| First Author | Salter DM | Year | 2019 |
| Journal | Dis Model Mech | Volume | 12 |
| Issue | 7 | PubMed ID | 31221668 |
| Mgi Jnum | J:278525 | Mgi Id | MGI:6356290 |
| Doi | 10.1242/dmm.038612 | Citation | Salter DM, et al. (2019) Development of mouse models of angiosarcoma driven by p53. Dis Model Mech 12(7):dmm038612 |
| abstractText | 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 , Trp53(fl/fl) mice), 65% developed lymphomas and 21% developed pleomorphic undifferentiated soft tissue sarcomas. None developed angiosarcomas. In contrast, 75% of Pdgfrb- Cre, Trp53(R172H/R172H) mice developed angiosarcomas, with 60% of these mice also developing lymphomas. The median lifespan of the Pdgfrb- Cre, Trp53(R172H/R172H) mice was 151 days. Re-implantation of angiosarcoma tumour fragments from Cdh5-Cre, Trp53(fl/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. |
