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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: IL-12 treatment strongly increased the cell vaccine efficacy.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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mRNA expression of angiogenic and antiangiogenic molecules determined by reverse transcriptase PCR in Neu/H-2d mammary carcinoma cells treated in vitro with IFN-γ. GAPDH, 20 cycles; MIG, 35 cycles; IP-10, 28 cycles; MMP-9, 28 cycles. Densitometric analysis was performed and values reported under each band.
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fig8: mRNA expression of angiogenic and antiangiogenic molecules determined by reverse transcriptase PCR in Neu/H-2d mammary carcinoma cells treated in vitro with IFN-γ. GAPDH, 20 cycles; MIG, 35 cycles; IP-10, 28 cycles; MMP-9, 28 cycles. Densitometric analysis was performed and values reported under each band.

Mentions: In IFN-γ knockout Balb-neuT mice the combined administration of Neu/H-2q cells plus IL-12 was totally ineffective (Fig. 7) . This fading of the protection points to the crucial role of IFN-γ in the prevention observed. Along with its numerous immunomodulatory activities, IFN-γ may also directly modulate tumor cell phenotype and the in vivo behavior of tumor cells. Our results suggest that induced IFN-γ can affect the behavior of Neu/H-2d cells by inhibiting their angiogenic phenotype and the HER-2/neu–mediated signaling pathways leading to the neoplastic behavior (11). In vitro, IFN-γ inhibited the proliferation of Neu/H-2d cells, downmodulated their membrane expression of p185neu (which was even reduced by 80% by the combination of IFN-γ and TNF-α) and the production of the proangiogenic protease MMP-9, while it strongly upmodulated the production of antiangiogenic cytokines such as IP-10 and MIG (Fig. 8) .


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)

mRNA expression of angiogenic and antiangiogenic molecules determined by reverse transcriptase PCR in Neu/H-2d mammary carcinoma cells treated in vitro with IFN-γ. GAPDH, 20 cycles; MIG, 35 cycles; IP-10, 28 cycles; MMP-9, 28 cycles. Densitometric analysis was performed and values reported under each band.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: mRNA expression of angiogenic and antiangiogenic molecules determined by reverse transcriptase PCR in Neu/H-2d mammary carcinoma cells treated in vitro with IFN-γ. GAPDH, 20 cycles; MIG, 35 cycles; IP-10, 28 cycles; MMP-9, 28 cycles. Densitometric analysis was performed and values reported under each band.
Mentions: In IFN-γ knockout Balb-neuT mice the combined administration of Neu/H-2q cells plus IL-12 was totally ineffective (Fig. 7) . This fading of the protection points to the crucial role of IFN-γ in the prevention observed. Along with its numerous immunomodulatory activities, IFN-γ may also directly modulate tumor cell phenotype and the in vivo behavior of tumor cells. Our results suggest that induced IFN-γ can affect the behavior of Neu/H-2d cells by inhibiting their angiogenic phenotype and the HER-2/neu–mediated signaling pathways leading to the neoplastic behavior (11). In vitro, IFN-γ inhibited the proliferation of Neu/H-2d cells, downmodulated their membrane expression of p185neu (which was even reduced by 80% by the combination of IFN-γ and TNF-α) and the production of the proangiogenic protease MMP-9, while it strongly upmodulated the production of antiangiogenic cytokines such as IP-10 and MIG (Fig. 8) .

Bottom Line: IL-12 treatment strongly increased the cell vaccine efficacy.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