MMP-9和SOX2在骨巨细胞瘤中的表达及其临床意义
摘要
目的：
骨巨细胞瘤(Giant cell tumor of bone,GCT)是一种常见的原发性骨肿瘤，主要具有局部侵袭性强和复发率高的特点，可发生肺转移。同时还具有对放化疗均不敏感，且放疗后极易癌变的特点。骨巨细胞瘤主要组织学表现为弥漫增生的单核基质细胞内出现大量的多核巨细胞，肿瘤细胞成分及功能比较复杂，其病理学分级和放射学分级往往不能正确反映肿瘤的生物学行为，对于判断肿瘤细胞的侵袭性程度以及指导临床治疗带来一定困难。因此，寻找特异性标记物，对于评价骨巨细胞瘤侵袭性程度以及探讨一种有效控制侵袭性、降低复发率的临床治疗方法有着重要意义。本实验探讨MMP‐9和SOX2在骨巨细胞瘤中发生发展中的作用，并分析骨巨细胞瘤中MMP‐9和SOX2的表达定位以及表达强度与肿瘤侵袭性的相关性，为骨巨细胞瘤的生物学行为和预后判断提供依据。
方法：
回顾分析我院骨科2004年1月‐2010年3月接受外科手术切除的骨巨细胞瘤标本23例，其中复发肿瘤病例11例，非复发病例12例，男9例，女14例，年龄15岁‐71岁(平均年龄35岁)。肿瘤组织用40g／L多聚甲醛固定，石蜡包埋，4um连续切片等操作。通过免疫组化染色方法检测骨巨细胞瘤标本中的MMP‐9、SOX2的表达，观察其在非复发肿瘤组和复发肿瘤组中的变化。
结果：
1、MMP‐9在骨巨细胞瘤中阳性表达率为52.71%，与性别、年龄、发病部位、Jaffe分级不同分组中均无显著差异(P>0.05)，预后组中有显著差异(P<0.05)，表达强度与临床预后呈正相关(r=0.489，P=0.003<0.05)。
2、SOX2在骨巨细胞瘤中阳性表达率为56.52%，与性别、年龄、发病部位、Jaffe分级及预后不同分组中均无显著差异(P>0.05)。
3、MMP‐9、SOX2在骨巨细胞瘤中的表达无明显相关性(P>0.05)。
结论：
MMP‐9和SOX2在骨巨细胞瘤中均有高度表达，其中MMP‐9阳性表达与预后存在明显的正相关。表明MMP‐9可能参与了骨巨细胞瘤的发生发展，它的表达状态可能影响骨巨细胞瘤的恶性程度和预后发展，可作为定性诊断骨巨细胞瘤新的肿瘤标记物。
Objective：
Giant celltumorofbone(GCT)is oneofthe primarybonetumorswhichhave strong invasiveness,poorclinical therapeutic response,sarcomatous change after radiation therapy,high recurrence rate and the tendency of pulmonary metastasis.The chief histology of giant cell tumor ismany well‐distributed multinucleated giant cells which suffusion and hyperplasia can findon the background of stromal cells.Pathologic grading can’tpredictthetumor’s biologic behavior correctly, which bring problems, such as correct diagosis and treatment.So it is importanttoidentifyatumorspceific makerwhich is importantinthedesignofan interventional procedure,guiding for clinical decisions and judging prognosis.Therefore, this experiment to study the roles of MMP‐9and SOX2in developmentand progressionofbonetumors.Tostudytheexpressionlevelsof MMP‐9and SOX2ingiant celltumorofboneanddetcetthe correlationbetweentheir expression levels and the histological grade, recurrence state ofthetumor.Tointendtofind possible prognostic indicationsoftheaggressive behavioroftheunderlying pathology.
Materials andmethods：
23cases of bone giant cell tumor fromJanuary2004to March2010in theOrthopeadieDepartmentofthe First Hospitalof Jilin University are taken for study, among which, there are11cases recurrent tumor,12cases of non‐recurrent, and9male and14female patients aged15years to71years old (average age35years). Thetumor tissues are embedded in paraffin with40g/L paraformaldehyde,buried by paraffin and cut as4um serial sections. The expression of MMP‐9,SOX2in Giant cell tumors of bone and its changes innon‐recurrent tumor group and the recurrent tumor group are observed byimmunohistochemistry.
Results：
1.The positive expression rate of MMP‐9in giant cell tumor of bone was52.71%.Therewerenorelevancebetweenthe expressionof MMP‐9andgender, age, invasiveloeation, Jaffegrade(P>0.05),buttheexpressionof MMP‐9wasrelevantto prognosis(P<0.05).Expressionof MMP‐9wassignificantlyhigheringian cell tumorofbonewithrecurrencethanthatingiant celltumorofbonewithoutrecurrence.
2.Thepositive expression rate of SOX2in giant cell tumor of bone was56.52%.Therewerenorelevancebetweenthe expressionof SOX2andgender, age, invasiveloeation, Jaffegrade and prognosis (P>0.05).
3.Therewas no significant correlationbetweenexpressionof MMP‐9and SOX2(P>0.05).
Conclusions：
MMP‐9and SOX2were both highly expressed in the giant celltumor of bone.Therewassignificant correlation betweenexpressionof MMP‐9and prognosis.Theoccurrencethat expressthatthe MMP‐9may participatesGCTevolve,andaffectsthemalignantdegreeandthe prognosis progressions, which canbeusedasthenewmarkingthingsoftumortodiagnoseGCTqualitatively.
