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Mouse genetic background influences whether expression plus knockdown causes angiosarcoma or undifferentiated pleomorphic sarcoma


Brandt, Laura P; Albers, Joachim; Hejhal, Tomas; Pfundstein, Svende; Gonçalves, Ana Filipa; Catalano, Antonella; Wild, Peter J; Frew, Ian J (2018). Mouse genetic background influences whether expression plus knockdown causes angiosarcoma or undifferentiated pleomorphic sarcoma. OncoTarget, 9(28):19753-19766.

Abstract

Soft tissue sarcomas are rare mesenchymal tumours accounting for 1% of adult malignancies and are fatal in approximately one third of patients. Two of the most aggressive and lethal forms of soft tissue sarcomas are angiosarcomas and undifferentiated pleomorphic sarcomas (UPS). To examine sarcoma-relevant molecular pathways, we employed a lentiviral gene regulatory system to attempt to generate models that reflect common molecular alterations of human angiosarcoma and UPS. Mice were intraveneously injected with MuLE lentiviruses expressing combinations of shRNA against , , and with or without expression of , or . The systemic injection of an ecotropic lentivirus expressing oncogenic together with the knockdown of or was sufficient to initiate angiosarcoma and/or UPS development, providing a flexible system to generate autochthonous mouse models of these diseases. Unexpectedly, different mouse strains developed different types of sarcoma in response to identical genetic drivers, implicating genetic background as a contributor to the genesis and spectrum of sarcomas.

Abstract

Soft tissue sarcomas are rare mesenchymal tumours accounting for 1% of adult malignancies and are fatal in approximately one third of patients. Two of the most aggressive and lethal forms of soft tissue sarcomas are angiosarcomas and undifferentiated pleomorphic sarcomas (UPS). To examine sarcoma-relevant molecular pathways, we employed a lentiviral gene regulatory system to attempt to generate models that reflect common molecular alterations of human angiosarcoma and UPS. Mice were intraveneously injected with MuLE lentiviruses expressing combinations of shRNA against , , and with or without expression of , or . The systemic injection of an ecotropic lentivirus expressing oncogenic together with the knockdown of or was sufficient to initiate angiosarcoma and/or UPS development, providing a flexible system to generate autochthonous mouse models of these diseases. Unexpectedly, different mouse strains developed different types of sarcoma in response to identical genetic drivers, implicating genetic background as a contributor to the genesis and spectrum of sarcomas.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Oncology
Language:German
Date:13 April 2018
Deposited On:10 Jan 2019 09:35
Last Modified:25 Jun 2020 21:37
Publisher:Impact Journals, LLC
ISSN:1949-2553
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.18632/oncotarget.24831
PubMed ID:29731980

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