Hemangiosarcoma in rodents: Mode-of-action evaluation and human relevance

Samuel Monroe Cohen, Richard D. Storer, Kay A. Criswell, Nancy G. Doerrer, Vicki L. Dellarco, David G. Pegg, Zbigniew W. Wojcinski, David E. Malarkey, Abigail C. Jacobs, James E. Klaunig, James A. Swenberg, Jon C. Cook

Research output: Contribution to journalReview article

64 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4-18
Number of pages15
JournalToxicological Sciences
Volume111
Issue number1
DOIs
StatePublished - Aug 27 2009

Fingerprint

Hemangiosarcoma
Endothelial cells
Tumors
Rodentia
Chemical activation
Thorium Dioxide
Tissue
Vinyl Chloride
Industrial chemicals
Macrophages
Cell proliferation
Rats
Intercellular Signaling Peptides and Proteins
Bone
Cytokines
Endothelial Cells
Pharmaceutical Preparations
Cell Hypoxia
Macrophage Activation
Angiogenesis Inducing Agents

Keywords

  • Angiogenesis
  • Endothelial cells
  • Endothelial precursor cells
  • Hemangiosarcoma
  • Human relevance
  • Mode of action
  • PPAR agonists

ASJC Scopus subject areas

  • Toxicology

Cite this

Cohen, S. M., Storer, R. D., Criswell, K. A., Doerrer, N. G., Dellarco, V. L., Pegg, D. G., ... Cook, J. C. (2009). Hemangiosarcoma in rodents: Mode-of-action evaluation and human relevance. Toxicological Sciences, 111(1), 4-18. https://doi.org/10.1093/toxsci/kfp131

Hemangiosarcoma in rodents : Mode-of-action evaluation and human relevance. / Cohen, Samuel Monroe; Storer, Richard D.; Criswell, Kay A.; Doerrer, Nancy G.; Dellarco, Vicki L.; Pegg, David G.; Wojcinski, Zbigniew W.; Malarkey, David E.; Jacobs, Abigail C.; Klaunig, James E.; Swenberg, James A.; Cook, Jon C.

In: Toxicological Sciences, Vol. 111, No. 1, 27.08.2009, p. 4-18.

Research output: Contribution to journalReview article

Cohen, SM, Storer, RD, Criswell, KA, Doerrer, NG, Dellarco, VL, Pegg, DG, Wojcinski, ZW, Malarkey, DE, Jacobs, AC, Klaunig, JE, Swenberg, JA & Cook, JC 2009, 'Hemangiosarcoma in rodents: Mode-of-action evaluation and human relevance', Toxicological Sciences, vol. 111, no. 1, pp. 4-18. https://doi.org/10.1093/toxsci/kfp131
Cohen SM, Storer RD, Criswell KA, Doerrer NG, Dellarco VL, Pegg DG et al. Hemangiosarcoma in rodents: Mode-of-action evaluation and human relevance. Toxicological Sciences. 2009 Aug 27;111(1):4-18. https://doi.org/10.1093/toxsci/kfp131
Cohen, Samuel Monroe ; Storer, Richard D. ; Criswell, Kay A. ; Doerrer, Nancy G. ; Dellarco, Vicki L. ; Pegg, David G. ; Wojcinski, Zbigniew W. ; Malarkey, David E. ; Jacobs, Abigail C. ; Klaunig, James E. ; Swenberg, James A. ; Cook, Jon C. / Hemangiosarcoma in rodents : Mode-of-action evaluation and human relevance. In: Toxicological Sciences. 2009 ; Vol. 111, No. 1. pp. 4-18.
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