骨巨细胞瘤(Giant cell tumor of bone,GCT)是一种常见的原发性骨肿瘤，主要具有局部侵袭性强和复发率高的特点，可发生肺转移。同时还具有对放化疗均不敏感，且放疗后极易癌变的特点。骨巨细胞瘤主要组织学表现为弥漫增生的单核基质细胞内出现大量的多核巨细胞，肿瘤细胞成分及功能比较复杂，其病理学分级和放射学分级往往不能正确反映肿瘤的生物学行为，对于判断肿瘤细胞的侵袭性程度以及指导临床治疗带来一定困难。因此，寻找特异性标记物，对于评价骨巨细胞瘤侵袭性程度以及探讨一种有效控制侵袭性、降低复发率的临床治疗方法有着重要意义。本实验探讨MMP‐9和SOX2在骨巨细胞瘤中发生发展中的作用，并分析骨巨细胞瘤中MMP‐9和SOX2的表达定位以及表达强度与肿瘤侵袭性的相关性，为骨巨细胞瘤的生物学行为和预后判断提供依据。
方法：
回顾分析我院骨科2004年1月‐2010年3月接受外科手术切除的骨巨细胞瘤标本23例，其中复发肿瘤病例11例，非复发病例12例，男9例，女14例，年龄15岁‐71岁(平均年龄35岁)。肿瘤组织用40g／L多聚甲醛固定，石蜡包埋，4um连续切片等操作。通过免疫组化染色方法检测骨巨细胞瘤标本中的MMP‐9、SOX2的表达，观察其在非复发肿瘤组和复发肿瘤组中的变化。
结果：
1、MMP‐9在骨巨细胞瘤中阳性表达率为52.71%，与性别、年龄、发病部位、Jaffe分级不同分组中均无显著差异(P>0.05)，预后组中有显著差异(P<0.05)，表达强度与临床预后呈正相关(r=0.489，P=0.003<0.05)。
2、SOX2在骨巨细胞瘤中阳性表达率为56.52%，与性别、年龄、发病部位、Jaffe分级及预后不同分组中均无显著差异(P>0.05)。
3、MMP‐9、SOX2在骨巨细胞瘤中的表达无明显相关性(P>0.05)。
结论：
MMP‐9和SOX2在骨巨细胞瘤中均有高度表达，其中MMP‐9阳性表达与预后存在明显的正相关。表明MMP‐9可能参与了骨巨细胞瘤的发生发展，它的表达状态可能影响骨巨细胞瘤的恶性程度和预后发展，可作为定性诊断骨巨细胞瘤新的肿瘤标记物。
Objective：
Giant celltumorofbone(GCT)is oneofthe primarybonetumorswhichhave strong invasiveness,poorclinical therapeutic response,sarcomatous change after radiation therapy,high recurrence rate and the tendency of pulmonary metastasis.The chief histology of giant cell tumor ismany well‐distributed multinucleated giant cells which suffusion and hyperplasia can findon the background of stromal cells.Pathologic grading can’tpredictthetumor’s biologic behavior correctly, which bring problems, such as correct diagosis and treatment.So it is importanttoidentifyatumorspceific makerwhich is importantinthedesignofan interventional procedure,guiding for clinical decisions and judging prognosis.Therefore, this experiment to study the roles of MMP‐9and SOX2in developmentand progressionofbonetumors.Tostudytheexpressionlevelsof MMP‐9and SOX2ingiant celltumorofboneanddetcetthe correlationbetweentheir expression levels and the histological grade, recurrence state ofthetumor.Tointendtofind possible prognostic indicationsoftheaggressive behavioroftheunderlying pathology.
Materials andmethods：
23cases of bone giant cell tumor fromJanuary2004to March2010in theOrthopeadieDepartmentofthe First Hospitalof Jilin University are taken for study, among which, there are11cases recurrent tumor,12cases of non‐recurrent, and9male and14female patients aged15years to71years old (average age35years). Thetumor tissues are embedded in paraffin with40g/L paraformaldehyde,buried by paraffin and cut as4um serial sections. The expression of MMP‐9,SOX2in Giant cell tumors of bone and its changes innon‐recurrent tumor group and the recurrent tumor group are observed byimmunohistochemistry.
Results：
1.The positive expression rate of MMP‐9in giant cell tumor of bone was52.71%.Therewerenorelevancebetweenthe expressionof MMP‐9andgender, age, invasiveloeation, Jaffegrade(P>0.05),buttheexpressionof MMP‐9wasrelevantto prognosis(P<0.05).Expressionof MMP‐9wassignificantlyhigheringian cell tumorofbonewithrecurrencethanthatingiant celltumorofbonewithoutrecurrence.
2.Thepositive expression rate of SOX2in giant cell tumor of bone was56.52%.Therewerenorelevancebetweenthe expressionof SOX2andgender, age, invasiveloeation, Jaffegrade and prognosis (P>0.05).
3.Therewas no significant correlationbetweenexpressionof MMP‐9and SOX2(P>0.05).
Conclusions：
MMP‐9and SOX2were both highly expressed in the giant celltumor of bone.Therewassignificant correlation betweenexpressionof MMP‐9and prognosis.Theoccurrencethat expressthatthe MMP‐9may participatesGCTevolve,andaffectsthemalignantdegreeandthe prognosis progressions, which canbeusedasthenewmarkingthingsoftumortodiagnoseGCTqualitatively.
引文
[1] Ghert MA, Rizzo M, Harrelson JM,Scully SP. Giant‐cell tumor of theappendicular skeleton[J]. Clin Orthop Relat Res.2002;(400):201‐10.
[2] Szendroi M. Giant‐cell tumour of bone[J]. J Bone Joint Surg Br.2004;86(1):5‐12.
[3] Szendroi M, Kiss J,Antal I. Surgical treatment and prognostic factors ingiant‐cell tumor of bone[J]. Acta Chir Orthop Traumatol Cech.2003;70(3):142‐50.
[4] Wulling M, Delling G,Kaiser E. The origin of the neoplastic stromal cellin giant cell tumor of bone[J]. Hum Pathol.2003;34(10):983‐93.
[5] Randall RL. Giant cell tumor of the sacrum[J]. Neurosurg Focus.2003;15(2): E13.
[6] Turcotte RE. Giant cell tumor of bone[J].(0030‐5898(Print)).
[7]Birkedal‐HansenH, Moore WG, Bodden MK, Windsor LJ,BirkedalHansen B, DeCarlo A, et al. Matrix metalloproteinases: areview[J]. Crit Rev Oral Biol Med.1993;4(2):197‐250.
[8] Deryugina EI. Matrix metalloproteinases and tumormetastasis[J].Cancer Metastasis Rev.2006;25(1):9‐34.
[9] Gokaslan ZL, Chintala SK, York JE, Boyapati V, Jasti S, Sawaya R, et al.Expression and role of matrix metalloproteinases MMP‐2and MMP‐9in human spinal column tumors[J]. Clin Exp Metastasis.1998;16(8):721‐8.
