摘要
目的通过对基底细胞癌(Basal cell carcinoma,BCC)皮损中不同标记朗格汉斯细胞(Langerhans cells,LC)特点的研究,了解BCC皮损中LC数量、形态及分布的变化,探讨其在皮肤肿瘤免疫中可能的作用。
方法应用免疫组化方法对30例BCC皮损分别进行CD1a、S-100蛋白和HLA-DR阳性LC染色,并以计算机图象分析系统对阳性细胞进行定量研究,同时设鳞状细胞癌、脂溢性角化病及正常人皮肤各15例作为对照组。
结果
1.朗格汉斯细胞计数:
①.CD1a+LC的表达:BCC皮损中CD1a+LC呈局灶性分布于癌巢,细胞形态呈点状或斑状,突起明显减少、缩短甚至消失;CD1a+LC的数量(77.36±21.53个/mm~2)较脂溢性角化病组(334.61±50.3个/mm~2)和正常皮肤组(216.92±48.75个/mm~2)显著下降(P＜0.05),与鳞状细胞癌组(74.29±18.11个/mm~2)相比,组间数量差异无统计学意义(P＞0.05)。
②.S-100+LC的表达:BCC皮损中S-100+LC呈弥漫性分布于癌巢和癌旁,细胞染色增强,突起明显增多、增长;S-100+LC的数量(294.48±43.63个/mm~2)较鳞状细胞癌组(79.30±20.58个/mm~2)和正常皮肤组(182.24±33.16个/mm~2)显著增加(P＜0.05),低于脂溢性角化病组(339.51±48.44个/mm~2),差异有统计学意义(P＜0.05)
③.HLA-DR+LC的表达:BCC皮损中HLA-DR+LC主要集中于癌旁,细胞形态与对照组相似;HLA-DR+LC的数量(232.12±50.06个/mm~2)较鳞状细胞癌组(226.29±46.83个/mm~2)和正常皮肤组(214.52±45.13个/mm~2)略增加,但差异无统计学意义(P＞0.05);其数量明显低于脂溢性角化病组(340.74±47.28个/mm~2)(P＜0.05)。
2.免疫组化定量分析结果显示:BCC皮损组中阳性细胞CD1a的平均灰度值高于脂溢性角化病组和正常皮肤组(P＜0.05),与鳞状细胞癌组相比差异无显著性(P＞0.05);BCC皮损组中阳性细胞S-100蛋白的平均灰度值低于鳞状细胞癌组和正常皮肤组(P＜0.05),而高于脂溢性角化病组(P＜0.05);BCC皮损组中阳性细胞HLA-DR抗原平均灰度值与鳞状细胞癌和正常皮肤组比较差异无显著性(P＞0.05),但高于脂溢性角化病组(P＜0.05)。
3.S-100+LC/CD1a+LC比例分析结果显示:30例BCC皮损中S-100+LC/CD1a+LC比值均数为3.89+0.72;15例正常人皮肤中S-100+LC/CD1a+LC比值均数为0.85±0.14,组间差异有统计学意义(P＜0.05)。
结论
1.BCC皮损中不同标记LC数量、形态及分布趋势各不相同,其中浸润以成熟型DC为主。
2.BCC皮损中不同标记LC数量、形态及分布的变化,提示其局部特殊细胞免疫状态;S-100+LC的高表达可能是其低转移性和较好预后的重要原因之一。
Objective To analyze some features of differently-labelled Langerhans cells(LC)in the lesions of Basal cell carcinoma(BCC),and to explore the changes of number,morphology and distribution of them and then assess the roles of them in the cutaneous tumor immunity.
Methods Immunohistochemistry technique was performed by using antibodies against the cell surface markers CD1a,S-100 protein and HLA-DR,and the positive cells were quantitatively estimated by the computer image analysis system.30 cases of BCC were included in this study,and 15 cases of Squamous cell carcinoma(SCC),15 cases of Seborrheic keratosis(SK)and 15 cases of normal skin were taken as controls,respectively.
