旋毛虫与Hela细胞相关抗原抗体抗肿瘤作用的研究
摘要
为了深入研究旋毛虫抗肿瘤的的作用,本试验先在体外利用MTT和细胞凋亡的检测的方法初步确定了旋毛虫可溶性抗原可以使Hela细胞发生凋亡,在用ELISA方法初步确定了旋毛虫与Hela细胞间存在共同抗原,并利用SDS-PAGE和Western-blotting方法测得了相关抗原的分子量。运用离心超滤装置及透析等技术对相关抗原进行了分离,FITC-免疫组化法对该抗原进行了定位分析。在此基础上,建立了Hela细胞裸鼠移植瘤动物模型,并对旋毛虫与Hela细胞相关抗原抗体进行了抗肿瘤实验。
实验结果显示:通过MTT法和细胞凋亡实验证明,旋毛虫可溶性抗原可以对Hela细胞的增殖具有抑制作用,ELISA法初步证明旋毛虫与Hela细胞间存在较强的免疫交叉反应;利用SDS-PAGE和Western-blotting方法获得了旋毛虫抗原与Hela细胞相关抗原的分子量分别是40KDa和55KDa。免疫组化定位分析该相关抗原位于Hela细胞表面抗原和旋毛虫的消化道上皮细胞膜上;应用相关抗原抗体在裸鼠体内进行抗肿瘤试验表明,相关抗原抗体具有抗肿瘤作用,抑瘤率为82.3%,且效果略好于可溶性抗原抗体组。首次以旋毛虫与Hela细胞相关抗原抗体为切入点研究旋毛虫抗肿瘤的机理,为旋毛虫抗肿瘤机制的研究与开发提供了理论依据。
Trichinosis is a globalized zoonotic parasitic disease.Trichinella spiralis that is the most frequent and food-transmitted helminth zoonosis can infect the human and 150 kinds of animals,what is more,cause people’s death.In the previous study ,some scholars discovered that when the hosts are infected with Trichinella spiralis their immunity can be enhanced,however,when hosts are infected with other nematodes,the host’s immunity is not remarkblely improved. It is suggested that Trichinella spiralis can activate the host’s immune system,moreover,it can contain some antitumor components.In order to study antitumor mechanism of Trichinella spiralis,the experiments were designed to investigate the anti-tumor mechanism of Trichinella spiralis and Hela cell related antigens-antibodies,furthermore,pave the way for inventing some new anti-tumor biological agent.
MTT assay and cell apoptosis experiments showed that the soluble antigen of Trichinella spiralis on the proliferation of Hela cells inhibit the antigen concentration was 177μg/μl, apoptosis rate was 48.2%, inhibition was the best.ELISA method proved soluble antigen of Trichinella spiralis and Hela cells produce soluble antigen antibody cross-reactivity, Hela cells with soluble antigen soluble antigen of Trichinella antibodies produced by cross-reaction, initially identified Trichinella Hela cells with immune cross-reaction between the Common antigen.SDS-PAGE electrophoresis showed that the soluble antigen of Trichinella and Hela cells the same size as the soluble antigen is present antigen are 83KDa, 55KDa, 40KDa, 28.5KDa, 20KDa, 17.6KDa and 14.4KDa. Western-blot showed that protein in the immune response occurs, the size of 40 KDa. Hela cells at exponential phase of growth were collected and spreaded uniformly on POLY-L-LYSINE treated glass slide. Experimental anti-tumor-associated antigen research: experiments on tumor-bearing mice to observe the anti-tumor effects.The related antigens could be the basis to study the anti-tumor mechanism of Trichinella spiralis.The results show that Trichinella -associated antigen is located on the digestive tract and the Hell cell surface. The model of Hela cells in nude mice is successfully established. Trichinella antibodies and soluble antigen Hela cell-associated antigen antibody can reduce tumor xenografts in nude mice, tumor inhibition rates were 52.2% and 82.3%.
实验结果显示:通过MTT法和细胞凋亡实验证明,旋毛虫可溶性抗原可以对Hela细胞的增殖具有抑制作用,ELISA法初步证明旋毛虫与Hela细胞间存在较强的免疫交叉反应;利用SDS-PAGE和Western-blotting方法获得了旋毛虫抗原与Hela细胞相关抗原的分子量分别是40KDa和55KDa。免疫组化定位分析该相关抗原位于Hela细胞表面抗原和旋毛虫的消化道上皮细胞膜上;应用相关抗原抗体在裸鼠体内进行抗肿瘤试验表明,相关抗原抗体具有抗肿瘤作用,抑瘤率为82.3%,且效果略好于可溶性抗原抗体组。首次以旋毛虫与Hela细胞相关抗原抗体为切入点研究旋毛虫抗肿瘤的机理,为旋毛虫抗肿瘤机制的研究与开发提供了理论依据。
Trichinosis is a globalized zoonotic parasitic disease.Trichinella spiralis that is the most frequent and food-transmitted helminth zoonosis can infect the human and 150 kinds of animals,what is more,cause people’s death.In the previous study ,some scholars discovered that when the hosts are infected with Trichinella spiralis their immunity can be enhanced,however,when hosts are infected with other nematodes,the host’s immunity is not remarkblely improved. It is suggested that Trichinella spiralis can activate the host’s immune system,moreover,it can contain some antitumor components.In order to study antitumor mechanism of Trichinella spiralis,the experiments were designed to investigate the anti-tumor mechanism of Trichinella spiralis and Hela cell related antigens-antibodies,furthermore,pave the way for inventing some new anti-tumor biological agent.
MTT assay and cell apoptosis experiments showed that the soluble antigen of Trichinella spiralis on the proliferation of Hela cells inhibit the antigen concentration was 177μg/μl, apoptosis rate was 48.2%, inhibition was the best.ELISA method proved soluble antigen of Trichinella spiralis and Hela cells produce soluble antigen antibody cross-reactivity, Hela cells with soluble antigen soluble antigen of Trichinella antibodies produced by cross-reaction, initially identified Trichinella Hela cells with immune cross-reaction between the Common antigen.SDS-PAGE electrophoresis showed that the soluble antigen of Trichinella and Hela cells the same size as the soluble antigen is present antigen are 83KDa, 55KDa, 40KDa, 28.5KDa, 20KDa, 17.6KDa and 14.4KDa. Western-blot showed that protein in the immune response occurs, the size of 40 KDa. Hela cells at exponential phase of growth were collected and spreaded uniformly on POLY-L-LYSINE treated glass slide. Experimental anti-tumor-associated antigen research: experiments on tumor-bearing mice to observe the anti-tumor effects.The related antigens could be the basis to study the anti-tumor mechanism of Trichinella spiralis.The results show that Trichinella -associated antigen is located on the digestive tract and the Hell cell surface. The model of Hela cells in nude mice is successfully established. Trichinella antibodies and soluble antigen Hela cell-associated antigen antibody can reduce tumor xenografts in nude mice, tumor inhibition rates were 52.2% and 82.3%.
