Interleukin 12–mediated Prevention of Spontaneous Mammary Adenocarcinomas in Two Lines of Her-2/neu Transgenic Mice

The ability of interleukin (IL)-12 to prevent tumors when administered to individuals with a genetic risk of cancer was studied in two lines of transgenic mice expressing rat HER-2/neu oncogene in the mammary gland. Female BALB/c (H-2d) mice carrying the activated HER-2/ neu oncogene show no morphological abnormalities of the mammary gland until 3 wk of age. They then progress through atypical hyperplasia to in situ lobular carcinoma and at 33 wk of age all 10 mammary glands display invasive carcinomas. Adult FVB mice (H-2q) carrying the HER-2/neu protooncogene develop mammary carcinomas with a longer latency (38-49 wk) and a lower multiplicity (mean of 2.6 tumors/mice). Treatment with IL-12 (5 daily intraperitoneal injections, 1 wk on, 3 wk off; the first course with 50 ng IL-12/day, the second with 100 ng IL-12/day) begun at 2 wk of age in BALB/c mice and at 21 wk of age in FVB mice markedly delayed tumor onset and reduced tumor multiplicity. Analogous results were obtained in immunocompetent and permanently CD8+ T lymphocyte–depleted mice. In both transgenic lines, tumor inhibition was associated with mammary infiltration of reactive cells, production of cytokines and inducible nitric oxide synthase, and reduction in microvessel number, in combination with a high degree of hemorrhagic necrosis.

[1]  R. Weinberg,et al.  Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts , 1981, Nature.

[2]  R. Cardiff,et al.  Activated neu Induces Rapid Tumor Progression (*) , 1996, The Journal of Biological Chemistry.

[3]  M. Colombo,et al.  Interleukin 12 potentiates the curative effect of a vaccine based on interleukin 2-transduced tumor cells. , 1996, Cancer research.

[4]  L. Old,et al.  Effect of interleukin 12 on tumor induction by 3-methylcholanthrene. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[5]  J. Wigginton,et al.  Interleukin 12 primes macrophages for nitric oxide production in vivo and restores depressed nitric oxide production by macrophages from tumor-bearing mice: implications for the antitumor activity of interleukin 12 and/or interleukin 2. , 1996, Cancer research.

[6]  C. Nathan,et al.  Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells , 1989, The Journal of experimental medicine.

[7]  P Signorelli,et al.  Antitumor efficacy of adenocarcinoma cells engineered to produce interleukin 12 (IL-12) or other cytokines compared with exogenous IL-12. , 1997, Journal of the National Cancer Institute.

[8]  Hiroshi Sato,et al.  Requirement for Vα14 NKT Cells in IL-12-Mediated Rejection of Tumors , 1997 .

[9]  R. Weinberg,et al.  Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[10]  C. Garlanda,et al.  Monoclonal antibodies specific for endothelial cells of mouse blood vessels. Their application in the identification of adult and embryonic endothelium. , 1994, European journal of cell biology.

[11]  G. Trinchieri.  Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. , 1995, Annual review of immunology.

[12]  J. Teruya-Feldstein,et al.  Mig, the monokine induced by interferon-gamma, promotes tumor necrosis in vivo. , 1997, Blood.

[13]  D. Hanahan,et al.  Induction of angiogenesis during the transition from hyperplasia to neoplasia , 1989, Nature.

[14]  P. Leder,et al.  IP-10, a -C-X-C- chemokine, elicits a potent thymus-dependent antitumor response in vivo , 1993, The Journal of experimental medicine.

[15]  R. Cardiff,et al.  Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Mihaela Skobe,et al.  Halting angiogenesis suppresses carcinoma cell invasion , 1997, Nature Medicine.

[17]  J. Teruya-Feldstein,et al.  Mig, the monokine induced by interferon-γ, promotes tumor necrosis in vivo , 1997 .

[18]  A. Villa,et al.  Early and multifocal tumors in breast, salivary, harderian and epididymal tissues developed in MMTY-Neu transgenic mice. , 1992, Cancer letters.

[19]  M. Cheever,et al.  Oncogenic proteins as tumor antigens. , 1996, Current opinion in immunology.

[20]  S. Aaronson,et al.  EGF receptor and erbB-2 tyrosine kinase domains confer cell specificity for mitogenic signaling. , 1990, Science.

[21]  G. Trinchieri,et al.  CD4 T cells inhibit in vivo the CD8‐mediated immune response against murine colon carcinoma cells transduced with interleukin‐12 genes , 1995, European journal of immunology.

[22]  C R King,et al.  erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. , 1987, Science.

[23]  G. Forni,et al.  Obligatory role of IFN-gamma in induction of lymphokine-activated and T lymphocyte killer activity, but not in boosting of natural cytotoxicity. , 1988, Journal of immunology.

[24]  A. Angiolillo,et al.  Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. , 1996, Blood.

[25]  R. D'Amato,et al.  Inhibition of angiogenesis in vivo by interleukin 12. , 1995, Journal of the National Cancer Institute.

[26]  Albert R. Jonsen,et al.  The advent of the ‘unpatients’ , 1996, Nature Medicine.

[27]  J. Finke,et al.  Cytokine and chemokine expression in tumors of mice receiving systemic therapy with IL-12. , 1996, Journal of immunology.