Results
1.Cells-counting of LC:
①CD1a-positive LC in BCC were topically observed in tumor nests,they revealed striking morphological changes:a reduced number of dendrites,with short and few branches;the number of CD1a+cells in BCC was significantly lower than in SK and normal skin(P<0.05).
②S-100-positive LC were observed even all over the BCC lesions. And S-100+cells displayed a more matured morphology,with longer and more dendrites.The number of LC in BCC was obviously increased compared with SCC and normal skin(P<0.05)
③HLA-DR-positive LC were focused by the peritumor area,their morphology were similar to the control;No significant differences were observed in the number of LC among SCC,normal control and BCC group(P>0.05).
2.In the quantitative analysis of immunohistochemistry,there were no significant differences in gray density of HLA-DR among SCC, normal control and BCC group(P>0.05).However,the gray density of CD1a- positive cells in BCC group was statistically higher than in SK and normal skin(P<0.05),and the gray density of S-100+LC in BCC was statistically lower than in SCC and normal skin(P<0.05).
3.The analysis of S-100+LC/CD1a+LC ratio showed:the ratios of S-100+LC to CD1a+LC in BCC groups were 3.89±0.72,and 0.85±0.14 in normal controls,and there were significant differences between them (P<0.05).
Conclusion
1.The number,morphology and distribution of differently-labelled Langerhans cells were significantly different in BCC,and the infiltration were mainly mature DC.
2.The alterations in numbers,morphology and distribution of differently-labelled LC in the lesions of BCC,were indications of their local cells immune status;the high expression of S-100-positive LC may be one of the important causes of their biological behavior,such as the favorable prognosis and the low metastasis.
引文
[1]王侠生,廖康煌.杨国亮皮肤病学.上海:上海科学技术文献出版社,2005:999-1001.
[2]Massari LP,Kastelan M,Gruber F.Epidermal malignant tumors:pathogenesis,influence of UV light and apoptosis.Coll Antropol,2007,31(Suppl 1):83-85.
[3]Karagas MR,Nelson HH,Sehr P,et al.Human papillomavirus infection and incidence of squamous cell and basal cell carcinomas of the skin.J Natl Cancer Inst.2006,98(6):389-395.
[4]Pons M,Quintanilla M.Molecular biology of malignant melanoma and other cutaneous tumors.Clin Transl Oncol.2006,8(7):466-474.
[5]Shore RE.Radiation-induced skin cancer in humans.Med Pediatr Oncol.2001,36(5):549-554.
[6]Yu HS,Liao WT,Chai CY.Arsenic carcinogenesis in the skin.J Biomed Sci.2006,13(5):657-666.
[7]Ceilley RI,Del Rosso JQ.Current modalities and new advances in the treatment of basal cell carcinoma.Int J Dermatol.2006,45(5):489-498.
[8]Albert MR,Weinstock MA.Keratinocyte carcinoma.CA Cancer J Clin.2003,53(5):292-302.
[9]Diepgen TL,Mahler V.The epidemiology of skin cancer.Br J Dermatol.2002,146(Suppl 61):1-6.
[10]De Vries E,Coebergh JW,van der Rhee H.Trends,causes,approach and consequences related to the skin-cancer epidemic in the Netherlands and Europe.Ned Tijdschr Geneeskd.2006,150(20):1108-1115.
[11]Cheng SY,Luk NM,Chong LY.Special features of non-melanoma skin cancer in Hong Kong Chinese patients:10-year retrospective study.Hong Kong Med J.2001,7(1):22-28.
[12]Rawashdeh MA,Matalka I.Basal cell carcinoma of the maxillofacial region:site distribution and incidence rates in Arab/Jordanians,1991 to 2000.J Oral Maxillofac Surg.2004,62(2):145-149.
[13]何勤,涂平,马圣清,等.皮肤恶性肿瘤及癌前病变707例统计分析.中华皮肤科杂志,2003,36(2):109.
[14]孙桂珍,张宗琴,朱晓琳,等.皮肤鳞状细胞癌、基底细胞癌、恶性黑素瘤449例统计分析.临床皮肤科杂志,1995,24:21-22.
