According to the American Cancer Society, more than half a million Americans will die from cancer in 2007. Although much effort has been focused on cancer research, it remains the 2nd most common cause of death in the U.S. As the need for cancer therapy remains, there is also a greater need to study in greater detail the fundamental mechanisms of how cancer cells operate. