Multiple roles of perforin in hampering ERBB-2 (Her-2/neu) carcinogenesis in transgenic male mice.
Perforin (pfp)-mediated cytotoxicity is one of the principal immunosurveillance mechanisms involved in the fight against cancer. However, its importance in spontaneous epithelial cancer is still poorly defined. In this study, we use a realistic mouse model that displays many features that are equivalent to human pathology to evaluate the role of pfp-dependent immunosurveillance by comparing tumor progression in rat ERBB-2 (neu) transgenic, pfp-proficient (neu(+)/pfp(+)) or pfp-deficient (neu(+)/pfp(-)) BALB/c male mice. Adult neu(+)/pfp(+) males developed poorly differentiated salivary carcinomas, whereas neu(+)/pfp(-) males displayed their salivary carcinomas noticeably earlier and showed zones of more highly differentiated tumor, indicating that pfp-mediated immunosurveillance is able not only to delay the growth kinetic of an aggressive epithelial tumor, but also to shape its histology. The role of pfp-mediated immunosurveillance appeared to be of even more dramatic importance against the less aggressive male mammary carcinomas. In neu(+)/pfp(+) males, the incidence of mammary carcinomas was a sporadic and late event. In contrast, in neu(+)/pfp(-) males their incidence was four-fold higher. This higher cancer incidence was associated with a 2-fold higher occurrence of persisting mammary remnants, a major risk factor for mammary cancer in male mice, and one that would appear to be due to pfp's previously unidentified involvement in male mammary gland rejection during embryogenesis. This work thus provides further proof of the complex role that the immune system plays in the body and gives new insight into the pathogenesis of epithelial tumors, demonstrating that the penetrance and malignancy of a tumor may be dramatically affected by pfp-dependent mechanisms.
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy;
Marco
M
Macagno
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy;
Silvio
S
Bandini
Aging Research Center, G. D'Annunzio University Foundation, 66013 Chieti, Italy;
Lorenzo
L
Stramucci
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy;
Elena
E
Quaglino
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy;
Laura
L
Conti
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy;
Elisa
E
Balmas
Immunology in Cancer and Infection Laboratory, Queensland Institute of Medical Research, Herston, Queensland 4006, Australia; School of Medicine, University of Queensland, Herston, Queensland 4006, Australia; and.
Mark J
MJ
Smyth
Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40126 Bologna, Italy.
Pier-Luigi
PL
Lollini
Aging Research Center, G. D'Annunzio University Foundation, 66013 Chieti, Italy;
Piero
P
Musiani
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy;
Guido
G
Forni
Aging Research Center, G. D'Annunzio University Foundation, 66013 Chieti, Italy;
Manuela
M
Iezzi
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy; federica.cavallo@unito.it.
Federica
F
Cavallo
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000276:immunology*; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*
D052899:Pore Forming Cytotoxic Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C483886:perforin, mouse; C524056:Erbb2 protein, mouse