Abi- Said D, et al. Sacral chordoma: 40-year experience at a major cancer center. Neurosurgery, 1999, 44: 74-79.
5.陈康武,杨惠林,王根林等,骶骨脊索瘤术后复发的相关因素分析,中国矫形外科杂志,2009,17(21):1613-1616。
6. Quezada SA , Jarvinen LZ , Lind EF , et a l. CD40/CD154 Interactions at the interface oftolerance and immunity. Annu Rev Immunol, 2004, 22: 307-328.
7. Sabel MS, Yamada M, Kawaguchi Y, et al. CD40 expression on human lung cancer correlates with metastatic spread. Cancer Immunol Immunother, 2000, 49: 101-108.
8. Weidner N, Semple JP, Welch WR, et al. Tumor angiogenesis and metastasis correlation in invasive breast carcinoma. Cancer, 2000, 89: 1102-1110.
9. Yang H, Zhu L, Ebraheim NA, et al. Analysis of risk factors for recurrence after the resection of sacral chordoma combined with embolization. Spine J. 2009 Dec; 9(12): 972-80.
10. Bergh P, Kindblom LG, Gunterberg B, et al. Prognostic factors in chordoma of the sacrum and mobile spine: a study of 39 patients. Cancer, 2000, 9: 2122-2134.
11. Fuchs B, Dickey ID, Yaszemski M J, et al. Operative management of sacral chordoma. J Bone Joint Surg Am, 2005, 87: 2211-2216.
12. Hanna SA, Aston W JS, Briggs T WR, et al. Sacral chordoma: can local recurrence after sacrectomy be predicted. Clin Orth Rela Res, 2008, 466: 2217-2223.
13. Van Kooten C,Banchereau J. CD40-CD40 1igand. Leukocyte Biol, 2000, 67(1): 2-17.
14. Tong AW, Stone MJ. Prospects for CD40-directed experimental therapy of human cancer. Cancer Gene Ther. 2003 Jan; 10(1):1-13. Review.
15. Seran C.Hill, Sarah J. Youde, Stephen Man, et al. Activation of CD40 in cervical carcinoma cell facilitates CTL responses and augments chemotherapy-induced apoptosis. J. Immunol. 2005, 168: 41-46
16. Voorzanger-Rousselot N, Alberti L, Blay JY. CD40L induces multidrug resistance to apoptosis in breast carcinoma and lymphoma cells through caspase independent and dependent pathways. BMC Cancer, 2006, 186: 75.
17. Dangerfield J,Larbik Y,Huang MT,et a1. PECAM-1 (CD31) homophilic interaetion upregulated d 6 B 1 on transmigrated neutrophils in vivo and plays a functional role in d1e ability of 6 integrinsto mediate leukoeyte migration through the perivaseular basementmembrane.J Exp Med, 2002, 196(9): 1201-1211.
18. Sumpio BE,Yun S,Cordova AC,et a1. MAP Kinases(ERK1/2,p38) and AKT can be phosphorylated by shear stress independently of PECAM一1(CD31)in vascular endothelial cells. J Biol Chem, 2005, 280(12): 11185-11191.
19. Weidner N.The relationship of tumor an giogenesis and metastasis with emphasis on invasive breast carcinoma. Advances in pathology and laboratory medicine edited by RS Weinstein. Chicago: Mosby Year Book. 1992:111-121。
20.李家谋,钟延丰,蔡钦林。脊索瘤中增殖细胞核抗原表达与细胞凋亡检测的临床意义.中国脊柱脊髓杂志, 2001,11: 210-212 .
21. Schattner EJ, Mascarenhas J, Bishop J, et al. CD4+ T-cell induction of Fas-mediated apoptosis in Burkitt’s lymphoma B cell. Blood, 1996, 88: 1375-1382.
22. Hill SC, Youde SJ, Man S, et al. Activation of CD40 in cervical carcinoma cells facilitates CTL responses and augments chemotherapy-induced apoptosis. Immunol, 2005, 174(1): 41-50
23.王东,陈俐,高奉浔.骨肉瘤血管内皮生长因子表达与肿瘤血管生成及预后的关系。癌症,1998,17(4): 264-256.
24. Holling HC, Kohn EC, Steinberg SM, et al. Tumor angiogenesis in advanced stage ovarian carcinoma. Am J Pathol, 1995, 147:33.
25. Narita M, Nakao K, Ogino N, et al. Independent prognostic factors in breast cancer patient. Am J Surg, 1998, 177: 73.