引文
[1] Trubcheninova LP,Chimishkian KL,Ovutian GSh,et al . Effect of Trichinella spiralis infection on the development of Rauscher leukemia[J]. Vopr virusol,1975(3):344-348.
[2] Lubiniecki AS,Cypess RH. Quantitative study of the effect of previous Trichinella spiralisinfection on sarcoma 180 ascitic tumor formation in mice[J]. Tropenmed Parasitol,1975,26(3):329-334.
[3] Molinari JA , Ebersole JL. Antineoplastic effects of long-term Trichinella spiralis infection on B-16 melanoma[J].Int Arch Allergy Appl immunol,1977; 55(1-6): 444-448.
[4] Molinari JA,Carrick L Jr,Lubiniecki AS. Influence of Trichinella spiralis infection on development of sarcoma-180 ascites tumors[J]. Trop enmed Parasitol,1979,30(4):429-433.
[5] Wing EJ,Krahenbuhl JL,Remington JS. Studies of macropHage function during Trichinella spiralis infection in mice[J].Immunology, 1979 Mar; 36(3): 479-485.
[6] Bellelli C, Frosi A, Chiovoloni M,et al . Trichinella spiralis as a modulator of Shope fibroma virus[J]. Parassitologia , 1989 ,31(2-3):145-152.
[7] Bany J,Janiak MK,Budzyński W. Activity of natural killer (NK) cells in the course of experimental trichinellosis in mice[J].Wiad Parazytol,1992,38(3-4):117-126.
[8] Wang XL,Fu BQ,Yang SJ,et al. Trichinella spiralis--a potential anti-tumor agent[J]. Vet Parasitol,2009,159(3-4):249-152.
[9] Gong P,Zhang J,Cao L, et al. Identification and characterization of myeloma-associated antigens in Trichinella spiralis[J]. Exp Parasitol,127(4):784-788.
[10]吴涛,张西臣,李建华,等.旋毛虫抗小鼠体内SP2/0肿瘤作用的研究[J].中国寄生虫病防治杂志,2005,18(6):445～447
[11]王学林,杨世杰,吴秀萍,等.旋毛虫重提蛋白对肝癌细胞H7402的抑制作用[J].中国肿瘤生物治疗杂志,2005,34(2):245-251
[12]谢春玲,瞿逢伊,汤英龙,等.旋毛虫感染小鼠血清对L929细胞的毒性作用[J].中国人兽共患病杂志,2001,28(5):273-275
[13] Meerovitch E,Bomford R. MacropHage potentiation by Trichinella spiralis[J]. Ann Trop Med Parasitol,1977,71(2):245-248
[14] Na HR,Seelig LL . In vitro TNF,IL-6 and IL-2 production by rat milk cells following Trichinella spiralis infection[J]. J Reprod Immunol,1993,25(2):119-131.
[15] Goyal PK,Wakelin D. Influence of variation in host strain and parasite isolate on inflammatory and antibody responses to Trichinella spiralis in mice[J]. Parasitology,1993,106(Pt4):371-378.
[16] Niborski V,Vallée I,Fonseca-Li?án R,Boireau P,Enciso A,Ortega-Pierres G,Yépez-Mulia L. Trichinella spiralis: stimulation of mast cells by TSL-1 antigens trigger cytokine mRNA expression and release of IL-4 and TNF through an Ig-independent pathway[J]. Exp Parasitol,2004,108(3-4):101-108.
[17] HumpHreys SR,Mantel N,Goldin A. Chemotherapy and surgery of spontaneous tumours of mice[J]. Eur J Cancer,1966,2:1–7.
[18] Shubik P. The growth potentialities of induced skin tumours in mice;the effects of different methods of chemical carcinogenesis[J].Cancer Res,1950,10:713–717.
[19] Hennings H, Boultwell RK. Studies on the mechanism of skin tumour promotion[J]. Cancer Res,1970,30(2):312–320.
[20] Watson JD , Berry A. DNA: The Secret of Life April 2003 publication[J]. Random House Trade ISBN 0-375-41546-7.
[21] Stehelin D,Varmus HE,Bishop JM, Vogt PK. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA[J]. Nature,1976,260:170–173.
[22] Shih C,Shilo BZ,Goldfarb MP,et al . Passage of pHenotypes of chemically transformed cells via transfection of DNA and chromatin[J]. Proc Natl Acad Sci USA,1979,76(11):5714–5718.
[23] Cooper GM,Neiman PE. Transforming genes of neoplasms induced by avian lympHoid leukosis viruses[J]. Nature , 1980 ,287(5783):656–659.
[24] Wigler M,Perucho M,Kurtz D,et al. Tra- nsformation of mammalian cells with an amplifiable dominantacting gene[J]. Proc Natl Acad Sci USA,1980,77(6):3567–3570.
[25] Tabin CJ,Bradley SM,Bargmann CI,et al. Mechanism of activation of a human oncogene[J]. Nature,1982,300(5888):143–149.
[26] Reddy EP,Reynolds RK,Santos E,Barbacid M. A point mutation is res- ponsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene[J]. Nature , 1982 ,300(5888):149–152.
[27] Taparowsky E,Suard Y,Fasano O,Shimizu K Goldfarb M,Wigler M. Ac- tivation of the T24 bladder carcinoma transforming gene islinked to a single amino acid change[J]. Nature.1982 ,300(5894):762–765.
[28] Balmain A,Pragnell IB. Mouse skin carcinomas induced in vivo by che- mical carcinogens have a transforming Harvey-ras oncogene[J]. Nature,1983, 303 (5912):72–74.
[29] Sukumar S,Notario V,Martin-Zanca D,Barbacid M. Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-ras-1 locus by single point mutations[J]. Nature,1983,306(5944): 658-661.
[30] Balmain A,Ramsden M,Bowden GT,Smith J. Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas[J]. Nature,1984, 307(5952):658–660.