[10] Kumta SM, Huang L, Cheng YY, Chow LT, Lee KM,Zheng MH.Expression of VEGF and MMP‐9in giant cell tumor of bone andother osteolytic lesions[J]. Life Sci.2003;73(11):1427‐36.
[11] Lee SK,Lorenzo J. Cytokines regulating osteoclast formation andfunction[J]. Curr Opin Rheumatol.2006;18(4):411‐8.
[12] Viguet‐Carrin S, Garnero P,Delmas PD. The role of collagen in bonestrength[J]. Osteoporos Int.2006;17(3):319‐36.
[13] Uchida M, Shima M, Shimoaka T, Fujieda A, Obara K, Suzuki H, et al.Regulation of matrix metalloproteinases (MMPs) and tissueinhibitors of metalloproteinases (TIMPs) by bone resorptive factorsin osteoblastic cells[J]. J Cell Physiol.2000;185(2):207‐14.
[14] Teti A, Farina AR, Villanova I, Tiberio A, Tacconelli A, Sciortino G, et al.Activation of MMP‐2by human GCT23giant cell tumour cellsinduced by osteopontin, bone sialoprotein and GRGDSP peptides isRGD and cell shape change dependent[J]. Int J Cancer.1998;77(1):82‐93.
[15] Rao VH, Singh RK, Bridge JA, Neff JR, Schaefer GB, Delimont DC, et al.Regulation of MMP‐9(92kDa type IV collagenase/gelatinase B)expression in stromal cells of human giant cell tumor of bone[J].Clin Exp Metastasis.1997;15(4):400‐9.
[16] Ueda Y, Imai K, Tsuchiya H, Fujimoto N, Nakanishi I, Katsuda S, et al.Matrix metalloproteinase9(gelatinase B) is expressed inmultinucleated giant cells of human giant cell tumor of bone and isassociated with vascular invasion[J]. Am J Pathol.1996;148(2):611‐22.
[17] Shingleton WD, Hodges DJ, Brick P,Cawston TE. Collagenase: a keyenzyme in collagen turnover[J]. Biochem Cell Biol.1996;74(6):759‐75.
[18] Chen Y, Shi L, Zhang L, Li R, Liang J, Yu W, et al. The molecularmechanism governing the oncogenic potential of SOX2in breastcancer[J]. J Biol Chem.2008;283(26):17969‐78.
[19] Li XL, Eishi Y, Bai YQ, Sakai H, Akiyama Y, Tani M, et al. Expression ofthe SRY‐related HMG box protein SOX2in human gastriccarcinoma[J]. Int J Oncol.2004;24(2):257‐63.
[20] Gupta R, Seethalakshmi V, Jambhekar NA, Prabhudesai S, MerchantN, Puri A, et al. Clinicopathologic profile of470giant cell tumors ofbone from a cancer hospital in western India[J]. Ann Diagn Pathol.2008;12(4):239‐48.
[21] Haque AU,Moatasim A. Giant cell tumor of bone: a neoplasm or areactive condition?[J]. Int J Clin Exp Pathol.2008;1(6):489‐501.
[22] Gandhe A, Sankhe A, Aeron G,Joshi A. Epiphyseal giant cell tumourin an immature skeleton[J]. Br J Radiol.2008;81(963): e75‐8.
[23] Breitenseher M, Dominkus M, Scharitzer M, Lechner M, Trieb K,Imhof H, et al.[Diagnostic imaging of giant cell tumors][J].Radiologe.2001;41(7):568‐76.
[24] Murphey MD NG, Flemming DJ,et al. From the archives of AFIP.Imaging of giant cell tumor and giant cell reparative granuloma ofbone: radiologic‐pathologic correlation[J]. Radiographics.2001;21(5):1283‐1309.
[25] Olivera P PE, Ortega A. Estrogen receptor expression in giant celltumors of the bone[J]. Hum Pathol.2002;33:165.
[26] Campanacci M. Giant‐cell tumor and chondrosarcomas: grading,treatment and results[J]. Recent Results Cancer Res.1994;999(54):257‐261.
[27] Tubbs WS, Brown LR, Beabout JW, Rock MG,Unni KK. Benigngiant‐cell tumor of bone with pulmonary metastases: clinicalfindings and radiologic appearance of metastases in13cases[J]. AJRAm J Roentgenol.1992;158(2):331‐4.
[28] Cheng JC,Johnston JO. Giant cell tumor of bone. Prognosis andtreatment of pulmonary metastases[J]. Clin Orthop Relat Res.1997;(338):205‐14.
[29] Bertoni F, Present D, Sudanese A, Baldini N, Bacchini P,CampanacciM. Giant‐cell tumor of bone with pulmonary metastases. Six casereports and a review of the literature[J]. Clin Orthop Relat Res.1988;(237):275‐85.
[30] Rock MG, Sim FH, Unni KK, Witrak GA, Frassica FJ, Schray MF, et al.Secondary malignant giant‐cell tumor of bone. Clinicopathologicalassessment of nineteen patients[J]. J Bone Joint Surg Am.1986;68(7):1073‐9.
[31] Nascimento AG, Huvos AG,Marcove RC. Primary malignant giant celltumor of bone: a study of eight cases and review of the literature[J].Cancer.1979;44(4):1393‐402.
[32] Marui T, Yamamoto T, Yoshihara H, Kurosaka M, Mizuno K,AkamatsuT. De novo malignant transformation of giant cell tumor of bone[J].Skeletal Radiol.2001;30(2):104‐8.
[33] Brien EW, Mirra JM, Kessler S, Suen M, Ho JK,Yang WT. Benign giantcell tumor of bone with osteosarcomatous transformation("dedifferentiated" primary malignant GCT): report of two cases[J].Skeletal Radiol.1997;26(4):246‐55.
[34] Schwartz HS, Juliao SF, Sciadini MF, Miller LK,Butler MG. Telomeraseactivity and oncogenesis in giant cell tumor of bone[J]. Cancer.1995;75(5):1094‐9.
[35] Schwartz HS, Jenkins RB, Dahl RJ,Dewald GW. Cytogenetic analyseson giant‐cell tumors of bone[J]. Clin Orthop Relat Res.1989;(240):250‐60.
[36] Schwartz HS, Dahir GA,Butler MG. Telomere reduction in giant celltumor of bone and with aging[J]. Cancer Genet Cytogenet.1993;71(2):132‐8.
