The goal of my laboratory is to understand mechanisms by which tumors interact with their microenvironment in such a way as to promote angiogenesis, metastasis, and contribute to the lethal nature of lung cancer. In our initial proposal we studied the promotion of angiogenesis in lung cancer by the cytokine MIF, and determined that tumors can create an angiogenic milieu by activating one of several different pathways. Our data show that MIF indudces angiogenesis indirectly by activating the expression of angiogenic promoters from infiltrating macrophages. Additionally, MIF may act by increasing proloiferation, and reducing apoptosis of the malignant cels themselves. The receptor through which this pro-tumor activity is mediated remains unclear, but may be CD74, a cell surface form of the invariant chain if the HLA class II peptide. We propose to extend observations by determining whether the MIF-CD74 axis is critical in promoting tumor angiogenesis, proliferation, and protection from apoptosis or some combination of these. We recently determined that CD74 was widely expressed in human lung cancer tumors, in both the malignant epithelial compartment as well as on stromal cells. Using flow cytometry on fresh tumor specimens, we showed that CD74 (normally a cytoplasmic protein, with a small proportion being expressed on the cell surface) was surface associated in tumors on both myeloid cells, as well as in specimens in which myeloid cells had been depleted with magnetic beads. The expression of CD74 in tumors was associated with increased levels of angiogenic CXC chemokines, and increased vascularity when compared to tumors where CD74 was not detected (American Journal of Pathology. 2009;174:638- 646). This amended proposal will test the hypothesis, that;MIF promotes tumor growth by inducing the expression of CXC chemokinedependent angiogenic activity, mediated by MIF signaling through the CD74 receptor. We propose to extend our observations made in human tumors and mouse models in the course of our original project by determining the molecular targets of MIF signaling in lung cancer. We will continue our previous studies of the MIF-dependent promotion of angiogenesis, by performing the following specific aims.
Specific aim : a) Determine the role of CD74 in the promotion of lung tumor growth by MIF, and b) to determine the role myeloid cells in the MIF-CD74 axis in lung cancer.
Lung cancer is the leading cause of cancer deaths in the United States, causing more deaths than the next three most common causes combined. This proposal focuses on key mechanisms behind the lethality of this disease, namely angiogenesis and how lung cancer tumors adapt to a changing microenvironment. Successful completion of these studies should improve our understanding of, and ability to target, this lethal disease.
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