[15]高天文,孙东杰,李春英,等.中国西部两医院1905例皮肤恶性肿瘤回顾分析.北京大学学报(医学版),2004,36(5):469-472.
[16]刘勇,岑瑛,许学文,等.236例皮肤恶性肿瘤临床分析.华西医学,2007,22(2):368-369.
[17]Anwar U,Al Ghazal SK,Ahmad M,et al.Horrifying basal cell carcinoma forearm lesion leading to shoulder disarticulation.Plast Reconstr Surg.2006,117(1):6-9.
[18]Knutson KL,Disis ML.Tumor antigen-specific T helper cells in cancer immunity and immunotherapy.Cancer Immunol Immunother.2005,54(8):721-728.
[19]Steinman RM,Hemmi H.Dendritic cells:translating innate to adaptive immunity.Curr Top Microbiol Immunol.2006,311:17-58.
[20]Berger CL,Vasquez JG,Shofner J,et al.Langerhans cells:mediators of immunity and tolerance.Int J Biochem Cell Biol.2006;38(10):1632-1636.
[21]Gottfried E,Kreutz M,Mackensen A.Tumor-induced modulation of dendritic cell function.Cytokine Growth Factor Rev.2008,19(1):65-77.
[22]Mathers AR,Larregina AT.Professional antigen-presenting cells of the skin.Immunol Res.2006,36(1-3):127-136.
[23]Cumberbatch M,Dearman RJ,Griffiths CE,et al.Langerhans cell migration.Clin Exp Dermatol.2000,25(5):413-418.
[24]Preynat-Seauve O,Schuler P,Contassot E,et al.Tumor-infiltrating dendritic cells are potent antigen-presenting cells able to activate T cells and mediate tumor rejection.J Immunol.2006,176(1):61-67.
[25]De Melo MR Jr,Araujo Filho JL,Patu VJ,et al.Langerhans cells in cutaneous tumours:immunohistochemistry study using a computer image analysis system.J Mol Histol,2006,37(8-9):321-325.
[26]Bergfelt L.UV-related skin conditions and Langerhans' cell populations in human skin.Acta Derm Venereol,1993,73(3):194-196.
[27]McArdle JP,Knight BA,Halliday GM,et al.Quantitative assessment of Langerhans cells in actinic keratosis,Bowen's disease,keratoacanthoma,squamous cell carcinoma and basal cell carcinoma.Pathology.1986,18(2):212-216.
[28]陈东明,鲍卫汉,王琦,等.树突状细胞在异常瘢痕中的免疫调控作用.中华整形外科杂志,2001,17(5):282-284.
[29]陈江,涂彩霞,王大光,等.白癜风复色区黑色细胞特异性抗原表达的研究.临床皮肤科杂志,2006,35(9):566-568.
[30] Austyn JM. Dendritic cells.Curr Opin Hematol. 1998,5(1):3-15.
[31] Wu L, Liu YJ.Development of dendritic-cell lineages.Immunity. 2007,26(6):741-750.
[32] Takeuchi S, Furue M. Dendritic cells: ontogeny. Allergol Int. 2007,56(3):215-223.
[33] Quah BJ, O'Neill HC.The immunogenicity of dendritic cell-derived exosomes.Blood Cells Mol Dis, 2005,35(2):94-110.
[34] Syme R, Gluck S.Generation of dendritic cells: role of cytokines and potential clinical applications.Transfus Apher Sci, 2001 ,24(2): 117-24.
[35] Nagaraj S, Gabrilovich DI.Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res, 2008 ,68(8):2561-2563.
[36] Vicari AP, Caux C, Trinchieri G.Tumour escape from immune surveillance through dendritic cell inactivation. Semin Cancer Biol. 2002,12(1):33-42..
[37] Vermi W,Bonecchi R,Facchetti F,et al.Recruitment of immature plasmacytoid dendritic cells(Plasmacytoid monocytes)and myeloid dendritic cells in Primary cutaneous melano mas.J Pathol,2003,200(2):255-268.