[31] Quintanilla M,Brown K,Ramsden M,Balmain A. Carcinogenspecific mut- ation and amplification of Ha-ras during mouse skin carcinogenesis[J]. Nature,1986, 322(6074):78–80.
[32] Balmain A,Harris CC. Carcinogenesis in mouse and human cells,parallels and paradoxes[J]. Carcinogenesis,2000,21(3):371–377.
[33] Brinster RL,Chen HY,Messing A,van Dyke T,Levine AJ,Palmiter RD. Transgenic mice harboring SV40 T-antigen genes develop characteristic brain tumours[J]. Cell,1984,37(2):367–379.
[34] Stewart TA , Pattengale PK , Leder P. Spontaneous mammary adenocarcin-omas in transgenic mice that carry and express MTV/myc fusion genes[J]. Cell,1984,38(3):627–637.
[35] Leder A,Pattengale PK,Kuo A,Stewart TA,Leder P. Consequences of widespread deregulation of the c-myc gene in transgenic mice,multiple neoplasms and normal development[J]. Cell , 1986 ,45(4):485–495.
[36] Robertson E,Bradley A,Kuehn M,Evans M. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector[J]. Nature.1986,323(6087):445–448.
[37] Thomas KR,Capecchi MR. Introduction of homologous DNA sequences into mammalian cells induces mutations in the cognate gene[J]. Nature,1986, 324(6092):34–38.
[38] Doetschman T,Maeda N,Smithies O. Targeted mutation of the Hprt gene in mouse embryonic stem cells[J]. Proc Natl Acad Sci USA,1988,85(22): 8583-8587.
[39] Donehower LA,Harvey M,Slagle BL,McArthur MJ,Montgomery Jr CA,Butel JS,et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours[J]. Nature,1992,356(6366):215–221.
[40] Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA. Weinberg RA effects of an RB mutation in the mouse[J]. Nature,1992,359(6393):295–300.
[41] Kemp CJ,Donehower LA,Bradley A,Balmain A. Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumours[J]. Cell,1993,74(5):813–822.
[42] Serrano M,Lee H,Chin L,Cordon-Cardo C,Beach D,DePinho RA. Role of the INK4a locus in tumour suppression and cell mortality[J].Cell,1996,85(1):27–37.
[43] Herzig M, Christofori G. Recent advances in cancer research,mouse mode ls of tumourigenesis[J]. Biochim BiopHys Acta , 2002 ,1602(2):97–113.
[44] Williams BO, Remington L, Albert DM, Mukai S, Bronson RT,Jacks T. Cooperative tumorigenic effects of germLine mutations in RB and p53[J]. Nat Genet,1994,7(4):480–484.
[45] Brodie SG, Xu X,Qiao W,Li WM,Cao L,Deng CX. Multiple genetic changes are associated with mammary tumorigenesis in BRCA1 conditional knockout mice[J]. Oncogene , 2001 ,20(51):7514–7523.
[46] Jonkers J, Berns A. Conditional mouse models of sporadic cancer[J]. Nat Rev Cancer,2002,2(4):251–265.
[47] Chan IT, Kutok JL,Williams IR,et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproli-Ferative disease[J]. J Clin Invest,2004,113(4):528–538.
[48] Chin L, Tam A, Pomerantz J,Wong M, Holash J,Bardeesy N,et al. Essential role for oncogenic Ras in tumour maintenance[J]. Nature,1999,400(6743): 468–472.
[49] Baron U, Bujard H. Tet repressor-based system for regulated gene expr- ession in eukaryotic cells,principles and advances[J]. Methods Enzymol,2000,327:401–421.
[50] Eilers M,Picard D,Yamamoto KR,Bishop JM. Chimaeras of myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells[J]. Nature,1989,340(6228):66–68.
[51] Pelengaris S,Littlewood T,Khan M,Elia G,Evan G. Reversible activati- on of c-Myc in skin, induction of a complex neoplastic pHenotype by a single oncogenic lesion[J]. Mol Cell , 1999 ,3(5):565–577.
[52] Horner J. Activated K-ras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma[J]. Genes Dev,2009,17(24): 312–317.
[53] Metzger D,Feil R. Engineering the mouse genome by site-specific re-combination[J]. Curr Opin Biotechnol,1999,10(5):470–476.
[54] Vooijs M,Jonkers J,Lyons S,Berns A. Non-invasive imaging of spo- ntaneous retinoblastoma pathway-dependent tumours in mice[J].Cancer Res,2002,62(6):1862–1867.
[55] Jonkers J,Meuwissen R,van der Gulden H,Peterse H,van derValk M,Berns A. Synergistic tumour suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer[J].Nat Genet,2001,29(4):418–425.
[56] Haase VH,Glickman JN,Socolovsky M,Jaenisch R. Vascular tumours in livers with targeted inactivation of the von Hippel–Lindau tumour suppressor[J]. Proc Natl Acad Sci USA , 2001 ,98(4):1583–1588.
[57] Giovannini M,Robanus-Maandag E,van der Valk M,Niwa-Kawakita M, Abramowski V,Goutebroze L,et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2[J]. Genes Dev,2000, 14(13):1617–1630.
[58] Xu X,Wagner KU,Larson D,Weaver Z,Li C,Ried T, et al. Conditional mutation of BRCA1 in mammary epithelial cells results in blunted ductal morpHogenesis and tumour formation[J].Nat Genet,1999,22(1):37–43.
[59] Meuwissen R,Linn SC,van der Valk M,Mooi WJ,Berns A. Mousemodel for lung tumourigenesis through Cre/lox controlled sporadic activation of the K-Ras oncogene[J]. Oncogene , 2001 ,20(45):6551–6558.
[60] Jackson EL,Willis N,Mercer K,Bronson RT,Crowley D,Montoya R, et al. Analysis of lung tumour initiation and progression using conditional expression of oncogenic K-ras[J]. Genes Dev 2001,15(24):3243–3248.
[61] Shibata H,Toyama K,Shioya H, Ito M, Hirota M, Hasegawa S,et al. Rapid colorectal adenoma formation initiated by conditional targeting of the APC gene[J]. Science,1997,278(5335):120–123.
[62] Ramirez-Solis R, Liu P, Bradley A. Chromosome engineering in mice[J]. Nature,1995,378(6558):720–724.
[63] Yu Y, Bradley A. Engineering chromosomal rearrangements in mice[J]. Nat Rev Genet,2001,2(10):780–790.
