Development of mouse models of angiosarcoma driven by p53

Disease Models & Mechanisms

Donald M. Salter¹  James R. Smith²  Neil C. Henderson²  Kylie Matchett²  Meredyth Griffin³  Andrew H. Sims³  Katy Teo³  Laura Gomez-Cuadrado³  Larry Hayward³  Jayne Culley³  Valerie G. Brunton³  Morwenna Muir³ 

[1]Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK

[2]Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Little France Crescent, Edinburgh EH16 4TJ, UK

[3]Edinburgh Cancer Research UK Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK

关键词: Angiosarcoma;    Trp53;    Genetically engineered mouse model;    Lymphomas;    Tumour;   

DOI  :  10.1242/dmm.038612

来源: DOAJ

【 摘 要 】

Angiosarcomas are a rare group of tumours which have poor prognosis and limited treatment options. The development of new therapies has been hampered by a lack of good preclinical models. Here, we describe the development of an autochthonous mouse model of angiosarcoma driven by loss of p53 in VE-cadherin-expressing endothelial cells. Using Cdh5-Cre to drive recombination in adult endothelial cells, mice developed angiosarcomas with 100% penetrance upon homozygous deletion of Trp53 with a median lifespan of 325 days. In contrast, expression of the R172H mutant p53 resulted in formation of thymic lymphomas with a more rapid onset (median lifespan 151 days). We also used Pdgfrb-Cre-expressing mice, allowing us to target predominantly pericytes, as these have been reported as the cell of origin for a number of soft tissue sarcomas. Pdgfrb-Cre also results in low levels of recombination in venous blood endothelial cells in multiple tissues during development. Upon deletion of Trp53 in Pdgfrb-Cre-expressing mice (Pdgfrb-Cre, Trp53fl/fl mice), 65% developed lymphomas and 21% developed pleomorphic undifferentiated soft tissue sarcomas. None developed angiosarcomas. In contrast, 75% of Pdgfrb-Cre, Trp53R172H/R172H mice developed angiosarcomas, with 60% of these mice also developing lymphomas. The median lifespan of the Pdgfrb-Cre, Trp53R172H/R172H mice was 151 days. Re-implantation of angiosarcoma tumour fragments from Cdh5-Cre, Trp53fl/fl mice provided a more consistent and rapid model of angiosarcoma than the two spontaneous models. The ability to passage tumour fragments through the mouse provides a novel model which is amenable to preclinical studies and will help the development of potential new therapies for angiosarcoma.

【 授权许可】

Unknown