Development of mouse models of angiosarcoma driven by p53

Abstract

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.

Inhibition of Endoglin Exerts Antitumor Effects through the Regulation of Non-Smad TGF-β Signaling in Angiosarcoma

“…FoxO and p53 concertedly enhance the transcription of several genes in angiosarcoma (Renault et al, 2011). In contrast, loss of p53 or FoxO1/3/4 expression induces the development of angiosarcoma in vivo (Paik et al, 2007;Salter et al, 2019).…”

Optimal Clinical Management and the Molecular Biology of Angiosarcomas

“…Zebrafish homozygous for tp53 deletion spontaneously develop tumours consistent with AS histology, as do mice with germline Trp53 deletion [ 88 , 90 , 91 ]. Furthermore, homozygous deletion of Trp53 in cadherin 5-expressing endothelial cells in mice also results in AS tumour development [ 89 ]. Interestingly, expression of a gain of function p53 mutant (R172H) in mouse endothelial cells does not lead to AS, but instead triggers lymphoma development [ 89 ].…”

“…Furthermore, homozygous deletion of Trp53 in cadherin 5-expressing endothelial cells in mice also results in AS tumour development [ 89 ]. Interestingly, expression of a gain of function p53 mutant (R172H) in mouse endothelial cells does not lead to AS, but instead triggers lymphoma development [ 89 ]. In contrast, expression of the R172H mutant within pericytes results in 75% of mice developing AS, illustrating the importance of the cell of origin in defining AS tumorigenesis [ 89 ].…”

“…Interestingly, expression of a gain of function p53 mutant (R172H) in mouse endothelial cells does not lead to AS, but instead triggers lymphoma development [ 89 ]. In contrast, expression of the R172H mutant within pericytes results in 75% of mice developing AS, illustrating the importance of the cell of origin in defining AS tumorigenesis [ 89 ]. The development of AS in animal models through genetic manipulation of TP53 provides direct evidence that this tumour suppressor is important for this disease.…”

Editorial: A Novel Monoclonal Antibody-Targeting Angiogenesis by Inhibiting Secreted Frizzled-Related Protein 2

“…Alternatively, genetically engineered mouse models such as FVB-Tg(C3-1-TAg) or the p53 null 'T11' models for triplenegative breast cancer or the Pdgfrb-Cre, Trp53 R172H/R172H and H2 K-fos-tg mouse models for angiosarcoma and osteosarcoma, respectively, could be used. [12][13][14][15] These models would need to be tested to see if they express the human target antigen, or otherwise engineered to do so. 16 Immunotherapy has become a widely used modality in many advanced cancers.…”