[38] Yilmaz M, Christofori G, Lehembre F.Distinct mechanisms of tumor invasion and metastasis.Trends Mol Med,2007,13(12):535-541
[39] Movassagh M, Spatz A, Davoust J, et al. Selective accumulation of mature DC-Lamp+dendritic cells in tumor sites is associated with efficient T-cell-mediated antitumor response and control of metastatic dissemination in melanoma. Cancer Res.2004,64(6):2192-2198.
[40] Coventry B, Heinzel S.CD1a in human cancers: a new role for an old molecule.Trends Immunol, 2004,25(5):242-248.
[41] Hunger RE, Sieling PA, Ochoa MT, et al.Langerhans cells utilize CD1a and langerin to efficiently present nonpeptide antigens to T cells.J Clin Invest, 2004,113(5):701-708.
[42] Zhou LJ, Schwarting R, Smith HM, et al.A novel cell-surface molecule expressed by human interdigitating reticulum cells, Langerhans cells, and activated lymphocytes is a new member of the Ig superfamily. J Immunol, 1992,149(2):735-742.
[43] Donato R. S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles.Int J Biochem Cell Biol. 2001,33(7):637-668.
[44]Campaner AB,Nadais RF,Galvao MA,et al.Evaluation of density of Langerhans cells in human cervical intraepithelial neoplasia.Acta Obstet Gynecol Scand,2007,86(3):361-366.
[45]Mueller A,Bachi T,Hochli M,et al.Subcellular distribution of S100proteins in tumor cells and their relocation in response to calcium activation.Histochem Cell Biol,1999,111(6):453-459.
[46]Holling TM,Schooten E,van Den Elsen PJ.Function and regulation of MHC class Ⅱ molecules in T-lymphocytes:of mice and men.Hum Immunol.2004,65(4):282-290.
[47]李惠翔,张云汉,高冬玲,等.食管癌发生中不同标志Langerhans细胞的比较.河南医科大学学报,1997,32(3):6-9.
[48]Tay SK,Jenkins D,Maddox P,et al.Subpopulations of Langerhans' cells in cervical neoplasia.Br J Obstet Gynaecol.1987,94(1):10-15.
[49]Bell D,Chomarat P,Broyles D,et al.In breast carcinoma tissue,immature dendritic cells reside within the tumor,whereas mature dendritic ceils are located in peritumoral areas.
[50]贾立敏,徐玉东,徐媛媛,等.喉癌组织中成熟与非成熟树突状细胞的免疫组化定位分析.哈尔滨医科大学学报,2003,37(4):287-289.
[51]Feng JY,Peng ZH,Tang XP,et al.Immunohistochemical and ultrastructural features of Langerhans cells in condyloma acuminatum.J Cutan Pathol,2008,35(1):15-20.
[52]La Rocca G,Anzalone R,Bucchieri F,et al.CDla and antitumour immune response.Immunol Lett,2004,95(1):1-4.
[53]Coventry BJ,Lee PL,Gibbs D,et al.Dendritic cell density and activation status in human breast cancer - CD1a,CMRF-44,CMRF-56 and CD-83 expression.Br J Cancer,2002,86(4):546-551.
[54]Baecher-Allan C,Wolf E,Hailer DA.MHC class Ⅱ expression identifies functionally distinct human regulatory T cells.J Immunol,2006,176(8):4622-4631
[55]Angel CE,George E,Ostrovsky LL,et al.Comprehensive analysis of MHC-Ⅱ expression in healthy human skin.Immunol Cell Biol,2007,85(5):363-369.
[56]Connor JP,Ferrer K,Kane JP,et al.Evaluation of Langerhans' cells in the cervical epithelium of women with cervical intraepithelial neoplasia.Gynecol Oncol,1999,75(1):130-135.
[57]Kikuchi K,Kusama K,Taguchi K,et al.Dendritic cells in human squamous cell carcinoma of the oral cavity.Anticancer Res,2002,22(2A):545-557.
