ToxSci Advance Access originally published online on June 12, 2009
Toxicological Sciences 2009 111(1):4-18; doi:10.1093/toxsci/kfp131
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Hemangiosarcoma in Rodents: Mode-of-Action Evaluation and Human Relevance
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* University of Nebraska Medical Center, Omaha, Nebraska 68198
Merck Research Laboratories, West Point, Pennsylvania 19486
Pfizer, Inc., Groton, Connecticut 06340
ILSI Health and Environmental Sciences Institute, Washington, DC 20005
¶ United States Environmental Protection Agency, Washington, DC 20460
|| Michigan Technology and Research Institute, Ann Arbor, Michigan 48104
||| Fulcrum Pharma Developments, Inc., Ann Arbor, Michigan 48103
|||| National Institute of Environmental Health Sciences, National Toxicology Program, Research Triangle Park, North Carolina 27709
# United States Food and Drug Administration, Silver Spring, Maryland 20993
** Indiana University School of Medicine, Indianapolis, Indiana 46202
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
1 To whom correspondence should be addressed at ILSI Health and Environmental Sciences Institute, 1156 Fifteenth St., NW, Second Floor, Washington, DC 20005. Fax: (202) 659-3306. E-mail: ndoerrer{at}hesiglobal.org.
Received April 7, 2009; accepted June 9, 2009
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Abstract |
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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.
Key Words: hemangiosarcoma; angiogenesis; endothelial cells; endothelial precursor cells; mode of action; human relevance; PPAR agonists.
This manuscript expresses the opinions of the authors and does not reflect the views of their institutions or agencies.
This review summarizes the presentations and discussions from an international Workshop titled "Hemangiosarcoma in Rodents: Mode-of-Action Evaluation and Human Relevance," which was held December 4–5, 2008, in Arlington, VA. This Workshop was part of the Society of Toxicology Contemporary Concepts in Toxicology series, was cosponsored by the ILSI Health and Environmental Sciences Institute (HESI), and was a follow-up to a HESI project focused on MOA for peroxisome proliferator–activated receptor agonists, many of which are known to induce hemangiosarcomas in mice.