[48] Buchholz F, Refaeli Y, Trumpp A, Bishop JM. Inducible chromosomal translocation of AML1 and ETO genes through Cre/loxP-mediated recombination in the mouse[J]. EMBO Rep,2000,1(2):133–139.
[64] Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice[J]. Nature , 2001 ,410(6832):1111–1116.
[65] Hasty P, Ramirez-Solis R, KrumLauf R, Bradley A. Introduction of a subtle mutation into the Hox-2.6 locus in embryonic stem cells[J]. Nature,1991,350(6315):243–246.
[66] Holland EC. Gliommagenesis , genetic alterations and mousemodels[J]. Nat Rev Genet,2001,2(2):120–129.
[67] Meuwissen R, Linn SC, Linnoila RI, Zevenhoven J, Mooi WJ, Berns A. Induction of small cell lung cancer by somatic inactivation of both Trp53 and RB1 in a conditional mouse model[J]. Cancer Cell,2003,4(3): 181–189.
[68] Holland EC,Celestino J,Dai C,Schaefer L,Sawaya RE, Fuller GN. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice[J]. Nat Genet,2000,25(1):55–57.
[69] Xiao A,Wu H,Pandolfi PP,Louis DN,Van Dyke T. Astrocyte inact-ivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation[J]. Cancer Cell,2002,1(2): 157–168.
[70] Ludwig T,Fisher P,Murty V,Efstratiadis A. Development of mammary adenocarcinomas by tissue-specific knockout of BRCA2 in mice[J]. Oncogene,2001,20(30):3937–3948.
[71] Hingorani SR,Petricoin EF,Maitra A,et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse[J]. Cancer Cell,200,34(6): 437–450.
[72] Aguirre AJ,Bardeesy N,Sinha M,Lopez L,Tuveson DA,Horner J, et al. Activated K-ras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma[J]. Genes Dev,2003,17(24): 3112–31126.
[73] Weissleder R. Scaling down imaging,molecularmapping of cancer in mice[J].Nat Rev Cancer,2002,2(1):11–18.
[74] Fisher GH,Wellen SL,Klimsta D,et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a kras transgenein the presence and absence of tumor suppressor genes[J]. Genes Dev,2001,15(24):3249–3262.
[75] Massoud TF,Gambhir SS. Molecular imaging in living subjects,seeing fundamental biological processes in a new light[J]. Genes Dev,2003,17(5): 545–580.
[76] Haubner R,Wester HJ,Weber WA,et al. Non-invasive imaging of alp- ha(v)beta3 integrin expression using 18F-labeled RGD-containing gly- copeptide and positron emission tomograpHy[J]. Cancer Res,2001,61(5): 1781–1785.
[77] Herschman HR. Micro-PET imaging and small animal models of disease[J]. Curr Opin Immunol,2003,15(4):378–384.
[78] Gambhir SS,Barrio JR,Wu L,Iyer M,Namavari M,Satyamurthy N, et al. Imaging of adenoviral-directed herpes simplex virus type1 thymidine kinase reporter gene expression in mice with radiolabeled ganciclovir[J]. J Nucl Med,1998,39(11): 2003–2011.
[79] Girardi M,Oppenheim DE,Steele CR,et al. Regulation of cutaneous malignancy by gammadelta T cells[J]. Science 2001,294(5542),605–609.
[80] Hennings H,Glick AB,Greenhalgh DA,et al. Critical aspects of initiation, promotion,and progression in multistage epidermal carcinogenesis[J]. Proc Soc Exp Biol Med,1993,202(1):1–8.
[81] Perez-Losada J,Balmain A. Stem-cell hierarchy in skin cancer[J]. Nat Rev Cancer,2003,3(6):434–443.
[82] Rehman I,Lowry DT,Adams C,Abdel-Fattah R,Holly A,Yuspa SH,Hennings H. Frequent codon 12 Ki-ras mutations in mouse skintumours initiated by N-methyl-N0-nitro-N-nitrosoguanidine and promoted by mezerein[J]. Mol Carcinogen,2000.
[83] Megosh L,Halpern M,Farkash E,O’Brien TG. Analysis of ras gene mutational spectra in epidermal papillomas from K6/ODC transgenic mice[J]. Mol Carcinogen 1998,22(3),145–149.
[84] Aydinlik H,Nguyen TD,Moennikes O,Buchmann A,Schwarz M. Selective pressure during tumour promotion by pHenobarbital leads to clonal outgrowth of b-catenin-mutated mouse liver tumours[J]. Oncogene 2001,20(53),7812–7816.
[85] Williams CS,Mann M,DuBois RN. The role of cyclooxygenases in inflammation, cancer,and development[J]. Oncogene 1999,18(55),7908–7916.
[86] Shiff SJ,Shivaprasad P,Santini DL. Cyclooxygenase inhibitors drugs for cancer prevention[J]. Curr Opin PHarmacol 2003,3(4),352–361.
[87] Ponder BA. Cancer genetics[J]. Nature 2001,411(6835),336–341.
[88] Peto J. Cancer epidemiology in the last century and the next decade[J]. Nature 2001,411(6835),390–395.
[89] Balmain A. Cancer as a complex genetic trait,tumour susceptibility in humans and mouse models[J]. Cell 2002,108(2),145–152.
[90] Demant P. Cancer susceptibility in the mouse,genetics,biology and implications for human cancer[J]. Nat Rev Genet 2003,4(9),721–734.
[91] Mao JH,Balmain A. Genomic approaches to identification of tumour-susceptibility genes using mouse models[J]. Curr Opin Genet Dev 2003,13(1),14–19.
[92] Tripodis N,Hart AA,Fijneman RJ,Demant P.Complexity of lung cancer modifiers,mapping of 30 genes and 25 interactions in half ofthe mouse genome[J]. J Natl Cancer Inst 2001,93(19),1484– 1491.
[93] Nagase H, Mao JH,de Koning JP,Minami T,Balmain A. Epistatic interactions between skin tumour modifier loci in interspecific (spretus/musculus) backcross mice[J]. Cancer Res 2001,61(4),1305–1308.
[94] Mott R, Flint J. Simultaneous detection and fine mapping of quantitative trait loci in mice using heterogeneous stocks[J]. Genetics 2002,160(4),1609–1618.
[95] Ewart-Toland A,Briassouli P, de Koning JP,et al. Identification of Stk6/STK15 as a candidate low-penetrance tumour-susceptibility gene in mouse and human[J]. Nat Genet 2003,34(4),403–412.
