Limits...
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.

Show MeSH

Related in: MedlinePlus

Morphologic and immunohistochemical analysis of mammary glands. Histology shows that at week 15 the mammary tissue of control mice (A) contains numerous foci of atypical hyperplasia with areas of lobular carcinoma in situ; the hyperplastic and neoplastic epithelial cells occupy and fill out all the ductal-lobular structures. The hyperplastic foci found in mice receiving IL-12 (B) or Neu/H-2q cells plus IL-12 (C) are less numerous and prosperous than in control mice and surrounded by an evident reactive infiltrate. At 27 wk in mice treated with Neu/H-2q cells plus IL-12 the few surviving foci of hyperplasia (D) are surrounded by an evident infiltrate composed of reactive cells that sometimes are found within epithelial cells after crossing or damaging the basal membrane. Immunohistochemistry reveals that granulocytes (E) and CD8+ lymphocytes (F) are present not only in the stroma but also inside the lobular structure after crossing the damaged basal membrane (arrowheads). A–C, original magnification: ×200; D, original magnification: ×400; E and F, original magnification: ×630.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2195980&req=5

fig4: Morphologic and immunohistochemical analysis of mammary glands. Histology shows that at week 15 the mammary tissue of control mice (A) contains numerous foci of atypical hyperplasia with areas of lobular carcinoma in situ; the hyperplastic and neoplastic epithelial cells occupy and fill out all the ductal-lobular structures. The hyperplastic foci found in mice receiving IL-12 (B) or Neu/H-2q cells plus IL-12 (C) are less numerous and prosperous than in control mice and surrounded by an evident reactive infiltrate. At 27 wk in mice treated with Neu/H-2q cells plus IL-12 the few surviving foci of hyperplasia (D) are surrounded by an evident infiltrate composed of reactive cells that sometimes are found within epithelial cells after crossing or damaging the basal membrane. Immunohistochemistry reveals that granulocytes (E) and CD8+ lymphocytes (F) are present not only in the stroma but also inside the lobular structure after crossing the damaged basal membrane (arrowheads). A–C, original magnification: ×200; D, original magnification: ×400; E and F, original magnification: ×630.

Mentions: By the third week of age foci of atypical hyperplasia were evident in the numerous side buds (9, 16) of control mice and subsequently extended to all 10 mammary glands. Foci of carcinoma in situ first apparent around the fifteenth week (Fig. 4 A) evolved to invasive lobular carcinomas by the twentieth. 10 wk later invasive lobular carcinomas were present in all the glands.


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)

Morphologic and immunohistochemical analysis of mammary glands. Histology shows that at week 15 the mammary tissue of control mice (A) contains numerous foci of atypical hyperplasia with areas of lobular carcinoma in situ; the hyperplastic and neoplastic epithelial cells occupy and fill out all the ductal-lobular structures. The hyperplastic foci found in mice receiving IL-12 (B) or Neu/H-2q cells plus IL-12 (C) are less numerous and prosperous than in control mice and surrounded by an evident reactive infiltrate. At 27 wk in mice treated with Neu/H-2q cells plus IL-12 the few surviving foci of hyperplasia (D) are surrounded by an evident infiltrate composed of reactive cells that sometimes are found within epithelial cells after crossing or damaging the basal membrane. Immunohistochemistry reveals that granulocytes (E) and CD8+ lymphocytes (F) are present not only in the stroma but also inside the lobular structure after crossing the damaged basal membrane (arrowheads). A–C, original magnification: ×200; D, original magnification: ×400; E and F, original magnification: ×630.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Morphologic and immunohistochemical analysis of mammary glands. Histology shows that at week 15 the mammary tissue of control mice (A) contains numerous foci of atypical hyperplasia with areas of lobular carcinoma in situ; the hyperplastic and neoplastic epithelial cells occupy and fill out all the ductal-lobular structures. The hyperplastic foci found in mice receiving IL-12 (B) or Neu/H-2q cells plus IL-12 (C) are less numerous and prosperous than in control mice and surrounded by an evident reactive infiltrate. At 27 wk in mice treated with Neu/H-2q cells plus IL-12 the few surviving foci of hyperplasia (D) are surrounded by an evident infiltrate composed of reactive cells that sometimes are found within epithelial cells after crossing or damaging the basal membrane. Immunohistochemistry reveals that granulocytes (E) and CD8+ lymphocytes (F) are present not only in the stroma but also inside the lobular structure after crossing the damaged basal membrane (arrowheads). A–C, original magnification: ×200; D, original magnification: ×400; E and F, original magnification: ×630.
Mentions: By the third week of age foci of atypical hyperplasia were evident in the numerous side buds (9, 16) of control mice and subsequently extended to all 10 mammary glands. Foci of carcinoma in situ first apparent around the fifteenth week (Fig. 4 A) evolved to invasive lobular carcinomas by the twentieth. 10 wk later invasive lobular carcinomas were present in all the glands.

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