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.

A1120, a Nonretinoid RBP4 Antagonist, Inhibits Formation of Cytotoxic Bisretinoids in the Animal Model of Enhanced Retinal Lipofuscinogenesis

“…11 However, independent of its activity as an antagonist of retinol binding to RBP4, fenretinide is an extremely active inducer of apoptosis in many cell types, [18][19][20][21][22] including the RPE, 23 Additionally, fenretinide is reported to stimulate formation of hemangiosarcomas in mice. 24 Moreover, fenretinide is theratogenic, 25,26 which makes its use problematic in Stargardt disease patients of childbearing age. As fenretinide safety profile may be incompatible with long-term dosing in individuals with blinding but nonlife-threatening conditions, identification of new classes of RBP4 antagonists is of significant importance.…”

Tesaglitazar, a Dual PPAR-α/γ Agonist, Hamster Carcinogenicity, Investigative Animal and Clinical Studies

“…The possible involvement of growth factors (such as VEGF) in the mode of action for hemangiosarcomas has also been discussed in the literature (Cohen et al 2009;Herman et al), and analyses of growth factors in preclinical as well as clinical studies with tesaglitazar was specifically requested by regulatory authorities. Circulating VEGF levels were slightly increased throughout the study.…”

“…The commonality in tumor findings across this class of compounds caused concerns regarding human risk, and investigative studies to elucidate the mode of action were initiated. A large number of pharmaceutical companies have been involved in the International Life Science Institute (ILSI) PPAR Initiative with the aim to produce mode of action frameworks for fibro-, lipo-, and hemangiosarcomas and urinary bladder tumors (Cohen et al 2006(Cohen et al , 2009Hardisty et al 2007;Meek et al 2003). Previous to the ILSI discussions, a hypothesis on the involvement of increased circulating levels of VEGF and other growth factors produced in adipose tissue had been suggested in the literature (Herman et al 2002).…”

Human safety risk assessment of lymph node angiomas observed in 2-year carcinogenicity studies in rats

“…For example, the incidences of spontaneous and xenobiotic-induced angiomas (primarily hemangiomas and hemangiosarcomas) are typically greater in mice than in rats (Cohen et al, 2009). Transgenic rasH2 mice are sensitive to the detection of genotoxic and non-genotoxic carcinogens and development of spontaneous and chemically-induced vascular angiomas such as hemangiomas and hemangiosarcomas (Usui et al, 2001;Watanabe et al, 2002).…”