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M-CSF and GM-CSF induce human monocytes to express either pro- or anti-angiogenic factors

Eubank, Tim
http://rave.ohiolink.edu/etdc/view?acc_num=osu1069772001

Abstract Details

2003, Doctor of Philosophy, Ohio State University, Ohio State Biochemistry Program.
Macrophage colony-stimulating factor (M-CSF) is essential in monocyte survival. Since M-CSF (+/-) mice are protected against tumor metastases, we hypothesized that M-CSF induced monocytes to produce pro-angiogenic factors that facilitate metastases. We report that M-CSF stimulates human monocytes to produce vascular endothelial growth factor (VEGF) in a dose-dependent manner and which peaks at five days. VEGF released by monocytes is biologically active as supernatants from M-CSF-stimulated monocytes induce both tube formation and migration from human umbilical vein endothelial cells (HUVECs) compared to supernatants from non-stimulated monocytes. Neutralizing antibodies for VEGF inhibit all pro-angiogenic effects of these supernatants while isogenic control antibodies do not. The second part of this study suggests granulocyte/ macrophage-colony stimulating factor (GM-CSF) and interleukin-3 (IL-3), cytokines responsible for proliferation and survival of monocytes to macrophages and dendrites, can induce monocytes to produce anti-angiogenic factors that may reduce tumor progression. GM-CSF and IL-3 both stimulate mRNA transcription and protein expression of the soluble VEGFR-1 receptor from monocytes as these supernatants blocked antigenic detection of rhVEGF from ELISA while rhVEGF was still detected when incubated with supernatants from non-stimulated cells. In vitro, these supernatants sequester VEGF and inhibit its biological activity toward endothelial cells by reducing both tube formation and cell migration. This data suggests GM-CSF and IL-3 stimulation induces the release of soluble VEGFR-1 from monocytes and can function as an anti-angiogenic agent and that these observations have implications in tumor therapy. To correlate the in vitro findings in vivo, we utilized the Matrigelä Plug Assay in mice and showed that M-CSF not only enhances angiogenesis in the plugs relative to a PBS controls and similar to rhVEGF control plugs, but that it does so in a dose-dependent manner. In cont rast, GM-CSF inhibits angiogenesis within the plugs comparable to the PBS control plugs and significantly reduced from the rhVEGF positive control plugs. These data suggest that monocytes play a role in both pro-angiogenic and anti-angiogenic activity when stimulated by M-CSF and GM-CSF, respectively. Macrophage colony-stimulating factor (M-CSF) is essential in monocyte survival. Since M-CSF (+/-) mice are protected against tumor metastases, we hypothesized that M-CSF induced monocytes to produce pro-angiogenic factors that facilitate metastases. We report that M-CSF stimulates human monocytes to produce vascular endothelial growth factor (VEGF) in a dose-dependent manner and which peaks at five days. VEGF released by monocytes is biologically active as supernatants from M-CSF-stimulated monocytes induce both tube formation and migration from human umbilical vein endothelial cells (HUVECs) compared to supernatants from non-stimulated monocytes. Neutralizing antibodies for VEGF inhibit all pro-angiogenic effects of these supernatants while isogenic control antibodies do not. The second part of this study suggests granulocyte/ macrophage-colony stimulating factor (GM-CSF) and interleukin-3 (IL-3), cytokines responsible for proliferation and survival of monocytes to macrophages and dendrites, can induce monocytes to produce anti-angiogenic factors that may reduce tumor progression. GM-CSF and IL-3 both stimulate mRNA transcription and protein expression of the soluble VEGFR-1 receptor from monocytes as these supernatants blocked antigenic detection of rhVEGF from ELISA while rhVEGF was still detected when incubated with supernatants from non-stimulated cells. In vitro, these supernatants sequester VEGF and inhibit its biological activity toward endothelial cells by reducing both tube formation and cell migration. This data suggests GM-CSF and IL-3 stimulation induces the release of soluble VEGFR-1 from monocytes and can function as an anti-angiogenic agent and that these observations have implications in tumor therapy. To correlate the in vitro findings in vivo, we utilized the Matrigelä Plug Assay in mice and showed that M-CSF not only enhances angiogenesis in the plugs relative to a PBS controls and similar to rhVEGF control plugs, but that it does so in a dose-dependent manner. In cont rast, GM-CSF inhibits angiogenesis within the plugs comparable to the PBS control plugs and significantly reduced from the rhVEGF positive control plugs. These data suggest that monocytes play a role in both pro-angiogenic and anti-angiogenic activity when stimulated by M-CSF and GM-CSF, respectively.
Clay Marsh (Advisor)
188 p.
Chemistry, Biochemistry
Angiogenesis; Matrigel plug assay in mice; GM-CSF; M-CSF; VEGF; soluble VEGFR-1

Recommended Citations

Citations

  • Eubank, T. (2003). M-CSF and GM-CSF induce human monocytes to express either pro- or anti-angiogenic factors [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1069772001

    APA Style (7th edition)

  • Eubank, Tim. M-CSF and GM-CSF induce human monocytes to express either pro- or anti-angiogenic factors. 2003. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1069772001.

    MLA Style (8th edition)

  • Eubank, Tim. "M-CSF and GM-CSF induce human monocytes to express either pro- or anti-angiogenic factors." Doctoral dissertation, Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1069772001

    Chicago Manual of Style (17th edition)

osu1069772001
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© 2003, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.