[96] Ruivenkamp CA,van Wezel T,Zanon C,et al. Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers[J]. Nat Genet 2002,31(3),295–300.
[97] Bergers G,Javaherian K,Lo KM,Folkman J,Hanahan D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice[J]. Science 1999, 284(5415),808–812.
[98] Hanahan D,Weinberg RA. The hallmarks of cancer. Cell 2000, 100(1), 57–70.
[99] Ganss R,Hanahan D. Tumour microenvironment can restrict the effectiveness of activated antitumour lympHocytes[J]. Cancer Res 1998,58(20),4673–4681.
[100] Girardi M,Oppenheim DE,Steele CR,et al. Regulation of cutaneous malignancy by gammadelta T cells[J]. Science 2001,294(5542),605–609.
[101] Hanahan D,Lanzavecchia A,Mihich E. Fourteenth annual pezcollersymposium , the novel dichotomy of immune interactions with tumours[J]. Cancer Res 2003,63(11),3005– 3008.
[102] Staelens J,Wielockx B,Puimege L,et al. Hyporesponsiveness of SPRET/Ei mice to lethal shock induced by tumour necrosis factor and implications for a TNF-based antitumour therapy[J]. Proc Natl Acad Sci USA 2002,99(14),9340– 9345.
[103] Anderson A. Oncomouse released[J]. Nature 1988,336(6197),300.
[104] Marshall E. Intellectual property. NIH cuts deal on use of OncoMouse[J]. Science 2000,287(5453),567.
[105] Marshall E. Intellectual property. DuPont ups ante on use of Harvard’s OncoMouse[J]. Science 2002,296(5571),1212– 1213.
[106] Scholler FS,PHilips FS,Sternberg SS Bittner JJ. A comparative study of chemotherapeutic agents in spontaneous mammary adenocarcinomas of mice and in transplants of recent origin[J]. Cancer 1956,9(2),240–251.
[107] Gorre ME,Mohammed M,Ellwood K,et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification[J]. Science 2001,293(5531),876–880.
[108] von Bubnoff N, Schneller F,Peschel C, Duyster J. BCR-ABL gene mutations in relation to clinical resistance of PHiladelpHia-chromosome-positive leukaemia to STI571a prospective study[J]. Lancet 2002,9359(9305),487–491.
[109]蒋雪,杨洪粒.细胞凋亡及其在肿瘤发生发展和治疗中的作用[J].临床荟萃,1997
[110]王英,张锡林,何谐,等.日本血吸虫与斯氏狸殖虫交叉抗原的筛选和鉴定[J].中国血吸虫病防治杂志,2009,15(4):262-265
[111]骆伟,谢可鸣,胡永德,等.日本血吸虫与支睾吸虫和姜片虫之间的交叉抗原及其血清学反应性[J].使用寄生虫杂志,1994,5(2):124-126
[112]曾庆仁,陆予云,易薪元,等.日本血吸虫虫卵与旋毛虫肌幼间相似抗原的研究[J].中国寄生虫学与寄生虫病杂志,1997,8(3):362-365
[113]张国芬,马天根,孟衍建,等.人精子与大肠埃希氏菌抗原交叉反应的初步观察[J].男性学杂志,1990,4(4):196-199
[114]倪灿荣,戴益民.藻红蛋白与FITC免疫荧光组化染色的对比研究[J].第二军医大学学报,1992,9(6):76-78
[115]周琪,梁后杰,阎晓初,等.人结肠癌裸鼠原位移植瘤模型的建立[J].重庆医学,2007,7(7):82-85
[2] Lubiniecki AS,Cypess RH. Quantitative study of the effect of previous Trichinella spiralisinfection on sarcoma 180 ascitic tumor formation in mice[J]. Tropenmed Parasitol,1975,26(3):329-334.
[3] Molinari JA , Ebersole JL. Antineoplastic effects of long-term Trichinella spiralis infection on B-16 melanoma[J].Int Arch Allergy Appl immunol,1977; 55(1-6): 444-448.
[4] Molinari JA,Carrick L Jr,Lubiniecki AS. Influence of Trichinella spiralis infection on development of sarcoma-180 ascites tumors[J]. Trop enmed Parasitol,1979,30(4):429-433.
[5] Wing EJ,Krahenbuhl JL,Remington JS. Studies of macropHage function during Trichinella spiralis infection in mice[J].Immunology, 1979 Mar; 36(3): 479-485.
[6] Bellelli C, Frosi A, Chiovoloni M,et al . Trichinella spiralis as a modulator of Shope fibroma virus[J]. Parassitologia , 1989 ,31(2-3):145-152.
[7] Bany J,Janiak MK,Budzyński W. Activity of natural killer (NK) cells in the course of experimental trichinellosis in mice[J].Wiad Parazytol,1992,38(3-4):117-126.
[8] Wang XL,Fu BQ,Yang SJ,et al. Trichinella spiralis--a potential anti-tumor agent[J]. Vet Parasitol,2009,159(3-4):249-152.
[9] Gong P,Zhang J,Cao L, et al. Identification and characterization of myeloma-associated antigens in Trichinella spiralis[J]. Exp Parasitol,127(4):784-788.
[10]吴涛,张西臣,李建华,等.旋毛虫抗小鼠体内SP2/0肿瘤作用的研究[J].中国寄生虫病防治杂志,2005,18(6):445～447
[11]王学林,杨世杰,吴秀萍,等.旋毛虫重提蛋白对肝癌细胞H7402的抑制作用[J].中国肿瘤生物治疗杂志,2005,34(2):245-251
[12]谢春玲,瞿逢伊,汤英龙,等.旋毛虫感染小鼠血清对L929细胞的毒性作用[J].中国人兽共患病杂志,2001,28(5):273-275
[13] Meerovitch E,Bomford R. MacropHage potentiation by Trichinella spiralis[J]. Ann Trop Med Parasitol,1977,71(2):245-248
[14] Na HR,Seelig LL . In vitro TNF,IL-6 and IL-2 production by rat milk cells following Trichinella spiralis infection[J]. J Reprod Immunol,1993,25(2):119-131.
[15] Goyal PK,Wakelin D. Influence of variation in host strain and parasite isolate on inflammatory and antibody responses to Trichinella spiralis in mice[J]. Parasitology,1993,106(Pt4):371-378.
