Establishment of a cervical cancer model via inoculating SiHa Cells into humanized severe combined immunodeficient mice

Purpose of investigation: To establish a human papillomavirus (HPV) 16 positive cervical cancer model in the humanized severe combined immunodeficient (SCID) mouse.

Methods: A HPV16 positive cervical carcinoma cell line (SiHa) was transplanted subcutaneously into SCID mice (SiHa-SCID); human peripheral blood lymphocyte (Hu-PBL) was transplanted intraperitoneally (Hu-PBL-SCID), Hu-PBL was transplated intraperitoneally and SiHa subcutaneously (Hu-PBL-SiHa-SCID), and, PBS was transplanted subcutaneously (PBS-SCID) as a control. The biological and immunological features were investigated.

Results: The transplanted tumor grew slowly and no metastasis was found. The survival time of Hu-PBL-SiHa-SCID was significantly longer than that of SiHa-SCID. HPV16 DNA could be detected in all of the tumor tissues, but not in peripheral blood and organ tissues. Human serum IgG levels in Hu-PBL-SCID and Hu-PBL-SiHa-SCID were significantly elevated following immuno-reconstructed time elongating, and significantly higher in Hu-PBL-SiHa-SCID than those in Hu-PBL-SCID. The numbers of human CD3+, CD4+ and CD8+ T cells were significantly increased in the peripheral blood and spleen of Hu-PBL-SiHa-SCID and Hu-PBL-SCID mice, and significantly higher in Hu-PBL-SiHa-SCID than those of Hu-PBL-SCID mice. The weight of the spleen was significantly increased in Hu-PBL-SiHa-SCID. Tumor infiltrating lymphocytes (TILs) and human CD4+ T cells were detected in Hu-PBL-SiHa-SCID but not in SiHa-SCID mice. The spleen cells of Hu-PBL-SiHa-SCID mice displayed significantly stronger cytotoxicity to target cells than those of SiHa-SCID mice. No graft-versus-host disease (GVHD) was found in either Hu-PBL or Hu-PBL-SiHa-SCID mice.

Conclusion: A HPV16 positive cervical carcinoma model has been successfully established in SCID mice. This model can perfectly simulate the biological features of spontaneous human cervical cancer, and present anti-tumor immune response after the human immune system is reconstructed.

Cercival carcinpma; HPV; SCID mice; Animal model

[1] Moniz M., Ling M.. Hung C.F., Wy T.C.: "HPV DNA vaccines". Front Biosci, 2003, 8, 55.

[2] Vizcaino A.P., Moreno V., Bosch F.X., Munoz N., Barros-D10s X.M.,B orras J. et al.: "International trends in incidence of cervical cancer: II. Squarnous-cell carcinoma". Int. J. Cancer, 2000, 86, 429.

[3] Walsh J.M.: "Cervical cancer: developments in screening and evaluation of the abnormal Pap smear". West J. Med.. 1998, 169, 304.

[4] Eiben G.L., da Silva D.M., Fausch S.C., Le Poole I.C., Nishimura M.I., Kast W.M.: "Cervical cancer vaccines: recent advances in HPV research". Viral Immunol, 2003, 16, 111.

[5] Bosch F.X., Manos M.M.. Munoz N., Sherman M., Jansen A.M.. Peto J. et al.: "Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group". J. Natl. Cancer Inst., 1995, 87, 796.

[6] Stoler M.H.: "Human papillornaviruses and cevical neoplas1a: a model for carcinogenesis". Int. J. Gynecol. Pathol., 2000. 19, 16.

[7] Porreca R.. Penn I., Droegenueller W.. Greer B., Makowski E "Gynecologic malignancies in imrnunosuppressed organo homograft recipients". Obstet. Gynecol., 1975, 45, 359.

[8] Wright T.C. Jr, Ellerbrock T.V., Chiasson M.A., Van Devanter N., Sun X.W.: "Cervical intraepithelial neoplasia in women infected with human immunodeficiency virus: prevalence, risk factors, and validity of Papanicolaou smears. New York Cervical Disease Study". Obstet. Gynecol., 1994, 84, 591.

[9] Sun X.W., Kuhn L., Ellerbrock T.V., Chiasson M.A., Bush T.J., Wright T.C. Jr.: "Human papillomavirus infection in women infected with the human immunodeficiency virus". N. Engl. J. Med., 1977, 337, 1343.

[10] Su P.F., Wu F.Y.-H.: "Differential suppression of the tumongemcity of Heal and SiHa cells by adeno-associated virus". Br. J. Cancer, 1996, 73, 1533.

[11] Gallo D., F erlini C., Distefano M., Cantelmo F., Gaggini C., Fattorossi A. et al.: "Anti-tumour activity of a panel of taxanes toward a cellular model of human cervical cancer". Cancer Chemother. Pharmacol., 2000, 45, 127.

[12] Williams S.S., Alosco T.R., Croy B.A., Bankert R.B.: "The study of human neoplastic disease in severe combined immunodeficient mice". Lab. Anim. Sci., 1993, 43, 139.

[13] Bonnet D., Warren E.H., Greenberg P.D., Dick J.E., Riddel S.R. "CD8 (+) minor histocompatib山ty antigen-specific cytotoxic T lymphocyte clones eliminate human acute nyeloid leukemia stem cells". Proc. Natl. Acad. Sci. USA, 1999, 96, 8639.

[14] Hu W.X., Zeng Z.J., Luo S.Q., Chen Q.: "Suicide gene theraphy of human breast cancer in SCID mice model by the regulation of Tet-On. Chin. Med. J. (Engl.), 2004, 117, 434.

[15] Krepler C., Wahceck V., Strommer S., Hartmann G., Polterauer P., Wolff K. et al.: "CpG oligonucleotides elicit anti tumor responses in a human melanoma NOD/SCID xenotransplantation mode". J Invest. Dermatol.. 2004, 122, 387.

[16] Mosier D.E.. Gulizia R.J., Baird S.M., Wilson D.B.: "Transfer of a functional human immune system to mice with severe combined immunodeficiency". Nature, 1988, 335, 256.

[17] Walker W., Gallagher G.: " T h e development of a noval immunotherapy model of human ovarian cancer in human PBLsevere combined immunodeficient (SCIO) mice". Clin. Exp. fmmunol., 1995, 101, 494.

[18] Schumacher U., Adam E., Horny H.P., Dietl J.:'Transplantat10nof a human ovarian cystadenocarcinoma into severe combined immunodeficient (SCIO) mice-formation of metastases without significant alteration of the tumour cell phenotype". Int. I. Exp Pathol., 1996, 77, 219.

[19] Walker W., Gallagher G.:'The in vivo production of specific human antibodies by vaccination of human-PBL-SCID mice" Immunology, 1994, 83, 163.

[20] Williamson L.M., Warwick R.M.:'Transfusion-associated graftversus-host disease and its prevention". Blood Rei,·,1995, 9, 251.

[21] Zhu H.,Y e D.,C hen H.,L u W,X ie X.: "Development of intraperitoneally transplantated human ovarian carcinoma model with immune reconstruction in severe combined immunodeficient mice". Zhonghua Yi Xue Za Zhi, 2002, 82, 630.

[22] Murase N., Starzl T.E., Tanabe M., Fujisaki S., Miyazawa H., Ye Q. et al.: "Variable chimerism, graft-versus-host disease, and tolerance after different kinds of cell and whole organ transplantation from Lewis to brown Norway rats". Transplantation, 1995, 60, 158.