Angiogenesis is a central feature in both physiologic and pathophysiologic processes (repair, remodeling, tumor growth, and chronic inflammation). Research in recent years has provided evidence that cytokine """"""""networks"""""""" operative in tumors are important in promoting angiogenesis. Elucidating the nature of these networks, while complicated, can provide important and novel insights into the biology of a tumor. Recent paradigms have suggested that tumors co-opt the host's repair and remodeling """"""""programs"""""""" such as those used in a healing wound. This analogy is useful in that it fosters the study of tumor biology as it parallels a healing wound. An example of a feature shared between wounds and tumors is the contribution of stromal cells to the angiogenic response. We have found that macrophage migration inhibitory factor (MTF) is an important cytokine expressed by lung cancer cells in vitro which influences monocytes to express increased levels of angiogenic CXC chemokines. MIF is a cytokine discovered over 30 years ago, and has a wide array of biological effects, including immunoregulatory activity, a prominent role in lethal endotoxeinia, steroid counter-regulatory activity, and even enzymatic activity. Recent evidence has suggested a role for MIF in regulating tumor growth and angiogenesis. However, our data suggest that MIF promotes angiogenesis indirectly, without any evidence of direct angiogenic activity of MIF in vitro. This proposal will more strictly define the mechanism by which MIF promotes tumor angiogenesis in vivo, and to correlate these findings with actual human tumors resected from patients with lung cancer. Among the questions to be addressed are; 1) Does inhibition of MIF in an animal model reduce CXC chemokine-dependent angiogenic activity, and does overexpression of MIF in vivo promote CXC chemokine dependent angiogenic activity? (i.e. Is MIF necessary and sufficient for inducing CXC chernokine dependent activity from infiltrating monocytes?) 2) Does MIF correlate with vascularity of human tumors? 3) Does MIF correlate with levels of angiogenic CXC chemokines in human tumors? 4) Does high expression of MIF predict poor clinical outcomes?
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