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Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice.

Nanni P, Nicoletti G, De Giovanni C, Landuzzi L, Di Carlo E, Cavallo F, Pupa SM, Rossi I, Colombo MP, Ricci C, Astolfi A, Musiani P, Forni G, Lollini PL - J. Exp. Med. (2001)

Bottom Line: The mammary glands of mice receiving the combined treatment displayed a markedly reduced epithelial cell proliferation, angiogenesis, and HER-2/neu expression, while the few hyperplastic foci were heavily infiltrated by granulocytes, macrophages, and CD8(+) lymphocytes.Specific anti-HER-2/neu antibodies were produced and a nonpolarized activation of CD4(+) and CD8(+) cells secreting IL-4 and interferon (IFN)-gamma were evident.In conclusion, our data show that an allogeneic HER-2/neu-expressing cell vaccine combined with IL-12 systemic treatment can prevent the onset of genetically determined tumors.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Section, Department of Experimental Pathology, University of Bologna, Italy.

ABSTRACT
Transgenic Balb/c mice expressing the transforming rat HER-2/neu oncogene develop early and multifocal mammary carcinomas. Within the first 5 months of life the tissue-specific expression of HER-2/neu causes a progression in all their 10 mammary glands from atypical hyperplasia to invasive carcinoma. It was previously observed that chronic administration of interleukin (IL)-12 increased tumor latency, but every mouse eventually succumbed to multiple carcinomas. A significant improvement in tumor prevention was sought by administering allogeneic mammary carcinoma cells expressing HER-2/neu combined with systemic IL-12. This treatment reduced tumor incidence by 90% and more than doubled mouse lifetime. For the maximum prevention p185(neu) antigen must be expressed by allogeneic cells. IL-12 treatment strongly increased the cell vaccine efficacy. The mammary glands of mice receiving the combined treatment displayed a markedly reduced epithelial cell proliferation, angiogenesis, and HER-2/neu expression, while the few hyperplastic foci were heavily infiltrated by granulocytes, macrophages, and CD8(+) lymphocytes. Specific anti-HER-2/neu antibodies were produced and a nonpolarized activation of CD4(+) and CD8(+) cells secreting IL-4 and interferon (IFN)-gamma were evident. A central role for IFN-gamma in the preventive effect was proven by the lack of efficacy of vaccination in IFN-gamma gene knockout HER-2/neu transgenic Balb/c mice. A possible requirement for IFN-gamma is related to its effect on antibody production, in particular on IgG2a and IgG2b subclasses, that were not induced in IFN-gamma knockout HER-2/neu mice. In conclusion, our data show that an allogeneic HER-2/neu-expressing cell vaccine combined with IL-12 systemic treatment can prevent the onset of genetically determined tumors.

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Inhibition of mammary carcinogenesis in Balb-neuT female mice. Groups of 7–8 mice received the indicated treatments. Tumor-free survival curve of mice treated with Neu/H-2q cells plus IL-12 is significantly different from all other curves (P < 0.005 at least by the Mantel-Haenszel test); tumor-free survival curves of mice treated with IL-12 or Neu/H-2q cells are significantly different (P < 0.05 at least) from MSA controls. Tumor multiplicity is calculated as the cumulative number of incident tumors/total number of mice and is shown as mean ± SEM.
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fig2: Inhibition of mammary carcinogenesis in Balb-neuT female mice. Groups of 7–8 mice received the indicated treatments. Tumor-free survival curve of mice treated with Neu/H-2q cells plus IL-12 is significantly different from all other curves (P < 0.005 at least by the Mantel-Haenszel test); tumor-free survival curves of mice treated with IL-12 or Neu/H-2q cells are significantly different (P < 0.05 at least) from MSA controls. Tumor multiplicity is calculated as the cumulative number of incident tumors/total number of mice and is shown as mean ± SEM.

Mentions: This combined treatment effectively inhibited the development of mammary carcinomas (Fig. 2) . All control mice developed their first mammary tumor within 22 wk, when all mice treated with Neu/H-2q cells plus IL-12 were completely tumor free. Within 30 wk all control mice developed tumors in all 10 mammary glands. At 52 wk (end of the study) 88% of mice treated with Neu/H-2q cells plus IL-12 were still completely tumor free; their lifetime was more than doubled.


Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice.