[37] Schwartz HS, Butler MG, Jenkins RB, Miller DA,Moses HL. Telomericassociations and consistent growth factor overexpression detectedin giant cell tumor of bone[J]. Cancer Genet Cytogenet.1991;56(2):263‐76.
[38] Bardi G, Pandis N, Mandahl N, Heim S, Sfikas K, Willen H, et al.Chromosomal abnormalities in giant cell tumors of bone[J]. CancerGenet Cytogenet.1991;57(2):161‐7.
[39] Bridge JA, Neff JR,Mouron BJ. Giant cell tumor of bone.Chromosomal analysis of48specimens and review of theliterature[J]. Cancer Genet Cytogenet.1992;58(1):2‐13.
[40] Montero O, Salle MT, Guevara R, Olivera P, MaldonadoV,Melendez‐Zajgla J. Cytogenetic analysis of the mononuclear cellcomponent of giant cell tumors of bone[J]. Cancer Genet Cytogenet.2003;146(2):170‐2.
[41] Sawyer JR, Goosen LS, Binz RL, Swanson CM,Nicholas RW. Evidencefor telomeric fusions as a mechanism for recurring structuralaberrations of chromosome11in giant cell tumor of bone[J].Cancer Genet Cytogenet.2005;159(1):32‐6.
[42] Bridge JA, Neff JR, Bhatia PS, Sanger WG,Murphey MD. Cytogeneticfindings and biologic behavior of giant cell tumors of bone[J].Cancer.1990;65(12):2697‐703.
[43] McComb EN, Johansson SL, Neff JR, Nelson M,Bridge JA.Chromosomal anomalies exclusive of telomeric associations in giantcell tumor of bone[J]. Cancer Genet Cytogenet.1996;88(2):163‐6.
[44] Atkins GJ, Bouralexis S, Haynes DR, Graves SE, Geary SM, Evdokiou A,et al. Osteoprotegerin inhibits osteoclast formation and boneresorbing activity in giant cell tumors of bone[J]. Bone.2001;28(4):370‐7.
[45] Atkins GJ, Haynes DR, Graves SE, Evdokiou A, Hay S, Bouralexis S, etal. Expression of osteoclast differentiation signals by stromalelements of giant cell tumors[J]. J Bone Miner Res.2000;15(4):640‐9.
[46] Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, etal. Osteoprotegerin: a novel secreted protein involved in theregulation of bone density[J]. Cell.1997;89(2):309‐19.
[47] Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M,Mochizuki S, et al. Osteoclast differentiation factor is a ligand forosteoprotegerin/osteoclastogenesis‐inhibitory factor and is identicalto TRANCE/RANKL[J]. Proc Natl Acad Sci U S A.1998;95(7):3597‐602.
[48] Huang L, Xu J, Wood DJ,Zheng MH. Gene expression ofosteoprotegerin ligand, osteoprotegerin, and receptor activator ofNF‐kappaB in giant cell tumor of bone: possible involvement intumor cell‐induced osteoclast‐like cell formation[J]. Am J Pathol.2000;156(3):761‐7.
[49] Nishimura M, Yuasa K, Mori K, Miyamoto N, Ito M, Tsurudome M, etal. Cytological properties of stromal cells derived from giant celltumor of bone (GCTSC) which can induce osteoclast formation ofhuman blood monocytes without cell to cell contact[J]. J Orthop Res.2005;23(5):979‐87.
[50] Lau YS, Sabokbar A, Gibbons CL, Giele H,Athanasou N. Phenotypicand molecular studies of giant‐cell tumors of bone and soft tissue[J].Hum Pathol.2005;36(9):945‐54.
[51] Kawaguchi K, Oda Y, Saito T, Yamamoto H, Takahira T, Tamiya S, et al.Decreased expression of transforming growth factor‐beta II receptoris associated with that of p27KIP1in giant cell tumor of bone: apossible link between transforming growth factor‐beta and cellcycle‐related protein[J]. Hum Pathol.2004;35(1):61‐8.
[52] Teot LA, O'Keefe RJ, Rosier RN, O'Connell JX, Fox EJ,Hicks DG.Extraosseous primary and recurrent giant cell tumors: transforminggrowth factor‐beta1and‐beta2expression may explain metaplasticbone formation[J]. Hum Pathol.1996;27(7):625‐32.
[53] Kartsogiannis V, Zhou H, Horwood NJ, Thomas RJ, Hards DK, QuinnJM, et al. Localization of RANKL (receptor activator of NF kappa Bligand) mRNA and protein in skeletal and extraskeletal tissues[J].Bone.1999;25(5):525‐34.
[54] Roux S, Amazit L, Meduri G, Guiochon‐Mantel A, Milgrom E,MarietteX. RANK (receptor activator of nuclear factor kappa B) and RANKligand are expressed in giant cell tumors of bone[J]. Am J Clin Pathol.2002;117(2):210‐6.
[55] James IE, Dodds RA, Olivera DL, Nuttall ME,Gowen M. Humanosteoclastoma‐derived stromal cells: correlation of the ability toform mineralized nodules in vitro with formation of bone in vivo[J].J Bone Miner Res.1996;11(10):1453‐60.
[56] Huang L, Teng XY, Cheng YY, Lee KM,Kumta SM. Expression ofpreosteoblast markers and Cbfa‐1and Osterix gene transcripts instromal tumour cells of giant cell tumour of bone[J]. Bone.2004;34(3):393‐401.
[57] Murata A, Fujita T, Kawahara N, Tsuchiya H,Tomita K. Osteoblastlineage properties in giant cell tumors of bone[J]. J Orthop Sci.2005;10(6):581‐8.
[58] Robinson D, Segal M,Nevo Z. Giant cell tumor of bone. The role offibroblast growth factor3positive mesenchymal stem cells in itspathogenesis[J]. Pathobiology.2002;70(6):333‐42.
[59] Gamberi G, Benassi MS, Ragazzini P, Pazzaglia L, Ponticelli F, Ferrari C,et al. Proteases and interleukin‐6gene analysis in92giant celltumors of bone[J]. Ann Oncol.2004;15(3):498‐503.
[60] Ohsaki Y, Takahashi S, Scarcez T, Demulder A, Nishihara T, Williams R,et al. Evidence for an autocrine/paracrine role for interleukin‐6inbone resorption by giant cells from giant cell tumors of bone[J].Endocrinology.1992;131(5):2229‐34.