1. Korn T, Bettelli E, Oukka M, et al. IL-17 and Th17 cells. Annu Rev Immunol, 2009, 27 (1): 485-517.
2. Afzali B, Lombardi G, Lechler RI, et al. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol, 2007, 148(1):32-46.
3. Dong C. Th17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol, 2008, 8 (5): 337-348.
4. Laan M, Lotvall J, Chung KF, et a1. IL-17-induced cytokine release in human bronchi epithelial cells in vitrn: role of mitogen-activated protein(MAP) kinases. Pharmacol, 2001, 133(1): 200-206.
5. GranB,.Zhang GX, Yu S, et al. IL-12p35-defcient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. Immunol, 2002, 169(12): 7104-7110.
6. Cua DJ, Sherlock J, Chen Y, et al. Interleukin 23 rather than interleukin 12 is the critical cytokine for autoimmune inflammation of the brain. Nature, 2003, 421 (6924): 744-748.
7. Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med, 2005, 201(2): 233-240.
8. Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effect or T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol, 2005, 6(11): 1123-1132.
9. Brentano F, Ospelt C, Stanczyk J, et al. Abundantexpression of the interleukin ( IL) 23 subunit p19, but lowlevels of bioactive IL23 in the rheumatoid synovium: differential expression and Toll like receptor ( TLR ) dependent regulation of the IL23 subunits, p19 and p40, in rheumatoid arthritis. Ann Rheum Dis, 2008, 68 (1): 143-150.
10. Bettelli E, Carrier Y, Gao W, et al. Reciprocal development l pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature, 2006, 441 ( 7091) :
11. Kimura A, Naka T, Kishimoto T. IL-6 dependent and independent pathways in the developmen to finterleukin17-producing T helper cells. Proc Natl Acad Sci USA, 2007, 104 (29): 12099-12104.
12. Chen Z, O’Shea JJ. Regulation of IL-17 production in human lymphocytes. Cytokine, 2008; 41(2): 71-78.
13. Chen Z, Tato CM, Muul L. Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum, 2007; 56(9): 2936-2946.
14. Wilson NJ, Boniface K, Chan JR, et al. Development cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol, 2007; 8(9): 950-957.
15. Yang XO, Panopoulos AD, Nurieva R, et al. STAT3 regulates cytokine mediated generation of inflammato ryhelper T cells. J Biol Chem, 2007, 282 (13): 9358-9363.
16. Napolitani G, Acosta-Rodriguez EV, Lanzavecchia A,et al. Prostaglandin E2 enhances Th17 responses via modulation of IL-17 and IFN-gamma production by memory CD4+ T cells. Eur J Immunol. 2009, 39(5):1301-1312.
17. Stumhofer JS, Laurence A, Wilson EH, et al. Interleukin 27 negatively regulates the development of interleukin 17 producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol, 2006, 7(9): 937-945.
18. Batten M, Li J, Yi S, et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleuk in 17 producing T cells. Nat.Immunol, 2006, 7 (9): 929-936.
19. Moisan J, Grenningloh R, Bettelli E, et al. Ets1 is anegative regulator of Th17 differentiation. J ExpMed, 2007, 204(12): 28256-28235.
20. Bozza S, Zelante T, Moretti S, et al. Lack of Toll IL-1R8 exacerbates Th17 ce ll responses in funga l infection. J Immunol, 2008, 180(6) : 4022-4031.
21. Liang SC, Nickerson-Nutter C, Pittman DD, et al. IL-22 induces an acute-phase response. J Immunol. 2010, 185(9): 5531-5538.
22. Aujla SJ, Chan YR, Zheng M, et al. IL-22 mediatesmucosa l host defense against G ram-negative bacterialpneumonia. NatMed, 2008, 14 ( 3): 275-281.
23. OuyangW, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity, 2008, 28( 4) : 454-467.
24. Wilson N J, Boniface K, Chan JR, et al. Development cytokine profile and function of human interleuk in 17–producing helper T cell[ J]. Nat Immunol, 2007, 8(9): 950-957.
25. Dambacher J, Beigel F, Zitzmann K, et al. The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut, 2008, 15. [ Epub ahead of print] .
26. Miossec P. Interleukin-17 in rheumatoid arthritis: if T cells were to contribute to inflammation and destruction through synergy. Arthritis Rheum, 2003, 48 ( 3) : 594-601.
27. Nistala K, Moncrieffe H, Newtonk R, et al. Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum, 2008, 58(3): 875-887.