Nanni P, Nicoletti G, De Giovanni C, Landuzzi L, Di Carlo E, Cavallo F, Pupa SM, Rossi I, Colombo MP, Ricci C, Astolfi A, Musiani P, Forni G, Lollini PL - J. Exp. Med. (2001)

Inhibition of mammary carcinogenesis in Balb-neuT female mice. Groups of 7–8 mice received the indicated treatments. Tumor-free survival curve of mice treated with Neu/H-2q cells plus IL-12 is significantly different from all other curves (P < 0.005 at least by the Mantel-Haenszel test); tumor-free survival curves of mice treated with IL-12 or Neu/H-2q cells are significantly different (P < 0.05 at least) from MSA controls. Tumor multiplicity is calculated as the cumulative number of incident tumors/total number of mice and is shown as mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195980&req=5

fig2: Inhibition of mammary carcinogenesis in Balb-neuT female mice. Groups of 7–8 mice received the indicated treatments. Tumor-free survival curve of mice treated with Neu/H-2q cells plus IL-12 is significantly different from all other curves (P < 0.005 at least by the Mantel-Haenszel test); tumor-free survival curves of mice treated with IL-12 or Neu/H-2q cells are significantly different (P < 0.05 at least) from MSA controls. Tumor multiplicity is calculated as the cumulative number of incident tumors/total number of mice and is shown as mean ± SEM.
Mentions: This combined treatment effectively inhibited the development of mammary carcinomas (Fig. 2) . All control mice developed their first mammary tumor within 22 wk, when all mice treated with Neu/H-2q cells plus IL-12 were completely tumor free. Within 30 wk all control mice developed tumors in all 10 mammary glands. At 52 wk (end of the study) 88% of mice treated with Neu/H-2q cells plus IL-12 were still completely tumor free; their lifetime was more than doubled.

Bottom Line: The mammary glands of mice receiving the combined treatment displayed a markedly reduced epithelial cell proliferation, angiogenesis, and HER-2/neu expression, while the few hyperplastic foci were heavily infiltrated by granulocytes, macrophages, and CD8(+) lymphocytes.Specific anti-HER-2/neu antibodies were produced and a nonpolarized activation of CD4(+) and CD8(+) cells secreting IL-4 and interferon (IFN)-gamma were evident.In conclusion, our data show that an allogeneic HER-2/neu-expressing cell vaccine combined with IL-12 systemic treatment can prevent the onset of genetically determined tumors.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Section, Department of Experimental Pathology, University of Bologna, Italy.

ABSTRACT
Transgenic Balb/c mice expressing the transforming rat HER-2/neu oncogene develop early and multifocal mammary carcinomas. Within the first 5 months of life the tissue-specific expression of HER-2/neu causes a progression in all their 10 mammary glands from atypical hyperplasia to invasive carcinoma. It was previously observed that chronic administration of interleukin (IL)-12 increased tumor latency, but every mouse eventually succumbed to multiple carcinomas. A significant improvement in tumor prevention was sought by administering allogeneic mammary carcinoma cells expressing HER-2/neu combined with systemic IL-12. This treatment reduced tumor incidence by 90% and more than doubled mouse lifetime. For the maximum prevention p185(neu) antigen must be expressed by allogeneic cells. IL-12 treatment strongly increased the cell vaccine efficacy. The mammary glands of mice receiving the combined treatment displayed a markedly reduced epithelial cell proliferation, angiogenesis, and HER-2/neu expression, while the few hyperplastic foci were heavily infiltrated by granulocytes, macrophages, and CD8(+) lymphocytes. Specific anti-HER-2/neu antibodies were produced and a nonpolarized activation of CD4(+) and CD8(+) cells secreting IL-4 and interferon (IFN)-gamma were evident. A central role for IFN-gamma in the preventive effect was proven by the lack of efficacy of vaccination in IFN-gamma gene knockout HER-2/neu transgenic Balb/c mice. A possible requirement for IFN-gamma is related to its effect on antibody production, in particular on IgG2a and IgG2b subclasses, that were not induced in IFN-gamma knockout HER-2/neu mice. In conclusion, our data show that an allogeneic HER-2/neu-expressing cell vaccine combined with IL-12 systemic treatment can prevent the onset of genetically determined tumors.

Show MeSH
Related in: MedlinePlus