[61] Wuelling M, Delling G,Kaiser E. Differential gene expression instromal cells of human giant cell tumor of bone[J]. Virchows Arch.2004;445(6):621‐30.
[62] Guenther R, Krenn V, Morawietz L, Dankof A, Melcher I, Schaser KD,et al. Giant cell tumors of the bone: molecular profiling andexpression analysis of Ephrin A1receptor, Claudin7, CD52, FGFR3and AMFR[J]. Pathol Res Pract.2005;201(10):649‐63.
[63] Oda Y, Walter H, Radig K, Rose I, Neumann W,Roessner A.Immunohistochemical analysis of nm23protein expression inmalignant bone tumors[J]. J Cancer Res Clin Oncol.1995;121(11):667‐73.
[64] Riminucci M, Kuznetsov SA, Cherman N, Corsi A, Bianco P,GehronRobey P. Osteoclastogenesis in fibrous dysplasia of bone: in situ andin vitro analysis of IL‐6expression[J]. Bone.2003;33(3):434‐42.
[65] Zhu XL, Hartwick W, Rohan T,Kandel R. Cyclin D1gene amplificationand protein expression in benign breast disease and breastcarcinoma[J]. Mod Pathol.1998;11(11):1082‐8.
[66] Sunters A, McCluskey J,Grigoriadis AE. Control of cell cycle geneexpression in bone development and during c‐Fos‐inducedosteosarcoma formation[J]. Dev Genet.1998;22(4):386‐97.
[67] Kauzman A, Li SQ, Bradley G, Bell RS, Wunder JS,Kandel R. Centralgiant cell granuloma of the jaws: assessment of cell cycle proteins[J].J Oral Pathol Med.2004;33(3):170‐6.
[68] Kandel R, Li SQ, Bell R, Wunder J, Ferguson P, Kauzman A, et al.Cyclin D1and p21is elevated in the giant cells of giant cell tumors[J].J Orthop Res.2006;24(3):428‐37.
[69] Zheng MH, Fan Y, Panicker A, Smith A, Robertson T, Wysocki S, et al.Detection of mRNAs for urokinase‐type plasminogen activator, itsreceptor, and type1inhibitor in giant cell tumors of bone with insitu hybridization[J]. Am J Pathol.1995;147(6):1559‐66.
[70] Cheng YY, Huang L, Lee KM, Xu JK, Zheng MH,Kumta SM.Bisphosphonates induce apoptosis of stromal tumor cells in giantcell tumor of bone[J]. Calcif Tissue Int.2004;75(1):71‐7.
[71] Cheng YY, Huang L, Kumta SM, Lee KM, Lai FM,Tam JS. Cytochemicaland ultrastructural changes in the osteoclast‐like giant cells of giantcell tumor of bone following bisphosphonate administration[J].Ultrastruct Pathol.2003;27(6):385‐91.
[72] Chang SS, Suratwala SJ, Jung KM, Doppelt JD, Zhang HZ, Blaine TA, etal. Bisphosphonates may reduce recurrence in giant cell tumor byinducing apoptosis[J]. Clin Orthop Relat Res.2004;(426):103‐9.
[73] Skubitz KM, Cheng EY, Clohisy DR, Thompson RC,Skubitz AP. Geneexpression in giant‐cell tumors[J]. J Lab Clin Med.2004;144(4):193‐200.
[74] Westerlund A, Hujanen E, Puistola U,Turpeenniemi‐Hujanen T.Fibroblasts stimulate human ovarian cancer cell invasion andexpression of72‐kDa gelatinase A (MMP‐2)[J]. Gynecol Oncol.1997;67(1):76‐82.
[75] Werner JA, Rathcke IO,Mandic R. The role of matrixmetalloproteinases in squamous cell carcinomas of the head andneck[J]. Clin Exp Metastasis.2002;19(4):275‐82.
[76] Takahashi M, Oka N, Naroda T, Nishitani MA, Kanda K, Kanayama HO,et al. Prognostic significance of matrix metalloproteinases‐2activation ratio in renal cell carcinoma[J]. Int J Urol.2002;9(10):531‐8.
[77] Oda Y, Sakamoto A, Saito T, Matsuda S, Tanaka K, Iwamoto Y, et al.Secondary malignant giant‐cell tumour of bone: molecularabnormalities of p53and H‐ras gene correlated with malignanttransformation[J]. Histopathology.2001;39(6):629‐37.
[78]王民,毕乃贵,赵光辉,王莹,杨益民. MMP‐9在骨巨细胞瘤中的表达及其临床意义[J].现代肿瘤医学.2007;(11):1662‐1664.
[79] Park ET, Gum JR, Kakar S, Kwon SW, Deng G,Kim YS. Aberrantexpression of SOX2upregulates MUC5AC gastric foveolar mucin inmucinous cancers of the colorectum and related lesions[J]. Int JCancer.2008;122(6):1253‐60.
[80] Schmitz M, Temme A, Senner V, Ebner R, Schwind S, Stevanovic S, etal. Identification of SOX2as a novel glioma‐associated antigen andpotential target for T cell‐based immunotherapy[J]. Br J Cancer.2007;96(8):1293‐301.
[81] Phi JH, Park SH, Kim SK, Paek SH, Kim JH, Lee YJ, et al. Sox2expression in brain tumors: a reflection of the neuroglialdifferentiation pathway[J]. Am J Surg Pathol.2008;32(1):103‐12.
[2] Szendroi M. Giant‐cell tumour of bone[J]. J Bone Joint Surg Br.2004;86(1):5‐12.
[3] Szendroi M, Kiss J,Antal I. Surgical treatment and prognostic factors ingiant‐cell tumor of bone[J]. Acta Chir Orthop Traumatol Cech.2003;70(3):142‐50.
[4] Wulling M, Delling G,Kaiser E. The origin of the neoplastic stromal cellin giant cell tumor of bone[J]. Hum Pathol.2003;34(10):983‐93.
[5] Randall RL. Giant cell tumor of the sacrum[J]. Neurosurg Focus.2003;15(2): E13.
[6] Turcotte RE. Giant cell tumor of bone[J].(0030‐5898(Print)).
