Oncotarget

Research Papers:

Genetic prevention of lymphoma in p53 knockout mice allows the early development of p53-related sarcomas

Lorena Landuzzi _, Marianna L. Ianzano, Giordano Nicoletti, Arianna Palladini, Valentina Grosso, Dario Ranieri, Massimiliano Dall’Ora, Elena Raschi, Roberta Laranga, Marco Gambarotti, Piero Picci, Carla De Giovanni, Patrizia Nanni and Pier-Luigi Lollini

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Oncotarget. 2014; 5:11924-11938. https://doi.org/10.18632/oncotarget.2650

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Abstract

Lorena Landuzzi1,2, Marianna L. Ianzano3, Giordano Nicoletti1,2, Arianna Palladini3, Valentina Grosso3, Dario Ranieri3, Massimiliano Dall’Ora3, Elena Raschi3, Roberta Laranga3, Marco Gambarotti4, Piero Picci1, Carla De Giovanni3, Patrizia Nanni3, Pier-Luigi Lollini3

1Laboratory of Experimental Oncology, Rizzoli Orthopedic Institute, Bologna, Italy

2PROMETEO Laboratory, STB, RIT Department, Rizzoli Orthopedic Institute, Bologna, Italy

3Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna Italy

4Anatomy and Pathological Histology, Rizzoli Orthopedic Institute, Bologna, Italy

Correspondence to:

Patrizia Nanni, e-mail: [email protected]

Keywords: p53-KO mice, Rag2KO/Il2rgKO mice, lymphoma, hemangiosarcoma, osteosarcoma

Received: August 04, 2014     Accepted: October 27, 2014     Published: November 18, 2014

ABSTRACT

Homozygous knockout of p53 in mice leads to early mortality from lymphoma, with almost complete penetrance, thus hampering studies of other tumor histotypes related to p53 alterations. To avoid lymphoma development, we crossed p53 knockout mice (BALB-p53 mice) with alymphocytic BALB/c Rag2−/−;Il2rg−/− (RGKO) mice. We compared the tumor spectrum of homozygous (BALB-p53−/−) and heterozygous (BALB-p53+/−) mice with alymphocytic mice (RGKO-p53−/− and RGKO-p53+/−). Lymphoma incidence in BALB-p53−/− mice exceeded 80%, whereas in RGKO-p53−/− it was strongly reduced. The prevalent tumor of RGKO-p53−/− mice was hemangiosarcoma (incidence over 65% in both sexes, mean latency 18 weeks), other tumors included soft tissue sarcomas (incidence ~10%), lung and mammary carcinomas. Tumor spectrum changes occurred also in p53 heterozygotes, in which lymphomas are relatively rare (~20%). RGKO-p53+/− had an increased incidence of hemangiosarcomas, reaching ~30%, and females had an increased incidence of osteosarcomas, reaching ~20%. Osteosarcomas shared with the corresponding human tumors the involvement of limbs and a high metastatic ability, mainly to the lungs. Specific alterations in the expression of p53-related genes (p16Ink4a, p19Arf, p15Ink4b, p21Cip1) were observed. Genetic prevention of lymphoma in p53 knockout mice led to new models of sarcoma development, available for studies on hemangiosarcoma and osteosarcoma onset and metastatization.


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