title: Generation of a murine hepatic angiosarcoma cell line and reproducible mouse tumor model.
abstract: 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.
authors.affiliation: Department of Biomedicine, University Basel, Basel, Switzerland.
authors.forename: Sonja
authors.initials: S
authors.lastname: Rothweiler
authors.affiliation: Department of Biomedicine, University Basel, Basel, Switzerland.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Dill
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Department of Biomedicine, University Basel, Basel, Switzerland.
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Makowska
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Quagliata
authors.affiliation: Institute of Anatomy, University of Bern, Bern, Switzerland.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Hlushchuk
authors.affiliation: Institute of Anatomy, University of Bern, Bern, Switzerland.
authors.forename: Valentin
authors.initials: V
authors.lastname: Djonov
authors.affiliation: 1] Department of Biomedicine, University Basel, Basel, Switzerland [2] Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland.
authors.forename: Markus H
authors.identifier: 0000000275234894
authors.initials: MH
authors.lastname: Heim
authors.affiliation: 1] Department of Biomedicine, University Basel, Basel, Switzerland [2] Division of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Semela
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006394:Hemangiosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008854:Microscopy, Electron; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010671:Phenylurea Compounds / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D047368:Tumor Burden / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C497762:Notch1 protein, mouse; D010671:Phenylurea Compounds; D051881:Receptor, Notch1; D009536:Niacinamide; D000077157:Sorafenib