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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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Mammary tissue from untreated 27-wk-old mice (A and B), mice receiving IL-12 (C and D), or Neu/H-2q cells plus IL-12 (E and F). Immunohistochemistry with anti-p185neu antibody reveals that all the neoplastic cells express the p185neu in the cytoplasm and on their membrane (A). A similar p185neu expression pattern is evident in the mammary epithelial cells of the carcinoma in situ present in the IL-12–treated mouse (C). The cytoplasmic and membrane expression of the p185neu is associated with a marked positivity of PCNA (B and D). The mammary glands of mice treated with Neu/H-2q cells plus IL-12 are mainly composed of ductules lined by a single layer of epithelial cells without or with a slight p185neu expression mainly confined in the epithelial cell cytoplasm (E); the epithelial proliferation rate was low as assessed by PCNA positivity (F). A–F, original magnification: ×400.
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fig5: Mammary tissue from untreated 27-wk-old mice (A and B), mice receiving IL-12 (C and D), or Neu/H-2q cells plus IL-12 (E and F). Immunohistochemistry with anti-p185neu antibody reveals that all the neoplastic cells express the p185neu in the cytoplasm and on their membrane (A). A similar p185neu expression pattern is evident in the mammary epithelial cells of the carcinoma in situ present in the IL-12–treated mouse (C). The cytoplasmic and membrane expression of the p185neu is associated with a marked positivity of PCNA (B and D). The mammary glands of mice treated with Neu/H-2q cells plus IL-12 are mainly composed of ductules lined by a single layer of epithelial cells without or with a slight p185neu expression mainly confined in the epithelial cell cytoplasm (E); the epithelial proliferation rate was low as assessed by PCNA positivity (F). A–F, original magnification: ×400.

Mentions: Immunohistochemical examination after the second course (fifteenth week of age) revealed a reduction of hyperplastic foci and TEBs containing epithelial cells expressing p185neu. At 27 wk, the mammary tissue of mice treated with Neu/H-2q cells plus IL-12 was only constituted by small ducts lined by a single layer of epithelial cells without or with a slight p185neu expression confined to the cytoplasm (Fig. 5 A, C, and E) associated with a poor positivity to PCNA (Fig. 5 B, D, and F). By contrast, a marked cytoplasmic and membrane p185neu expression, similar to hyperplastic and neoplastic lesions from untreated and IL-12–treated mice, was displayed by the few carcinomas detected in mice treated with IL-12 and cell vaccine.


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)

Mammary tissue from untreated 27-wk-old mice (A and B), mice receiving IL-12 (C and D), or Neu/H-2q cells plus IL-12 (E and F). Immunohistochemistry with anti-p185neu antibody reveals that all the neoplastic cells express the p185neu in the cytoplasm and on their membrane (A). A similar p185neu expression pattern is evident in the mammary epithelial cells of the carcinoma in situ present in the IL-12–treated mouse (C). The cytoplasmic and membrane expression of the p185neu is associated with a marked positivity of PCNA (B and D). The mammary glands of mice treated with Neu/H-2q cells plus IL-12 are mainly composed of ductules lined by a single layer of epithelial cells without or with a slight p185neu expression mainly confined in the epithelial cell cytoplasm (E); the epithelial proliferation rate was low as assessed by PCNA positivity (F). A–F, original magnification: ×400.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2195980&req=5

fig5: Mammary tissue from untreated 27-wk-old mice (A and B), mice receiving IL-12 (C and D), or Neu/H-2q cells plus IL-12 (E and F). Immunohistochemistry with anti-p185neu antibody reveals that all the neoplastic cells express the p185neu in the cytoplasm and on their membrane (A). A similar p185neu expression pattern is evident in the mammary epithelial cells of the carcinoma in situ present in the IL-12–treated mouse (C). The cytoplasmic and membrane expression of the p185neu is associated with a marked positivity of PCNA (B and D). The mammary glands of mice treated with Neu/H-2q cells plus IL-12 are mainly composed of ductules lined by a single layer of epithelial cells without or with a slight p185neu expression mainly confined in the epithelial cell cytoplasm (E); the epithelial proliferation rate was low as assessed by PCNA positivity (F). A–F, original magnification: ×400.
Mentions: Immunohistochemical examination after the second course (fifteenth week of age) revealed a reduction of hyperplastic foci and TEBs containing epithelial cells expressing p185neu. At 27 wk, the mammary tissue of mice treated with Neu/H-2q cells plus IL-12 was only constituted by small ducts lined by a single layer of epithelial cells without or with a slight p185neu expression confined to the cytoplasm (Fig. 5 A, C, and E) associated with a poor positivity to PCNA (Fig. 5 B, D, and F). By contrast, a marked cytoplasmic and membrane p185neu expression, similar to hyperplastic and neoplastic lesions from untreated and IL-12–treated mice, was displayed by the few carcinomas detected in mice treated with IL-12 and cell vaccine.

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