[7]Birkedal‐HansenH, Moore WG, Bodden MK, Windsor LJ,BirkedalHansen B, DeCarlo A, et al. Matrix metalloproteinases: areview[J]. Crit Rev Oral Biol Med.1993;4(2):197‐250.
[8] Deryugina EI. Matrix metalloproteinases and tumormetastasis[J].Cancer Metastasis Rev.2006;25(1):9‐34.
[9] Gokaslan ZL, Chintala SK, York JE, Boyapati V, Jasti S, Sawaya R, et al.Expression and role of matrix metalloproteinases MMP‐2and MMP‐9in human spinal column tumors[J]. Clin Exp Metastasis.1998;16(8):721‐8.
[10] Kumta SM, Huang L, Cheng YY, Chow LT, Lee KM,Zheng MH.Expression of VEGF and MMP‐9in giant cell tumor of bone andother osteolytic lesions[J]. Life Sci.2003;73(11):1427‐36.
[11] Lee SK,Lorenzo J. Cytokines regulating osteoclast formation andfunction[J]. Curr Opin Rheumatol.2006;18(4):411‐8.
[12] Viguet‐Carrin S, Garnero P,Delmas PD. The role of collagen in bonestrength[J]. Osteoporos Int.2006;17(3):319‐36.
[13] Uchida M, Shima M, Shimoaka T, Fujieda A, Obara K, Suzuki H, et al.Regulation of matrix metalloproteinases (MMPs) and tissueinhibitors of metalloproteinases (TIMPs) by bone resorptive factorsin osteoblastic cells[J]. J Cell Physiol.2000;185(2):207‐14.
[14] Teti A, Farina AR, Villanova I, Tiberio A, Tacconelli A, Sciortino G, et al.Activation of MMP‐2by human GCT23giant cell tumour cellsinduced by osteopontin, bone sialoprotein and GRGDSP peptides isRGD and cell shape change dependent[J]. Int J Cancer.1998;77(1):82‐93.
[15] Rao VH, Singh RK, Bridge JA, Neff JR, Schaefer GB, Delimont DC, et al.Regulation of MMP‐9(92kDa type IV collagenase/gelatinase B)expression in stromal cells of human giant cell tumor of bone[J].Clin Exp Metastasis.1997;15(4):400‐9.
[16] Ueda Y, Imai K, Tsuchiya H, Fujimoto N, Nakanishi I, Katsuda S, et al.Matrix metalloproteinase9(gelatinase B) is expressed inmultinucleated giant cells of human giant cell tumor of bone and isassociated with vascular invasion[J]. Am J Pathol.1996;148(2):611‐22.
[17] Shingleton WD, Hodges DJ, Brick P,Cawston TE. Collagenase: a keyenzyme in collagen turnover[J]. Biochem Cell Biol.1996;74(6):759‐75.
[18] Chen Y, Shi L, Zhang L, Li R, Liang J, Yu W, et al. The molecularmechanism governing the oncogenic potential of SOX2in breastcancer[J]. J Biol Chem.2008;283(26):17969‐78.
[19] Li XL, Eishi Y, Bai YQ, Sakai H, Akiyama Y, Tani M, et al. Expression ofthe SRY‐related HMG box protein SOX2in human gastriccarcinoma[J]. Int J Oncol.2004;24(2):257‐63.
[20] Gupta R, Seethalakshmi V, Jambhekar NA, Prabhudesai S, MerchantN, Puri A, et al. Clinicopathologic profile of470giant cell tumors ofbone from a cancer hospital in western India[J]. Ann Diagn Pathol.2008;12(4):239‐48.
[21] Haque AU,Moatasim A. Giant cell tumor of bone: a neoplasm or areactive condition?[J]. Int J Clin Exp Pathol.2008;1(6):489‐501.
[22] Gandhe A, Sankhe A, Aeron G,Joshi A. Epiphyseal giant cell tumourin an immature skeleton[J]. Br J Radiol.2008;81(963): e75‐8.
[23] Breitenseher M, Dominkus M, Scharitzer M, Lechner M, Trieb K,Imhof H, et al.[Diagnostic imaging of giant cell tumors][J].Radiologe.2001;41(7):568‐76.
[24] Murphey MD NG, Flemming DJ,et al. From the archives of AFIP.Imaging of giant cell tumor and giant cell reparative granuloma ofbone: radiologic‐pathologic correlation[J]. Radiographics.2001;21(5):1283‐1309.
[25] Olivera P PE, Ortega A. Estrogen receptor expression in giant celltumors of the bone[J]. Hum Pathol.2002;33:165.
[26] Campanacci M. Giant‐cell tumor and chondrosarcomas: grading,treatment and results[J]. Recent Results Cancer Res.1994;999(54):257‐261.
[27] Tubbs WS, Brown LR, Beabout JW, Rock MG,Unni KK. Benigngiant‐cell tumor of bone with pulmonary metastases: clinicalfindings and radiologic appearance of metastases in13cases[J]. AJRAm J Roentgenol.1992;158(2):331‐4.
[28] Cheng JC,Johnston JO. Giant cell tumor of bone. Prognosis andtreatment of pulmonary metastases[J]. Clin Orthop Relat Res.1997;(338):205‐14.
[29] Bertoni F, Present D, Sudanese A, Baldini N, Bacchini P,CampanacciM. Giant‐cell tumor of bone with pulmonary metastases. Six casereports and a review of the literature[J]. Clin Orthop Relat Res.1988;(237):275‐85.
[30] Rock MG, Sim FH, Unni KK, Witrak GA, Frassica FJ, Schray MF, et al.Secondary malignant giant‐cell tumor of bone. Clinicopathologicalassessment of nineteen patients[J]. J Bone Joint Surg Am.1986;68(7):1073‐9.
[31] Nascimento AG, Huvos AG,Marcove RC. Primary malignant giant celltumor of bone: a study of eight cases and review of the literature[J].Cancer.1979;44(4):1393‐402.
[32] Marui T, Yamamoto T, Yoshihara H, Kurosaka M, Mizuno K,AkamatsuT. De novo malignant transformation of giant cell tumor of bone[J].Skeletal Radiol.2001;30(2):104‐8.
