Palabras clave
imunologia
tumor experimental
modelos murinos
tumorigênese
células tumorais
Cómo citar
Resumen
Nos últimos anos, a pesquisa do câncer proporcionou avanços importantes quanto à complexidade de desenvolvimento do tumor, em particular, sobre os mecanismos moleculares que são a base da transformação progressiva de células normais em derivados altamente malignos. A análise molecular do desenvolvimento tumoral em pacientes não é trivial, pois necessita da disponibilidade de biópsias em diversos estágios de transformação. Além disso, os estudos dos processos de metástase, de angiogênese e da resposta imune contra os tumores in vitro não mimetizam o que ocorre in vivo. Por esta razão, os modelos murinos experimentais de câncer têm desempenhado papel vital na compreensão da tumorigênese e suas relações com o ambiente in vivo, em que existe a dificuldade de avaliação de novos métodos diagnósticos e as ações terapêuticas de drogas contra tumores em pacientes. Nesta revisão, são discutidas as abordagens experimentais, técnicas e estratégias utilizadas no estudo de tumores em modelos murinos com ênfase na resposta imune contra o câncer e, ainda, as limitações conceituais e clínicas de cada sistema na sua aplicação no estudo do câncer em humanos.Citas
1. Conmy S, Nasheuer HP. The use of transgenic mice in cancer and genome stability research. Subcell Biochem 2010;50:325-36.
2. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100(1):57-70.
3. Instituto Nacional de Câncer - INCA. Atlas TNM. Classificação de Tumores Malignos. 6ª ed. Springer - Verlag; 2004.
4. Hann B, Balmain A. Building validated mouse models of human cancer. Curr Opin Biol 2001;13(6):778-84.
5. Kim HS, Cho HR, Choi SH, Woo JS, Moon WK. In vivo imaging of tumor transduced with bimodal lentiviral vector encoding human ferritin and green fluorescent protein on a 1.5T clinical magnetic resonance scanner.Cancer Res 2010;70(18):7315-24.
6. Wei S, Sun Y, Yang Z, Song Y. Establishment of orthotopic lung cancer model expressing enhanced green fluorescent protein.Zhongguo Fei Ai Za Zhi 2010;13(7):670-5.
7. Kaneko K, Yano M, Yamano T, Tsujinaka T, Miki H, Akiyama Y et al. Detection of peritoneal micrometastases of gastric carcinoma with green fluorescent protein and carcinoembryonic antigen promoter. Cancer Res 2001;61(14):5570-4.
8. Huang DC, Cory S, Strasser A. Bcl-2, Bcl-XL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death. Oncogene 1997;14(4):405-14.
9. MacDonald TJ, Tabrizi P, Shimada H, Zlokovic BV, Laug WE. Detection of brain tumor invasion and micrometastasis in vivo by expression of enhaced green fluorescent protein. Neurosurgery 1998;43(6):1437-42.
10. Li X, Wang J, An Z, Yang M, Baranov E, Jiang P et al. Opitically imageable metastatic model of human brest cancer. Clin Exp Metastasis 2002;19(4):347-50.
11. Sturn JW, Keese MA, Petruch B, Bonninghoff RG, Zhang H, Gretz N et al. Enhanced green fluorescent protein-transfection of murine colon carcinoma cells: key for early tumor detection and qualification. Clin Exp Metastasis 2003;20(5):395-405.
12. de Jong M, Maina T. Of mice and humans: are they the same? - Implications in cancer translational research. J Nucl Med 2010;51(4):501-4.
13. Clarke R. Human breast cancer cell line xenografts as models of breast cancer. Th immunobiologies of recipient mice and the characteristics of several tumorigenic cell lines. Breast Cancer Res Treat 1996;39(1):69-86.
14. van Muijen GN, Jansen KF, Cornelissen IM, Smeets DF, Beck JL, Ruiter DJ. Establishment and characterization of a human melanoma cell line (MV3) which is highly metastaic in nude mice. Int J Cancer 1991;48(1):85-91.
15. Roodman GD. Mechanisms of bone lesions in mutiple myeloma and lymphoma. Cancer 1997;80(Suppl 8):1557-63.
16. Hillman GG, Singh-Gupta V, Al-Bashir AK, Zhang H, Yunker CK, Patel AD et al. Dynamic contrast-enhanced magnetic resonance imaging of sunitinib-induced vascular changes to schedule chemotherapy in renal cell carcinoma xenograft tumors.Transl Oncol. 2010;3(5):293-306.