[58]陈文宽,陈福进,曾宗渊,等.S100标记树突细胞在声门型喉鳞癌癌周组织中的表达及其与预后的关系.癌症,2005,24(10):1272-1275.
[59]Yilmaz T,Gedikoglu G;Celik A,et al.Prognostic significance of Langerhans cell infiltration in cancer of the larynx.Otolaryngol Head Neck Surg,2005,132(2):309-316.
[1] Roewert-Huber J, Lange-Asschenfeldt B, Stockfleth E, et al.Epidemiology and aetiology of basal cell carcinoma. Br J Dermatol. 2007,157 (Suppl 2):47-51.
[2] Athar M, Tang X, Lee JL, et al.Hedgehog signalling in skin development and cancer. Exp Dermatol. 2006,15(9):667-677.
[3] Lupi O.Correlations between the Sonic Hedgehog pathway and basal cell carcinoma. Int J Dermatol. 2007,46(11):1113-1117.
[4] Lam CW, Xie J, To KF, et al.A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene. 1999,18(3):833-836.
[5] Reifenberger J, Wolter M, Knobbe CB, et al.Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol. 2005,152(1):43-51.
[6] Williams JA, Guicherit OM, Zaharian BI, et al.Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions.Proc Natl Acad Sci U S A. 2003,100(8):4616-4621.
[7] Athar M, Li C, Tang X, et al.Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis. Cancer Res. 2004,64(20):7545-7552.
[8] Amstad PA, Cerutti PA.Ultraviolet-B-light-induced mutagenesis of C-H-ras codons 11 and 12 in human skin fibroblasts. Int J Cancer,1995,63(1):136-139.
[9] Pierceall WE, Goldberg LH, Tainsky MA, et al.Ras gene mutation and amplification in human nonmelanoma skin cancers.Mol Carcinog. 1991,4(3): 196-202.
[10] Hussein MR.Ultraviolet radiation and skin cancer: molecular mechanisms.J Cutan Pathol,2005,32(3):191-205.
[11] Barshack I, Goldberg I, Davidson B, et al.Expression of rasGTPase activating protein in basal cell carcinoma of the skin. Mod Pathol. 1998,11(3):271-275.
[12]Milde-Langosch K.The Fos family of transcription factors and their role in tumourigenesis.Eur J Cancer. 2005,41(16):2449-2461.
[13]Urabe A, Nakayama J, Taniguchi S, et al.Expression of the fos oncogene in basal cell carcinoma.J Dermatol Sci,1994,8(1):50-53
[14]Takahashi S, Pearse A D, Marks R.Expression of c-fos proto-oncogene mRNA in non-melanoma skin cancer. J Dermatol Sci, 1994, 7(1):54-62.
[15] Moasser MM.The oncogene HER2:its signaling and transforming functions and its role in human cancer pathogenesis.Oncogene.2007,26(45):6469-6487.
[16] Lebeau S, Masouye I, Berti M, et al.Comparative analysis of the expression of ERBIN and Erb-B2 in normal human skin and cutaneous carcinomas.Br J Dermatol. 2005,152(6): 1248-55.
[17] Liu B, Zhang H, Li S,et al. The expression of c-erbB-1 and c-erbB-2 oncogenes in basal cell carcinoma and squamous cell carcinoma of skin. Chin Med Sci J.1996,11 (2): 106-109.
[18] Tashiro E, Tsuchiya A, Imoto M.Functions of cyclin D1 as an oncogene and regulation of cyclin Dl expression.Cancer Sci. 2007,98(5):629-635.
[19] Utikal J, Udart M, Leiter U, et al.Numerical abnormalities of the Cyclin D1 gene locus on chromosome 11q13 in non-melanoma skin cancer. Cancer Lett. 2005,219(2): 197-204.
[20] Liang SB, Furihata M, Takeuchi T, et al.Overexpression of cyclin Dl in nonmelanocytic skin cancer.Virchows Arch. 2000,436(4):370-376.