[33] Brien EW, Mirra JM, Kessler S, Suen M, Ho JK,Yang WT. Benign giantcell tumor of bone with osteosarcomatous transformation("dedifferentiated" primary malignant GCT): report of two cases[J].Skeletal Radiol.1997;26(4):246‐55.
[34] Schwartz HS, Juliao SF, Sciadini MF, Miller LK,Butler MG. Telomeraseactivity and oncogenesis in giant cell tumor of bone[J]. Cancer.1995;75(5):1094‐9.
[35] Schwartz HS, Jenkins RB, Dahl RJ,Dewald GW. Cytogenetic analyseson giant‐cell tumors of bone[J]. Clin Orthop Relat Res.1989;(240):250‐60.
[36] Schwartz HS, Dahir GA,Butler MG. Telomere reduction in giant celltumor of bone and with aging[J]. Cancer Genet Cytogenet.1993;71(2):132‐8.
[37] Schwartz HS, Butler MG, Jenkins RB, Miller DA,Moses HL. Telomericassociations and consistent growth factor overexpression detectedin giant cell tumor of bone[J]. Cancer Genet Cytogenet.1991;56(2):263‐76.
[38] Bardi G, Pandis N, Mandahl N, Heim S, Sfikas K, Willen H, et al.Chromosomal abnormalities in giant cell tumors of bone[J]. CancerGenet Cytogenet.1991;57(2):161‐7.
[39] Bridge JA, Neff JR,Mouron BJ. Giant cell tumor of bone.Chromosomal analysis of48specimens and review of theliterature[J]. Cancer Genet Cytogenet.1992;58(1):2‐13.
[40] Montero O, Salle MT, Guevara R, Olivera P, MaldonadoV,Melendez‐Zajgla J. Cytogenetic analysis of the mononuclear cellcomponent of giant cell tumors of bone[J]. Cancer Genet Cytogenet.2003;146(2):170‐2.
[41] Sawyer JR, Goosen LS, Binz RL, Swanson CM,Nicholas RW. Evidencefor telomeric fusions as a mechanism for recurring structuralaberrations of chromosome11in giant cell tumor of bone[J].Cancer Genet Cytogenet.2005;159(1):32‐6.
[42] Bridge JA, Neff JR, Bhatia PS, Sanger WG,Murphey MD. Cytogeneticfindings and biologic behavior of giant cell tumors of bone[J].Cancer.1990;65(12):2697‐703.
[43] McComb EN, Johansson SL, Neff JR, Nelson M,Bridge JA.Chromosomal anomalies exclusive of telomeric associations in giantcell tumor of bone[J]. Cancer Genet Cytogenet.1996;88(2):163‐6.
[44] Atkins GJ, Bouralexis S, Haynes DR, Graves SE, Geary SM, Evdokiou A,et al. Osteoprotegerin inhibits osteoclast formation and boneresorbing activity in giant cell tumors of bone[J]. Bone.2001;28(4):370‐7.
[45] Atkins GJ, Haynes DR, Graves SE, Evdokiou A, Hay S, Bouralexis S, etal. Expression of osteoclast differentiation signals by stromalelements of giant cell tumors[J]. J Bone Miner Res.2000;15(4):640‐9.
[46] Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, etal. Osteoprotegerin: a novel secreted protein involved in theregulation of bone density[J]. Cell.1997;89(2):309‐19.
[47] Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M,Mochizuki S, et al. Osteoclast differentiation factor is a ligand forosteoprotegerin/osteoclastogenesis‐inhibitory factor and is identicalto TRANCE/RANKL[J]. Proc Natl Acad Sci U S A.1998;95(7):3597‐602.
[48] Huang L, Xu J, Wood DJ,Zheng MH. Gene expression ofosteoprotegerin ligand, osteoprotegerin, and receptor activator ofNF‐kappaB in giant cell tumor of bone: possible involvement intumor cell‐induced osteoclast‐like cell formation[J]. Am J Pathol.2000;156(3):761‐7.
[49] Nishimura M, Yuasa K, Mori K, Miyamoto N, Ito M, Tsurudome M, etal. Cytological properties of stromal cells derived from giant celltumor of bone (GCTSC) which can induce osteoclast formation ofhuman blood monocytes without cell to cell contact[J]. J Orthop Res.2005;23(5):979‐87.
[50] Lau YS, Sabokbar A, Gibbons CL, Giele H,Athanasou N. Phenotypicand molecular studies of giant‐cell tumors of bone and soft tissue[J].Hum Pathol.2005;36(9):945‐54.
[51] Kawaguchi K, Oda Y, Saito T, Yamamoto H, Takahira T, Tamiya S, et al.Decreased expression of transforming growth factor‐beta II receptoris associated with that of p27KIP1in giant cell tumor of bone: apossible link between transforming growth factor‐beta and cellcycle‐related protein[J]. Hum Pathol.2004;35(1):61‐8.
[52] Teot LA, O'Keefe RJ, Rosier RN, O'Connell JX, Fox EJ,Hicks DG.Extraosseous primary and recurrent giant cell tumors: transforminggrowth factor‐beta1and‐beta2expression may explain metaplasticbone formation[J]. Hum Pathol.1996;27(7):625‐32.
[53] Kartsogiannis V, Zhou H, Horwood NJ, Thomas RJ, Hards DK, QuinnJM, et al. Localization of RANKL (receptor activator of NF kappa Bligand) mRNA and protein in skeletal and extraskeletal tissues[J].Bone.1999;25(5):525‐34.
[54] Roux S, Amazit L, Meduri G, Guiochon‐Mantel A, Milgrom E,MarietteX. RANK (receptor activator of nuclear factor kappa B) and RANKligand are expressed in giant cell tumors of bone[J]. Am J Clin Pathol.2002;117(2):210‐6.
[55] James IE, Dodds RA, Olivera DL, Nuttall ME,Gowen M. Humanosteoclastoma‐derived stromal cells: correlation of the ability toform mineralized nodules in vitro with formation of bone in vivo[J].J Bone Miner Res.1996;11(10):1453‐60.
[56] Huang L, Teng XY, Cheng YY, Lee KM,Kumta SM. Expression ofpreosteoblast markers and Cbfa‐1and Osterix gene transcripts instromal tumour cells of giant cell tumour of bone[J]. Bone.2004;34(3):393‐401.