17. Kim IK, Baek SH. Mouse models for breast cancer metastasis. Biochem Biophys Res Commun 2010;394(3):443-7.
18. Arbeit JM, Munger K, Howley PM, Hanahan D. Neuroepithelial carcinomas in mice transgenic with human papillomavirus type 16 E6/E7 ORFs. Am J Pathol 1993;142(4):1187-97.
19. Lane DP. Cancer. P53, guardian of the genome. Nature 1992;358(6381):15-6.
20. Donehower LA. The p53-deficient mouse: a model for basic and applied cancer studies. Semin Cancer Biol 1996;7(5):269-78.
21. 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. Nature 2001;410(6832):1111-6.
22. Resor L, Bowen TJ, Wynshaw-Boris A. Unraveling human cancer in the mouse: recent refinements to modeling and analysis. Hum Mol Genet 2001;10(7):669-75.
23. Bernardi R, Grisendi S, Pandolfi PP. Modeling haematopoietic malignancies in the mouse and therapeutical implications. Oncogene 2002;21(21):3445-58.
24. Ren R. Modeling the dosage effect of oncogenes in leukemogenesis. Curr Opin Hematol 2004;11(1):25-34.
25. Sengupta N, MacFie TS, MacDonald TT, Pennington D, Silver AR. Cancer immunoediting and “spontaneus” tumor regression. Pathol Res Pract 2010;206(1):1-8.
26. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004;21(2):137-48.
27. Malmberg KJ, Ljunggren HG. Escape from immune- and nonimmune-mediated tumor surveillance. Semin Cancer Biol 2006;16(1):16-31.
28. Mincheff M. Immunosurveillance and immunoediting - can the immune response be made more “immunodemocratic”? J BUON 2010;14(Suppl 1):S89-96.
29. Karre K, Ljunggren HG, Piontek G, Kiessling R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 1986;319(6055):675-8.
30. Chang CC, Campoli M, Ferrone S. HLA class I antigen expression in malignant cells: why does it not always correlate with CTL-mediated lysis? Curr Opin Immunol 2004;16(5):644-50.
31. Powis SJ, Townsend AR, Deverson EV, Bastin J, Butcher GW, Howard JC. Restoration of antigen presentation to the mutant cell line RMA-S by MHC-linked transporter. Nature 1991;354(6354):528-31.
32. Attaya M, Jameson S, Martinez CK, Hermel E, Aldrich C, Forman J et al. Ham-2 corrects the class I antigen-processing defect in RMA-S cells. Nature 1992;355(6361):647-9.
33. Yang Y, Früh K, Chambers J, Waters JB, Wu L, Spies T et al. Major histocompatibility complex (MHC)-encoded HAM2 is necessary for antigenic peptide loading onto class I MHC molecules. J Biol Chem 1992;267(17):11669-72.
34. Kleijmeer MJ, Kelly A, Geuze HJ, Slot JW, Townsend A, Trowsdale J.Location of MHC-encoded transporters in the endoplasmic reticulum and cis-Golgi. Nature 1992;357(6376):342-4.
35. Townsend A, Bodmer H. Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol 1989;7:601-24.
36. Sabapathy K, Nam SY. Defective MHC class I antigen surface expression promotes cellular survival through elevated ER stress and modulation of p53 function. Cell Death Differ 2008;15(9):1364-74.
37. Levine AJ, Hu W, Feng Z. The P53 pathway: what questions remain to be explored? Cell Death Differ 2006;13(6):1027-36.
38. Aylon Y, Oren M. Living with p53, dying of p53. Cell 2007;130(4):597-600.
39. Grufman P, Kärre K. Innate and adaptive immunity to tumors: IL-12 is required for optimal responses. Eur J Immunol 2000;30(4):1088-93.
40. Humblet C, Greimers R, Boniver J, Defrense MP. Stages in the development of radiation-induced thymic lymphomas in C57 BL/Ka mice: preleukemic cells become progressively resistant to the tumor preventing effects of a bone marrow graft. Exp Hematol 1997;25(2):109-13.
Esta obra está bajo una licencia internacional Creative Commons Atribución 4.0.
Derechos de autor 2010 Revista del Instituto Adolfo Lutz