[21] Lindstrom E, Shimokawa T, Toftgard R, Zaphiropoulos PG.PTCH mutations: distribution and analyses. Hum Mutat. 2006,27(3):215-219.
[22] Unden AB, Zaphiropoulos PG, Bruce K, et al.Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma.Cancer Res. 1997,57(12):2336-2340.
[23] Nagano T, Bito T, Kallassy M, et al.Overexpression of the human homologue of Drosophila patched (PTCH) in skin tumours: specificity for basal cell carcinoma. Br J Dermatol. 1999,140(2):287-290.
[24] Erb P, Ji J, Wernli M, et al. Role of apoptosis in basal cell and squamous cell carcinoma formation.Immunol Lett. 2005 ,100(1):68-72.
[25] Bolshakov S, Walker CM, Strom SS, et al.p53 mutations in human aggressive and nonaggressive basal and squamous cell carcinomas. Clin Cancer Res. 2003,9(1):228-234.
[26] Ghaderi R, Haghighi F.Immunohistochemistry assessment of p53 protein in Basal cell carcinoma. Iran J Allergy Asthma Immunol. 2005 ,4(4): 167-171.
[27] Ansarin H, Daliri M, Soltani-Arabshahi R.Expression of p53 in aggressive and non-aggressive histologic variants of basal cell carcinoma. Eur J Dermatol. 2006 ,16(5):543-547.
[28] Saridaki Z, Koumantaki E, Liloglou T, et al.Spandidos DA.High frequency of loss of heterozygosity on chromosome region 9p21-p22 but lack of p16INK4a/p19ARF mutations in greek patients with basal cell carcinoma of the skin.J Invest Dermatol.2000,115(4):719-25.
[29]Niu Y,Zhou Z,Liu F,et al.Expression of P16 protein and Bcl-2 protein in malignant eyelid tumors.Chin Med J(Engl).2002,115(1):21-25.
[30]Conscience I,Jovenin N,Coissard C,et al.P16 is overexpressed in cutaneous carcinomas located on sun-exposed areas.Eur J Dermatol.2006,16(5):518-522.
[31]Soufir N,Moles JP,Vilmer C,et al.P16 UV mutations in human skin epithelial tumors.Oncogene.1999,18(39):5477-5481.
[32]Wilson A,Radtke F.Multiple functions of Notch signaling in self-renewing organs and cancer.FEBS Lett.2006,80(12):2860-2868.
[33]Nicolas M,Wolfer A,Raj K,et al.Notchl functions as a tumor suppressor in mouse skin.Nat Genet.2003,33(3):416-421.
[34]Li L,Ross AH.Why is PTEN an important tumor suppressor? J Cell Biochem.2007,102(6):1368-1374.
[35]滕蔚,史同新,曲才杰.PTEN和Survivin在基底细胞癌中的表达.中国麻风皮肤病杂志,2005,21(4):262-264.
[36]陈海霞,肖君刚.表皮生长因子受体和PTEN蛋白在尖锐湿疣皮损中的检测及意义.中国皮肤性病学杂志,2006(20)10:592-594.
[37]Boissan M,Poupon MF,Lacombe ML.NM23 and metastasis suppressor genes:update.Med Sci(Paris).2007,23(12):1115-1123.
[38]Kanitakis J,Euvrard S,Bourchany D,et al.Expression of the nm23metastasis-suppressor gene product in skin tumors.J Cutan Pathol.1997,24(3):151-156.
[38]Whiteside TL.The role of death receptor ligands in shaping tumor microenvironment.Immunol Invest.2007,36(1):25-46.
[40]Shaker O,Youssef R.Role of apoptosis stimulus factor and its ligand in the induction of apoptosis in some ultraviolet induced diseases.Dermatol Online J.2006,12(3):4.
[41]Boldrini L,Loggini B,Gisfredi S,et al.Mutations of Fas(APO-1/CD95)and p53 genes in nonmelanoma skin cancer.J Cutan Med Surg.2003,7(2):112-118.
[42]Filipowicz E,Adegboyega P,Sanchez RL,et al.Expression of CD95(Fas)in sun-exposed human skin and cutaneous carcinomas.Cancer.2002,94(3):814-9.