[16] Niborski V,Vallée I,Fonseca-Li?án R,Boireau P,Enciso A,Ortega-Pierres G,Yépez-Mulia L. Trichinella spiralis: stimulation of mast cells by TSL-1 antigens trigger cytokine mRNA expression and release of IL-4 and TNF through an Ig-independent pathway[J]. Exp Parasitol,2004,108(3-4):101-108.
[17] HumpHreys SR,Mantel N,Goldin A. Chemotherapy and surgery of spontaneous tumours of mice[J]. Eur J Cancer,1966,2:1–7.
[18] Shubik P. The growth potentialities of induced skin tumours in mice;the effects of different methods of chemical carcinogenesis[J].Cancer Res,1950,10:713–717.
[19] Hennings H, Boultwell RK. Studies on the mechanism of skin tumour promotion[J]. Cancer Res,1970,30(2):312–320.
[20] Watson JD , Berry A. DNA: The Secret of Life April 2003 publication[J]. Random House Trade ISBN 0-375-41546-7.
[21] Stehelin D,Varmus HE,Bishop JM, Vogt PK. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA[J]. Nature,1976,260:170–173.
[22] Shih C,Shilo BZ,Goldfarb MP,et al . Passage of pHenotypes of chemically transformed cells via transfection of DNA and chromatin[J]. Proc Natl Acad Sci USA,1979,76(11):5714–5718.
[23] Cooper GM,Neiman PE. Transforming genes of neoplasms induced by avian lympHoid leukosis viruses[J]. Nature , 1980 ,287(5783):656–659.
[24] Wigler M,Perucho M,Kurtz D,et al. Tra- nsformation of mammalian cells with an amplifiable dominantacting gene[J]. Proc Natl Acad Sci USA,1980,77(6):3567–3570.
[25] Tabin CJ,Bradley SM,Bargmann CI,et al. Mechanism of activation of a human oncogene[J]. Nature,1982,300(5888):143–149.
[26] Reddy EP,Reynolds RK,Santos E,Barbacid M. A point mutation is res- ponsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene[J]. Nature , 1982 ,300(5888):149–152.
[27] Taparowsky E,Suard Y,Fasano O,Shimizu K Goldfarb M,Wigler M. Ac- tivation of the T24 bladder carcinoma transforming gene islinked to a single amino acid change[J]. Nature.1982 ,300(5894):762–765.
[28] Balmain A,Pragnell IB. Mouse skin carcinomas induced in vivo by che- mical carcinogens have a transforming Harvey-ras oncogene[J]. Nature,1983, 303 (5912):72–74.
[29] Sukumar S,Notario V,Martin-Zanca D,Barbacid M. Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-ras-1 locus by single point mutations[J]. Nature,1983,306(5944): 658-661.
[30] Balmain A,Ramsden M,Bowden GT,Smith J. Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas[J]. Nature,1984, 307(5952):658–660.
[31] Quintanilla M,Brown K,Ramsden M,Balmain A. Carcinogenspecific mut- ation and amplification of Ha-ras during mouse skin carcinogenesis[J]. Nature,1986, 322(6074):78–80.
[32] Balmain A,Harris CC. Carcinogenesis in mouse and human cells,parallels and paradoxes[J]. Carcinogenesis,2000,21(3):371–377.
[33] Brinster RL,Chen HY,Messing A,van Dyke T,Levine AJ,Palmiter RD. Transgenic mice harboring SV40 T-antigen genes develop characteristic brain tumours[J]. Cell,1984,37(2):367–379.
[34] Stewart TA , Pattengale PK , Leder P. Spontaneous mammary adenocarcin-omas in transgenic mice that carry and express MTV/myc fusion genes[J]. Cell,1984,38(3):627–637.
[35] Leder A,Pattengale PK,Kuo A,Stewart TA,Leder P. Consequences of widespread deregulation of the c-myc gene in transgenic mice,multiple neoplasms and normal development[J]. Cell , 1986 ,45(4):485–495.
[36] Robertson E,Bradley A,Kuehn M,Evans M. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector[J]. Nature.1986,323(6087):445–448.
[37] Thomas KR,Capecchi MR. Introduction of homologous DNA sequences into mammalian cells induces mutations in the cognate gene[J]. Nature,1986, 324(6092):34–38.
[38] Doetschman T,Maeda N,Smithies O. Targeted mutation of the Hprt gene in mouse embryonic stem cells[J]. Proc Natl Acad Sci USA,1988,85(22): 8583-8587.
[39] Donehower LA,Harvey M,Slagle BL,McArthur MJ,Montgomery Jr CA,Butel JS,et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours[J]. Nature,1992,356(6366):215–221.
[40] Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA. Weinberg RA effects of an RB mutation in the mouse[J]. Nature,1992,359(6393):295–300.
[41] Kemp CJ,Donehower LA,Bradley A,Balmain A. Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumours[J]. Cell,1993,74(5):813–822.
[42] Serrano M,Lee H,Chin L,Cordon-Cardo C,Beach D,DePinho RA. Role of the INK4a locus in tumour suppression and cell mortality[J].Cell,1996,85(1):27–37.
[43] Herzig M, Christofori G. Recent advances in cancer research,mouse mode ls of tumourigenesis[J]. Biochim BiopHys Acta , 2002 ,1602(2):97–113.
[44] Williams BO, Remington L, Albert DM, Mukai S, Bronson RT,Jacks T. Cooperative tumorigenic effects of germLine mutations in RB and p53[J]. Nat Genet,1994,7(4):480–484.
[45] Brodie SG, Xu X,Qiao W,Li WM,Cao L,Deng CX. Multiple genetic changes are associated with mammary tumorigenesis in BRCA1 conditional knockout mice[J]. Oncogene , 2001 ,20(51):7514–7523.
[46] Jonkers J, Berns A. Conditional mouse models of sporadic cancer[J]. Nat Rev Cancer,2002,2(4):251–265.
[47] Chan IT, Kutok JL,Williams IR,et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproli-Ferative disease[J]. J Clin Invest,2004,113(4):528–538.
[48] Chin L, Tam A, Pomerantz J,Wong M, Holash J,Bardeesy N,et al. Essential role for oncogenic Ras in tumour maintenance[J]. Nature,1999,400(6743): 468–472.
[49] Baron U, Bujard H. Tet repressor-based system for regulated gene expr- ession in eukaryotic cells,principles and advances[J]. Methods Enzymol,2000,327:401–421.
