title: ARF suppresses hepatic vascular neoplasia in a carcinogen-exposed murine model.
abstract: Hepatic haemangiosarcoma is a deadly malignancy whose aetiology remains poorly understood. Inactivation of the CDKN2A locus, which houses the ARF and p16(INK4a) tumour suppressor genes, is a common event in haemangiosarcoma patients, but the precise role of ARF in vascular tumourigenesis is unknown. To determine the extent to which ARF suppresses vascular neoplasia, we examined the incidence of hepatic vascular lesions in Arf-deficient mice exposed to the carcinogen urethane [intraperitoneal (i.p.), 1 mg/g]. Loss of Arf resulted in elevated morbidity and increased the incidence of both haemangiomas and incipient haemangiosarcomas. Suppression of vascular lesion development by ARF was heavily dependent on both Arf gene-dosage and the genetic strain of the mouse. Trp53-deficient mice also developed hepatic vascular lesions after exposure to urethane, suggesting that ARF signals through a p53-dependent pathway to inhibit the development of hepatic haemangiosarcoma. Our findings provide strong evidence that inactivation of Arf is a causative event in vascular neoplasia and suggest that the ARF pathway may be a novel molecular target for therapeutic intervention in haemangiosarcoma patients.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Busch
authors.forename: Kay E
authors.initials: KE
authors.lastname: Gurley
authors.forename: Russell D
authors.initials: RD
authors.lastname: Moser
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kemp
mesh_terms: D000818:Animals; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D006394:Hemangiosarcoma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D015398:Signal Transduction; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D014520:Urethane
chemical_list: D002273:Carcinogens; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53; D014520:Urethane