[43]Adams JM,Cory S.Bcl-2-regulated apoptosis:mechanism and therapeutic potential.Curr Opin Immunol.2007,19(5):488-496.
[44]颜兰香,陈明亮,余桂英,等.基底细胞癌中p53,bcl-2及bax蛋白的表达.湖南医科大学学报.1999,24(2):179-180.
[45]Tilli CM,Stavast-Koey AJ,Ramaekers FC,et al.Bax expression and growth behavior of basal cell carcinomas.J Cutan Pathol.2002,29(2):79-87.
[46]Li F,Brattain MG.Role of the Survivin gene in pathophysiology.Am J Pathol.2006,169(1):1-11.
[47]Duffy MJ,O'Donovan N,Brennan DJ,Gallagher WM,Ryan BM.Survivin:a promising tumor biomarker.Cancer Lett.2007,249(1):49-60.
[48]Bowen AR,Hanks AN,Murphy KJ,et al.Proliferation,apoptosis,and survivin expression in keratinocytic neoplasms and hyperplasias.Am J Dermatopathol.,2004,26(3):177-181.
[49]Nieminen AI,Partanen JI,Klefstrom J.c-Myc blazing a trail of death:coupling of the mitochondrial and death receptor apoptosis pathways by c-Myc.Cell Cycle.2007,6(20):2464-2472.
[50]王家璧,毛旭明,晋红中,等.皮肤鳞状细胞癌和基底细胞癌中p53和C-myc突变基因及蛋白的检测.中国皮肤性病学杂志,2000,14(2):73-76.
[51]Wu A,Ichihashi M,Ueda M.Correlation of the expression of human telomerase subunits with telomerase activity in normal skin and skin tumors.Cancer.1999,86(10):2038-2044.
[52]Carpenter EL,Vonderheide RH.Telomerase-based immunotherapy of cancer.Expert Opin Biol Ther.2006,6(10):1031-1039.
[53]Park HR,Min SK,Cho HD,et al.Expression profiles of p63,p53,survivin,and hTERT in skin tumors.J Cutan Pathol,2004,31(8):544-549.
[54]丁颖果,武玲慎,涂平.端粒酶逆转录酶在皮肤肿瘤原位表达水平的比较.中国皮肤性病学杂志,2004,18(1):8-10.
[55]Saleh S,King-Yin Lam A,Gertraud Buettner P,et al.Telomerase activity of basal cell carcinoma in patients living in North Queensland,Australia.Hum Pathol,2007,38(7):1023-1029.
[56]Bowden J,Brennan PA,Umar T,et al.Expression of vascular endothelial growth factor in basal cell carcinoma and cutaneous squamous cell carcinoma of the head and neck.J Cutan Pathol.2002,29(10):585-589.
[57]Oh CK,Kwon YW,Kim YS,et al.Expression of basic fibroblast growth factor,vascular endothelial growth factor,and thrombospondin-1 related to microvessel density in nonaggressive and aggressive basal cell carcinomas.J Dermatol.2003,30(4):306-313.
[58]Weninger W,Uthman A,Pammer J,et al.Vascular endothelial growth factor production in normal epidermis and in benign and malignant epithelial skin tumors.Lab Invest,1996,75(5):647-657.
[59]Ng YS,Krilleke D,Shima DT.VEGF function in vascular pathogenesis.Exp Cell Res.2006,312(5):527-537.
[60]Nakopoulou L,Stefanaki K,Panayotopoulou E,et al.Athanassiadou P,Gakiopoulou-Givalou H,Louvrou A.Expression of the vascular endothelial growth factor receptor-2/Flk-1 in breast carcinomas:correlation with proliferation.Hum Pathol.2002,33(9):863-870.
[61]卜璋于,蔡绥勃,满孝勇,等.皮肤基底细胞癌组织中血管内皮细胞生长因子受体-2的表达.中华皮肤科杂志,2007,40(9):533-535.