[50] Eilers M,Picard D,Yamamoto KR,Bishop JM. Chimaeras of myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells[J]. Nature,1989,340(6228):66–68.
[51] Pelengaris S,Littlewood T,Khan M,Elia G,Evan G. Reversible activati- on of c-Myc in skin, induction of a complex neoplastic pHenotype by a single oncogenic lesion[J]. Mol Cell , 1999 ,3(5):565–577.
[52] Horner J. Activated K-ras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma[J]. Genes Dev,2009,17(24): 312–317.
[53] Metzger D,Feil R. Engineering the mouse genome by site-specific re-combination[J]. Curr Opin Biotechnol,1999,10(5):470–476.
[54] Vooijs M,Jonkers J,Lyons S,Berns A. Non-invasive imaging of spo- ntaneous retinoblastoma pathway-dependent tumours in mice[J].Cancer Res,2002,62(6):1862–1867.
[55] Jonkers J,Meuwissen R,van der Gulden H,Peterse H,van derValk M,Berns A. Synergistic tumour suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer[J].Nat Genet,2001,29(4):418–425.
[56] Haase VH,Glickman JN,Socolovsky M,Jaenisch R. Vascular tumours in livers with targeted inactivation of the von Hippel–Lindau tumour suppressor[J]. Proc Natl Acad Sci USA , 2001 ,98(4):1583–1588.
[57] Giovannini M,Robanus-Maandag E,van der Valk M,Niwa-Kawakita M, Abramowski V,Goutebroze L,et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2[J]. Genes Dev,2000, 14(13):1617–1630.
[58] Xu X,Wagner KU,Larson D,Weaver Z,Li C,Ried T, et al. Conditional mutation of BRCA1 in mammary epithelial cells results in blunted ductal morpHogenesis and tumour formation[J].Nat Genet,1999,22(1):37–43.
[59] Meuwissen R,Linn SC,van der Valk M,Mooi WJ,Berns A. Mousemodel for lung tumourigenesis through Cre/lox controlled sporadic activation of the K-Ras oncogene[J]. Oncogene , 2001 ,20(45):6551–6558.
[60] Jackson EL,Willis N,Mercer K,Bronson RT,Crowley D,Montoya R, et al. Analysis of lung tumour initiation and progression using conditional expression of oncogenic K-ras[J]. Genes Dev 2001,15(24):3243–3248.
[61] Shibata H,Toyama K,Shioya H, Ito M, Hirota M, Hasegawa S,et al. Rapid colorectal adenoma formation initiated by conditional targeting of the APC gene[J]. Science,1997,278(5335):120–123.
[62] Ramirez-Solis R, Liu P, Bradley A. Chromosome engineering in mice[J]. Nature,1995,378(6558):720–724.
[63] Yu Y, Bradley A. Engineering chromosomal rearrangements in mice[J]. Nat Rev Genet,2001,2(10):780–790.
[48] Buchholz F, Refaeli Y, Trumpp A, Bishop JM. Inducible chromosomal translocation of AML1 and ETO genes through Cre/loxP-mediated recombination in the mouse[J]. EMBO Rep,2000,1(2):133–139.
[64] Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice[J]. Nature , 2001 ,410(6832):1111–1116.
[65] Hasty P, Ramirez-Solis R, KrumLauf R, Bradley A. Introduction of a subtle mutation into the Hox-2.6 locus in embryonic stem cells[J]. Nature,1991,350(6315):243–246.
[66] Holland EC. Gliommagenesis , genetic alterations and mousemodels[J]. Nat Rev Genet,2001,2(2):120–129.
[67] Meuwissen R, Linn SC, Linnoila RI, Zevenhoven J, Mooi WJ, Berns A. Induction of small cell lung cancer by somatic inactivation of both Trp53 and RB1 in a conditional mouse model[J]. Cancer Cell,2003,4(3): 181–189.
[68] Holland EC,Celestino J,Dai C,Schaefer L,Sawaya RE, Fuller GN. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice[J]. Nat Genet,2000,25(1):55–57.
[69] Xiao A,Wu H,Pandolfi PP,Louis DN,Van Dyke T. Astrocyte inact-ivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation[J]. Cancer Cell,2002,1(2): 157–168.
[70] Ludwig T,Fisher P,Murty V,Efstratiadis A. Development of mammary adenocarcinomas by tissue-specific knockout of BRCA2 in mice[J]. Oncogene,2001,20(30):3937–3948.
[71] Hingorani SR,Petricoin EF,Maitra A,et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse[J]. Cancer Cell,200,34(6): 437–450.
[72] Aguirre AJ,Bardeesy N,Sinha M,Lopez L,Tuveson DA,Horner J, et al. Activated K-ras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma[J]. Genes Dev,2003,17(24): 3112–31126.
[73] Weissleder R. Scaling down imaging,molecularmapping of cancer in mice[J].Nat Rev Cancer,2002,2(1):11–18.
[74] Fisher GH,Wellen SL,Klimsta D,et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a kras transgenein the presence and absence of tumor suppressor genes[J]. Genes Dev,2001,15(24):3249–3262.
[75] Massoud TF,Gambhir SS. Molecular imaging in living subjects,seeing fundamental biological processes in a new light[J]. Genes Dev,2003,17(5): 545–580.
[76] Haubner R,Wester HJ,Weber WA,et al. Non-invasive imaging of alp- ha(v)beta3 integrin expression using 18F-labeled RGD-containing gly- copeptide and positron emission tomograpHy[J]. Cancer Res,2001,61(5): 1781–1785.
[77] Herschman HR. Micro-PET imaging and small animal models of disease[J]. Curr Opin Immunol,2003,15(4):378–384.
[78] Gambhir SS,Barrio JR,Wu L,Iyer M,Namavari M,Satyamurthy N, et al. Imaging of adenoviral-directed herpes simplex virus type1 thymidine kinase reporter gene expression in mice with radiolabeled ganciclovir[J]. J Nucl Med,1998,39(11): 2003–2011.
[79] Girardi M,Oppenheim DE,Steele CR,et al. Regulation of cutaneous malignancy by gammadelta T cells[J]. Science 2001,294(5542),605–609.
[80] Hennings H,Glick AB,Greenhalgh DA,et al. Critical aspects of initiation, promotion,and progression in multistage epidermal carcinogenesis[J]. Proc Soc Exp Biol Med,1993,202(1):1–8.
