(See Inslfucllons): The plan for the upcoming ROO phase of the award includes finalization of Specific Aim 2 using the clodronated liposomes as an alternate method for mononuclear phagocyte removal {as discussed In """"""""Changes made to alms'), completion of Specific Aim 3 on the effects of GM-CSF on the growth, angiogenesis, and metastases in human breast cancer in Immunodeficient mice, and further investigation into monocyte and macrophage subpopulations generated in response to GM-CSF treatment. Thus the Specific Aims will address the following questions: Central Hypothesis (modification from original): GM-CSF treatment induces a phenotype switch In tumor infiltrating mononuclear phagocytes and triggers an anti-angiogenic program.
Specific Aim 2 (fmm parent gmnt): To determine the cells responsible for sVEGFR-1 production In response to GM-CSF.
Specific Aim 3 (from parent grant): Does GM-CSF Inhibit tumor growth, angiogenesis, and metastases of human tumors In nude mice? New Aims based on preliminary data generated from the parent grant and/or collaboration:
Specific Aim 4 : To determine if GM-CSF changes mononuclear phagocyte cell phenotypes using gene expression signatures and proteomic evaluation.
Our data suggest that GM-CSF not only inhibits tumor angiogenesis by inducing sVEGFR-1 expression from tumor macrophages, but that it also induces a phenotype switch from M2, tumor helping cells to M1, tumor-fighting cells. Because the presence of infiltrating immune cells like monocytes and macrophages in breast cancer predict a poor outcome, the understanding of the specific phenotypes of these cells and their activity is essential to correlate to which type of cells are responsible for poor prognosis and which subpopulation of macrophages help the patient.