[62]Arbiser JL,Byers HR,Cohen C,et al.Altered basic fibroblast growth factor expression in common epidermal neoplasms:examination with in situ hybridization and immunohistochemistry.J Am Acad Dermatol,2000,42(6):73-977.
[63]常建民,付裕,杨敏.bFGF、NGF在基底细胞癌表达的研究.中国麻风皮肤病杂志,2005,21(8):605-606.
[64]Yee KL,Weaver VM,Hammer DA.Integrin-mediated signalling through the MAP-kinase pathway.IET Syst Biol.2008,2(1):8-15.
[65]Orimoto AM,Neto CF,Pimentel ER,et al.High numbers of human skin cancers express MMP2 and several integrin genes.J Cutan Pathol.2008,35(3):285-291.
[66]Whittock NV,Bower C.Genetic evidence for a novel human desmosomal cadherin,desmoglein 4.J Invest Dermatol.2003,120(4):523-530.
[67]Tada H,Hatoko M,Tanaka A,et al.J Cutan Pathol.2000,27(1):24-29.Expression of desmoglein I and plakoglobin in skin carcinomas.
[68]汤占利,涂平,韩钢文,等.皮肤基底癌组织中桥粒芯糖蛋白1+2表达的研究.临床皮肤科杂志,2003,32(5):252-253.
[69]Pizarro A,Benito N,Navarro P,et al.E-cadherin expression in basal cell carcinoma.Br J Cancer.1994,69(1):157-162.
[70]葛新红,涂平,韩钢文,等.E-钙粘着蛋白在不同表皮肿瘤中的表达及意义. 中国皮肤性病学杂志,2004,18(3):129-131.
[71]蔡绥勍,陈丽荣,王海军,等.磷酸化信号传导和转录激活因子3和上皮钙黏着蛋白在表皮肿瘤的表达.中华皮肤科杂志,2005,38(2):86-89.
[72]Expression of T-cadherin in Basal keratinocytes of skin.J Invest Dermatol.2002,118(6):1080-1084.
[73]Ivanov D,Philippova M,Tkachuk V,et al.Cell adhesion molecule T-cadherin regulates vascular cell adhesion,phenotype and motility.Exp Cell Res.2004,293(2):207-218.
[74]Cavallaro U,Liebner S,Dejana E.Endothelial cadherins and tumor angiogenesis.Exp Cell Res.2006,312(5):659-667.
[75]于波,程滨珠,钟绮丽,等.皮肤基底细胞癌T钙黏蛋白的表达及其DNA异常甲基化分析.中华皮肤科杂志,2007,40(3):152-154.
[76]Takeuchi T,Liang SB,Ohtsuki Y.Downregulation of expression of a novel cadherin molecule,T-cadherin,in basal cell carcinoma of the skin.Mol Carcinog.2002,35(4):173-9.
[77]Ilyas M,Tomlinson IP.The interactions of APC,E-cadherin and betacatenin in tumour development and progression.J Pathol,1997,182(2):128-137.
[78]Boonchai W,Walsh M,Cummings M,et al.Expression of beta-catenin,a key mediator of the WNT signaling pathway,in basal cell carcinoma.Arch Dermatol.2000,136(7):937-938.
[79]Yamazaki F,Aragane Y,Kawada A,et al.Immunohistochemicaldetection for nuclear beta- catenin in sporadic basal cell carcino-ma.Br J Dermatol,2001,145(5):771-777.
[80]El-Bahrawy M,El-Masry N,Alison M,et al.Expression of beta-catenin in basal cell carcinoma.Br J Dermatol.2003,148(5):964-70.
[81]Fukumaru K,Yoshii N,Kanzaki T,et al.Immunohistochemical comparison of beta-catenin expression by human normal epidermis and epidermal tumors.J Dermatol.2007,4(11):746-753.
[82]Hattori Y,Nerusu KC,Bhagavathula N,et al.Vascular expression of matrix metalloproteinase-13(collagenase-3)in basal cell carcinoma.Exp Mol Pathol.2003,74(3):230-237.