title: Hemangiosarcoma in rodents: mode-of-action evaluation and human relevance.
abstract: Although rarely occurring in humans, hemangiosarcomas (HS) have become important in evaluating the potential human risk of several chemicals, including industrial, agricultural, and pharmaceutical agents. Spontaneous HS arise frequently in mice, less commonly in rats, and frequently in numerous breeds of dogs. This review explores knowledge gaps and uncertainties related to the mode of action (MOA) for the induction of HS in rodents, and evaluates the potential relevance for human risk. For genotoxic chemicals (vinyl chloride and thorotrast), significant information is available concerning the MOA. In contrast, numerous chemicals produce HS in rodents by nongenotoxic, proliferative mechanisms. An overall framework is presented, including direct and indirect actions on endothelial cells, paracrine effects in local tissues, activation of bone marrow endothelial precursor cells, and tissue hypoxia. Numerous obstacles are identified in investigations into the MOA for mouse HS and the relevance of the mouse tumors to humans, including lack of identifiable precursor lesions, usually late occurrence of the tumors, and complexities of endothelial biology. This review proposes a working MOA for HS induced by nongenotoxic compounds that can guide future research in this area. Importantly, a common MOA appears to exist for the nongenotoxic induction of HS, where there appears to be a convergence of multiple initiating events (e.g., hemolysis, decreased respiration, adipocyte growth) leading to either dysregulated angiogenesis and/or erythropoiesis that results from hypoxia and macrophage activation. These later events lead to the release of angiogenic growth factors and cytokines that stimulate endothelial cell proliferation, which, if sustained, provide the milieu that can lead to HS formation.
authors.affiliation: University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
authors.forename: Richard D
authors.initials: RD
authors.lastname: Storer
authors.forename: Kay A
authors.initials: KA
authors.lastname: Criswell
authors.forename: Nancy G
authors.initials: NG
authors.lastname: Doerrer
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Dellarco
authors.forename: David G
authors.initials: DG
authors.lastname: Pegg
authors.forename: Zbigniew W
authors.initials: ZW
authors.lastname: Wojcinski
authors.forename: David E
authors.initials: DE
authors.lastname: Malarkey
authors.forename: Abigail C
authors.initials: AC
authors.lastname: Jacobs
authors.forename: James E
authors.initials: JE
authors.lastname: Klaunig
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
authors.forename: Jon C
authors.initials: JC
authors.lastname: Cook
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D004247:DNA / Q000187:drug effects; D004285:Dogs; D006394:Hemangiosarcoma / Q000139:chemically induced / Q000453:epidemiology / Q000473:pathology*; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D051381:Rats; D018570:Risk Assessment; D013045:Species Specificity; D014752:Vinyl Chloride / Q000633:toxicity
chemical_list: D002273:Carcinogens; D047492:Peroxisome Proliferator-Activated Receptors; D004247:DNA; D014752:Vinyl Chloride