[57] Murata A, Fujita T, Kawahara N, Tsuchiya H,Tomita K. Osteoblastlineage properties in giant cell tumors of bone[J]. J Orthop Sci.2005;10(6):581‐8.
[58] Robinson D, Segal M,Nevo Z. Giant cell tumor of bone. The role offibroblast growth factor3positive mesenchymal stem cells in itspathogenesis[J]. Pathobiology.2002;70(6):333‐42.
[59] Gamberi G, Benassi MS, Ragazzini P, Pazzaglia L, Ponticelli F, Ferrari C,et al. Proteases and interleukin‐6gene analysis in92giant celltumors of bone[J]. Ann Oncol.2004;15(3):498‐503.
[60] Ohsaki Y, Takahashi S, Scarcez T, Demulder A, Nishihara T, Williams R,et al. Evidence for an autocrine/paracrine role for interleukin‐6inbone resorption by giant cells from giant cell tumors of bone[J].Endocrinology.1992;131(5):2229‐34.
[61] Wuelling M, Delling G,Kaiser E. Differential gene expression instromal cells of human giant cell tumor of bone[J]. Virchows Arch.2004;445(6):621‐30.
[62] Guenther R, Krenn V, Morawietz L, Dankof A, Melcher I, Schaser KD,et al. Giant cell tumors of the bone: molecular profiling andexpression analysis of Ephrin A1receptor, Claudin7, CD52, FGFR3and AMFR[J]. Pathol Res Pract.2005;201(10):649‐63.
[63] Oda Y, Walter H, Radig K, Rose I, Neumann W,Roessner A.Immunohistochemical analysis of nm23protein expression inmalignant bone tumors[J]. J Cancer Res Clin Oncol.1995;121(11):667‐73.
[64] Riminucci M, Kuznetsov SA, Cherman N, Corsi A, Bianco P,GehronRobey P. Osteoclastogenesis in fibrous dysplasia of bone: in situ andin vitro analysis of IL‐6expression[J]. Bone.2003;33(3):434‐42.
[65] Zhu XL, Hartwick W, Rohan T,Kandel R. Cyclin D1gene amplificationand protein expression in benign breast disease and breastcarcinoma[J]. Mod Pathol.1998;11(11):1082‐8.
[66] Sunters A, McCluskey J,Grigoriadis AE. Control of cell cycle geneexpression in bone development and during c‐Fos‐inducedosteosarcoma formation[J]. Dev Genet.1998;22(4):386‐97.
[67] Kauzman A, Li SQ, Bradley G, Bell RS, Wunder JS,Kandel R. Centralgiant cell granuloma of the jaws: assessment of cell cycle proteins[J].J Oral Pathol Med.2004;33(3):170‐6.
[68] Kandel R, Li SQ, Bell R, Wunder J, Ferguson P, Kauzman A, et al.Cyclin D1and p21is elevated in the giant cells of giant cell tumors[J].J Orthop Res.2006;24(3):428‐37.
[69] Zheng MH, Fan Y, Panicker A, Smith A, Robertson T, Wysocki S, et al.Detection of mRNAs for urokinase‐type plasminogen activator, itsreceptor, and type1inhibitor in giant cell tumors of bone with insitu hybridization[J]. Am J Pathol.1995;147(6):1559‐66.
[70] Cheng YY, Huang L, Lee KM, Xu JK, Zheng MH,Kumta SM.Bisphosphonates induce apoptosis of stromal tumor cells in giantcell tumor of bone[J]. Calcif Tissue Int.2004;75(1):71‐7.
[71] Cheng YY, Huang L, Kumta SM, Lee KM, Lai FM,Tam JS. Cytochemicaland ultrastructural changes in the osteoclast‐like giant cells of giantcell tumor of bone following bisphosphonate administration[J].Ultrastruct Pathol.2003;27(6):385‐91.
[72] Chang SS, Suratwala SJ, Jung KM, Doppelt JD, Zhang HZ, Blaine TA, etal. Bisphosphonates may reduce recurrence in giant cell tumor byinducing apoptosis[J]. Clin Orthop Relat Res.2004;(426):103‐9.
[73] Skubitz KM, Cheng EY, Clohisy DR, Thompson RC,Skubitz AP. Geneexpression in giant‐cell tumors[J]. J Lab Clin Med.2004;144(4):193‐200.
[74] Westerlund A, Hujanen E, Puistola U,Turpeenniemi‐Hujanen T.Fibroblasts stimulate human ovarian cancer cell invasion andexpression of72‐kDa gelatinase A (MMP‐2)[J]. Gynecol Oncol.1997;67(1):76‐82.
[75] Werner JA, Rathcke IO,Mandic R. The role of matrixmetalloproteinases in squamous cell carcinomas of the head andneck[J]. Clin Exp Metastasis.2002;19(4):275‐82.
[76] Takahashi M, Oka N, Naroda T, Nishitani MA, Kanda K, Kanayama HO,et al. Prognostic significance of matrix metalloproteinases‐2activation ratio in renal cell carcinoma[J]. Int J Urol.2002;9(10):531‐8.
[77] Oda Y, Sakamoto A, Saito T, Matsuda S, Tanaka K, Iwamoto Y, et al.Secondary malignant giant‐cell tumour of bone: molecularabnormalities of p53and H‐ras gene correlated with malignanttransformation[J]. Histopathology.2001;39(6):629‐37.
[78]王民,毕乃贵,赵光辉,王莹,杨益民. MMP‐9在骨巨细胞瘤中的表达及其临床意义[J].现代肿瘤医学.2007;(11):1662‐1664.
[79] Park ET, Gum JR, Kakar S, Kwon SW, Deng G,Kim YS. Aberrantexpression of SOX2upregulates MUC5AC gastric foveolar mucin inmucinous cancers of the colorectum and related lesions[J]. Int JCancer.2008;122(6):1253‐60.
[80] Schmitz M, Temme A, Senner V, Ebner R, Schwind S, Stevanovic S, etal. Identification of SOX2as a novel glioma‐associated antigen andpotential target for T cell‐based immunotherapy[J]. Br J Cancer.2007;96(8):1293‐301.
[81] Phi JH, Park SH, Kim SK, Paek SH, Kim JH, Lee YJ, et al. Sox2expression in brain tumors: a reflection of the neuroglialdifferentiation pathway[J]. Am J Surg Pathol.2008;32(1):103‐12.