Generation of a murine hepatic angiosarcoma cell line and reproducible mouse tumor model

Rothweiler, Sonja; Dill, Michael T; Terracciano, Luigi; Makowska, Zuzanna; Quagliata, Luca; Hlushchuk, Ruslan; Djonov, Valentin; Heim, Markus H; Semela, David (2014). Generation of a murine hepatic angiosarcoma cell line and reproducible mouse tumor model. Laboratory investigation, 95(3), pp. 351-362. Nature Publishing Group 10.1038/labinvest.2014.141

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Hepatic angiosarcoma (AS) is a rare and highly aggressive tumor of endothelial origin with dismal prognosis. Studies of the molecular biology of AS and treatment options are limited as animal models are rare. We have previously shown that inducible knockout of Notch1 in mice leads to spontaneous formation of hepatic AS. The aims of this study were to: (1) establish and characterize a cell line derived from this murine AS, (2) identify molecular pathways involved in the pathogenesis and potential therapeutic targets, and (3) generate a tumor transplantation model. AS cells retained specific endothelial properties such as tube formation activity, as well as expression of CD31 and Von Willebrand factor. However, electron microscopy analysis revealed signs of dedifferentiation with loss of fenestrae and loss of contact inhibition. Microarray and pathway analysis showed substantial changes in gene expression and revealed activation of the Myc pathway. Exposing the AS cells to sorafenib reduced migration, filopodia dynamics, and cell proliferation but did not induce apoptosis. In addition, sorafenib suppressed ERK phosphorylation and expression of cyclin D2. Injection of AS cells into NOD/SCID mice resulted in formation of undifferentiated tumors, confirming the tumorigenic potential of these cells. In summary, we established and characterized a murine model of spontaneous AS formation and hepatic AS cell lines as a useful in vitro tool. Our data demonstrate antitumor activity of sorafenib in AS cells with potent inhibition of migration, filopodia formation, and cell proliferation, supporting further evaluation of sorafenib as a novel treatment strategy. In addition, AS cell transplantation provides a subcutaneous tumor model useful for in vivo preclinical drug testing.Laboratory Investigation advance online publication, 24 November 2014; doi:10.1038/labinvest.2014.141.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy

UniBE Contributor:

Hlushchuk, Ruslan and Djonov, Valentin

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0023-6837

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Ruslan Hlushchuk

Date Deposited:

09 Feb 2015 14:19

Last Modified:

26 Jun 2016 01:58

Publisher DOI:

10.1038/labinvest.2014.141

PubMed ID:

25418579

Additional Information:

Epub ahead of print

BORIS DOI:

10.7892/boris.62654

URI:

https://boris.unibe.ch/id/eprint/62654

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