RT info:eu-repo/semantics/article
T1 Development of mouse models of angiosarcoma driven by p53
A1 Salter, Donald M.
A1 Griffin, Meredyth
A1 Muir, Morwenna
A1 Teo, Katy
A1 Culley, Jayne
A1 Smith, James R.
A1 Gómez Cuadrado, Laura
A1 Matchett, Kylie
A1 Sims, Andrew H.
A1 Hayward, Larry
A1 Henderson, Neil C.
A1 Brunton, Valerie G.
K1 Angiosarcoma
K1 TRP53
K1 Genetically engineered mouse model
K1 Lymphomas
K1 Tumour
K1 Oncología
K1 Oncology
K1 Salud
K1 Health
K1 Medicina
K1 Medicine
AB 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.
PB The Company of Biologists
SN 1754-8403
YR 2019
FD 2019-06
LK http://hdl.handle.net/10259/9798
UL http://hdl.handle.net/10259/9798
LA eng
NO This work was supported by Cancer Research UK (C157/A15703, C157/A9148 and C6088/A12063), a Wellcome Trust Senior Research Fellowship in Clinical Science (103749) to N.C.H., a Wellcome Trust Clinical Training Fellowship to J.R.S., a Wellcome Trust Institutional Strategic Support Fund award, the Edinburgh and Lothians Health Foundation Margaret Lee Oncology fund, the Charon Fund (registered charity SC022161) and NHS Health Scotland.
DS Repositorio Institucional de la Universidad de Burgos
RD 05-feb-2025