Hypoxia Inducible Factors-Mediated Inhibition of Cancer by GM-CSF: A Mathematical Model
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Hypoxia Inducible Factors-Mediated Inhibition of Cancer by GM-CSF: A Mathematical Model Duan Chen · Julie M. Roda · Clay B. Marsh · Timothy D. Eubank · Avner Friedman
Received: 21 March 2012 / Accepted: 20 September 2012 / Published online: 17 October 2012 © Society for Mathematical Biology 2012
Abstract Under hypoxia, tumor cells, and tumor-associated macrophages produce VEGF (vascular endothelial growth factor), a signaling molecule that induces angiogenesis. The same macrophages, when treated with GM-CSF (granulocyte/macrophage colony-stimulating factor), produce sVEGFR-1 (soluble VEGF receptor-1), a soluble protein that binds with VEGF and inactivates its function. The production of VEGF by macrophages is regulated by HIF-1α (hypoxia inducible factor-1α), and the production of sVEGFR-1 is mediated by HIF-2α. Recent experiments measured the effect of inhibiting tumor growth by GM-CSF treatment in mice with HIF-1α-deficient or HIF-2α-deficient macrophages. In the present paper, we represent these experiments by a mathematical model based on a system of partial differential equations. We show that the model simulations agree with the above experiments. The model can then be used to suggest strategies for inhibiting tumor growth. For example, the model qualitatively predicts the extent to which GM-CSF treatment in combination with a small molecule inhibitor that stabilizes HIF-2α will reduce tumor volume and angiogenesis. Keywords Free boundary model · Tumor growth
D. Chen () · A. Friedman Mathematical Biosciences Institute, The Ohio State University, Columbus, OH, USA e-mail: [email protected] A. Friedman Department of Mathematics, The Ohio State University, Columbus, OH, USA J.M. Roda · C.B. Marsh · T.D. Eubank Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA
Hypoxia Inducible Factors-Mediated Inhibition of Cancer by GM-CSF
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1 Introduction Macrophages play an important role in tumor growth and progression (Pollard 1997). In murine models, breast tumor cells can secrete factors that usurp normal macrophage antitumor function, like macrophage colony-stimulating factor (MCSF), and induce a phenotype switch to pro-tumor “tumor-associated macrophages” or TAMs that can help aid in tumor progression. These TAMs, recruited by monocyte chemoattractant protein-1 (MCP-1/CCL2), secrete vascular endothelial growth factor (VEGF), thereby promoting angiogenesis and tumor growth. Interestingly, a second growth factor, granulocyte/macrophage colony-stimulating factor (GM-CSF), has been shown to “re-educate” TAMs back into a more tumor-fighting phenotype. Treating macrophages with GM-CSF induces the production of soluble VEGF receptor-1 (sVEGFR-1), which binds and sequesters VEGF, neutralizing its proliferative effects on endothelial cells. Thus, GM-CSF tends to reverse the pro-tumor “education” of macrophages (Eubank et al. 2003, 2004, 2009). The transcriptional response to hypoxia is driven by a family of hypoxia inducible factors (HIFs
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