[81] Perez-Losada J,Balmain A. Stem-cell hierarchy in skin cancer[J]. Nat Rev Cancer,2003,3(6):434–443.
[82] Rehman I,Lowry DT,Adams C,Abdel-Fattah R,Holly A,Yuspa SH,Hennings H. Frequent codon 12 Ki-ras mutations in mouse skintumours initiated by N-methyl-N0-nitro-N-nitrosoguanidine and promoted by mezerein[J]. Mol Carcinogen,2000.
[83] Megosh L,Halpern M,Farkash E,O’Brien TG. Analysis of ras gene mutational spectra in epidermal papillomas from K6/ODC transgenic mice[J]. Mol Carcinogen 1998,22(3),145–149.
[84] Aydinlik H,Nguyen TD,Moennikes O,Buchmann A,Schwarz M. Selective pressure during tumour promotion by pHenobarbital leads to clonal outgrowth of b-catenin-mutated mouse liver tumours[J]. Oncogene 2001,20(53),7812–7816.
[85] Williams CS,Mann M,DuBois RN. The role of cyclooxygenases in inflammation, cancer,and development[J]. Oncogene 1999,18(55),7908–7916.
[86] Shiff SJ,Shivaprasad P,Santini DL. Cyclooxygenase inhibitors drugs for cancer prevention[J]. Curr Opin PHarmacol 2003,3(4),352–361.
[87] Ponder BA. Cancer genetics[J]. Nature 2001,411(6835),336–341.
[88] Peto J. Cancer epidemiology in the last century and the next decade[J]. Nature 2001,411(6835),390–395.
[89] Balmain A. Cancer as a complex genetic trait,tumour susceptibility in humans and mouse models[J]. Cell 2002,108(2),145–152.
[90] Demant P. Cancer susceptibility in the mouse,genetics,biology and implications for human cancer[J]. Nat Rev Genet 2003,4(9),721–734.
[91] Mao JH,Balmain A. Genomic approaches to identification of tumour-susceptibility genes using mouse models[J]. Curr Opin Genet Dev 2003,13(1),14–19.
[92] Tripodis N,Hart AA,Fijneman RJ,Demant P.Complexity of lung cancer modifiers,mapping of 30 genes and 25 interactions in half ofthe mouse genome[J]. J Natl Cancer Inst 2001,93(19),1484– 1491.
[93] Nagase H, Mao JH,de Koning JP,Minami T,Balmain A. Epistatic interactions between skin tumour modifier loci in interspecific (spretus/musculus) backcross mice[J]. Cancer Res 2001,61(4),1305–1308.
[94] Mott R, Flint J. Simultaneous detection and fine mapping of quantitative trait loci in mice using heterogeneous stocks[J]. Genetics 2002,160(4),1609–1618.
[95] Ewart-Toland A,Briassouli P, de Koning JP,et al. Identification of Stk6/STK15 as a candidate low-penetrance tumour-susceptibility gene in mouse and human[J]. Nat Genet 2003,34(4),403–412.
[96] Ruivenkamp CA,van Wezel T,Zanon C,et al. Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers[J]. Nat Genet 2002,31(3),295–300.
[97] Bergers G,Javaherian K,Lo KM,Folkman J,Hanahan D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice[J]. Science 1999, 284(5415),808–812.
[98] Hanahan D,Weinberg RA. The hallmarks of cancer. Cell 2000, 100(1), 57–70.
[99] Ganss R,Hanahan D. Tumour microenvironment can restrict the effectiveness of activated antitumour lympHocytes[J]. Cancer Res 1998,58(20),4673–4681.
[100] Girardi M,Oppenheim DE,Steele CR,et al. Regulation of cutaneous malignancy by gammadelta T cells[J]. Science 2001,294(5542),605–609.
[101] Hanahan D,Lanzavecchia A,Mihich E. Fourteenth annual pezcollersymposium , the novel dichotomy of immune interactions with tumours[J]. Cancer Res 2003,63(11),3005– 3008.
[102] Staelens J,Wielockx B,Puimege L,et al. Hyporesponsiveness of SPRET/Ei mice to lethal shock induced by tumour necrosis factor and implications for a TNF-based antitumour therapy[J]. Proc Natl Acad Sci USA 2002,99(14),9340– 9345.
[103] Anderson A. Oncomouse released[J]. Nature 1988,336(6197),300.
[104] Marshall E. Intellectual property. NIH cuts deal on use of OncoMouse[J]. Science 2000,287(5453),567.
[105] Marshall E. Intellectual property. DuPont ups ante on use of Harvard’s OncoMouse[J]. Science 2002,296(5571),1212– 1213.
[106] Scholler FS,PHilips FS,Sternberg SS Bittner JJ. A comparative study of chemotherapeutic agents in spontaneous mammary adenocarcinomas of mice and in transplants of recent origin[J]. Cancer 1956,9(2),240–251.
[107] Gorre ME,Mohammed M,Ellwood K,et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification[J]. Science 2001,293(5531),876–880.
[108] von Bubnoff N, Schneller F,Peschel C, Duyster J. BCR-ABL gene mutations in relation to clinical resistance of PHiladelpHia-chromosome-positive leukaemia to STI571a prospective study[J]. Lancet 2002,9359(9305),487–491.
[109]蒋雪,杨洪粒.细胞凋亡及其在肿瘤发生发展和治疗中的作用[J].临床荟萃,1997
[110]王英,张锡林,何谐,等.日本血吸虫与斯氏狸殖虫交叉抗原的筛选和鉴定[J].中国血吸虫病防治杂志,2009,15(4):262-265
[111]骆伟,谢可鸣,胡永德,等.日本血吸虫与支睾吸虫和姜片虫之间的交叉抗原及其血清学反应性[J].使用寄生虫杂志,1994,5(2):124-126
[112]曾庆仁,陆予云,易薪元,等.日本血吸虫虫卵与旋毛虫肌幼间相似抗原的研究[J].中国寄生虫学与寄生虫病杂志,1997,8(3):362-365
[113]张国芬,马天根,孟衍建,等.人精子与大肠埃希氏菌抗原交叉反应的初步观察[J].男性学杂志,1990,4(4):196-199
[114]倪灿荣,戴益民.藻红蛋白与FITC免疫荧光组化染色的对比研究[J].第二军医大学学报,1992,9(6):76-78
[115]周琪,梁后杰,阎晓初,等.人结肠癌裸鼠原位移植瘤模型的建立[J].重庆医学,2007,7(7):82-85