This proposal focuses on understanding the mechanism of GM-CSF-induced sVEGFR-1 production from mononuclear phagocytes and the resulting anti-tumor activity therein. Our data indicates when normal FVB/N female mice are injected with PyMT tumor cells and form a tumor, local injection of rmGM-CSF significantly inhibits tumor growth, metastases to the lung, oxygen within the tumors, as well as increases overall survival of the mouse. Our hypothesis is that GM-CSF will induce the monocytes and macrophages, which reside in mammary tumors, to produce and release the soluble form of the VEGF receptor-1 (sVEGFR-1). This decoy receptor is an alternately-spliced variant of the membrane-bound VEGFR-1 that binds and sequesters VEGF from biological activity. With reduced VEGF in the tumor environment, which is essential in maintaining endothelial cell survival and normal blood vascular beds, the tumor vasculature will break down and result in patterned necrosis within the tumor and eventual tumor cell death. We have published these effects in vivo in a Matrigel plug assay and show reduced angiogenesis within these plugs. Preliminary data in this proposal suggest that GM-CSF significantly reduces tumor growth and metastases in a murine model of breast cancer, in part, by inhibiting the available oxygen to the tumor. It is essential to further these findings by evaluating the effects of GM-CSF in a human tumor environment. We will be using immunodeficient, athymic nude female mice in conjunction with MCF10A, MCF10AT1k, MCF10CA1h and MCF10CA1a human tumor cell lines to see these effects. These cell lines, tumorigenic when injected into the mammary fat pad of nude mice, are immortalized mammary epithelial cells and vary in metastatic aggressiveness. Thus the Specific Aims will address the following questions:
Aim 1. To determine the effect of GM-CSF-induced sVEGFR-1 on angiogenesis and metastases in breast tumors.
Aim 2. To determine the cells responsible for sVEGFR-1 production in response to GM-CSF.
Aim 3. Does GM-CSF inhibit tumor growth, angiogenesis, and metastases of human tumors in nude mice? We anticipate the findings from these studies will provide novel insight in the mechanisms of tumorassociated cells, in this case mononuclear phagocytes, and the potential to change their phenotype from that of tumor-supporting to that of tumor-suppressive.
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|Szomolay, Barbara; Eubank, Tim D; Roberts, Ryan D et al. (2012) Modeling the inhibition of breast cancer growth by GM-CSF. J Theor Biol 303:141-51|
|Eubank, Tim D; Roda, Julie M; Liu, Haowen et al. (2011) Opposing roles for HIF-1? and HIF-2? in the regulation of angiogenesis by mononuclear phagocytes. Blood 117:323-32|
|Roda, Julie M; Sumner, Laura A; Evans, Randall et al. (2011) Hypoxia-inducible factor-2? regulates GM-CSF-derived soluble vascular endothelial growth factor receptor 1 production from macrophages and inhibits tumor growth and angiogenesis. J Immunol 187:1970-6|
|Parihar, Arti; Eubank, Timothy D; Doseff, Andrea I (2010) Monocytes and macrophages regulate immunity through dynamic networks of survival and cell death. J Innate Immun 2:204-15|
|Eubank, Tim D; Roberts, Ryan D; Khan, Mahmood et al. (2009) Granulocyte macrophage colony-stimulating factor inhibits breast cancer growth and metastasis by invoking an anti-angiogenic program in tumor-educated macrophages. Cancer Res 69:2133-40|