28. Bullens DM, Truyen E, Coteur L, et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflamm at ionandgranulocyic influx? Respir Res, 2006, 7 (1): 135-139.
29. Mok MY, Wu HJ, Lo Y, et al. The relation of interleukin 17 (IL-17) and IL-23 to Th1/Th2 cytokines and disease activity in systemic lupus erythematosus. J Rheumatol. 2010, 37(10): 2046-2052.
30. Fransson ME, Liljenfeldt LS, Fagius J, et al. The T-cell pool is anergized in patients with multiple sclerosis in remission. Immunology, 2009, 126(1): 92-101.
31. Hwang SY, Kim HY. Expression of IL-17 homologs and their receptors in the synovial cells of rheumatoid arthritis patients. Mol Cells, 2005, 19(2): 180-184
32. Joosten LA, Abdollahi Roodsaz S, HeuvelmansJacobs M, et al. T cell dependence of chronic destructivemurine arthritis induced by repeated local activation of Toll-like receptor-drivenpathways: crucial role of both interleukin-1beta and interleukin-17. Arthritis Rheum, 2008, 58 ( 1): 98-108.
33. Ohsugi Y. Recent advances in immunopathophysiology of interleukin-6: an innovative therapeutic drug, tocilizumab (recombinant humanized anti-human interleukin-6 receptor antibody), unveils the mysterious etiology of immune-mediated inflammatory diseases. Biol. Pharm. Bull, 2007, 30(11): 2001-2006。
34. Wong CK, Lit LC, Tam LS, et al. Hyperproduction of IL-23 and IL-17 in patients with systemic lupuse rythematosus: implications for Th17-mediated inflammation in autoimmunity. Clin Immunol, 2008, 127( 3): 385-393.
35. Kebir H, Kreymborg K, Ifergan I, et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007, 13(10):1173-1175.
36. Jain R, Tartar DM, Gregg RK, et al. Innocuous IFN gamm a induced by adjuvant free antigen restoresnormoglycemia in NOD mice through inhibition of IL-17 production. J ExpMed, 2008, 205(1): 207-218.
37. Kato T, Furumoto H, Ogura T, et al. Express ion of IL-17 mRNA inovarian cancer. B iochem BiophysRes Commun, 2001, 282( 3) : 735- 738.
38. Kryczek I, Banerjee M, Cheng P, et al. Phenotype, distribution, generation, functional and clinical relevance of Th17 cells in the human tumor environments. Blood, 2009, 114( 6 ) : 1141 - 1149.
39. Miyahara Y, Odunsi K, ChenW, et al. Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer. Proc Nat l Acad Sci USA, 2008, 105 ( 40) : 15505- 15510.
40. Zhang B, Rong G, Wei H, et al. The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun, 2008, 374( 3 ) : 533 - 537.
41. Zhang JP, Yan J, Xu J, et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol, 2009, 50( 5 ): 980-989.
42. Kryczek I, Wei S, Zou L, et al. Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immuno,l 2007, 178 ( 11) : 6730- 6733.
43. Sfanos KS, Bruno TC, Maris CH, et al. Phenotypic analysis of prostate infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res, 2008, 14( 11) : 3254- 3261.
44. Tosolini M, Kirilovsky A, Mlecnik B, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011, 15; 71(4):1263-1271.
45. Le GS, Bastuji-Garin S, Aloulou N, et al. High prevalence of Foxp3 and IL-17 inMMR-proficient colorectal carcinomas. Gut, 2008, 57( 6) : 772- 779.
46. Krycak I, Wei S, Szeliga W, et al. Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood, 2009 [ 2009-04-13 ] . h ttp: / /blood journal hematology library. org/cgi/ content / abstract /blood, 2008, 09, 177360v1.
47. Wrobel T, Mazur G, Jazwiec B, et al. Interleukin-17 in acute myeloid leukemia. Cell Mol Med, 2003, 7(4): 472-474
48. Horlock C, Stott B, Dyson PJ, et al. The effects of trastuzumabon the CD4+ CD25+ FoxP3+ and CD4+ IL17A+ T-cell axis in patients with breast cancer. Br J Cancer, 2009, 100 ( 7 ): 1061-1067.
49. Benchetrit F, Circe A, Vires V, et al. Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood, 2002, 99( 6 ): 2114-2 l21.
50. Muranski P, Boni A, Antony PA, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood, 2008, 112( 2 ) : 362-373.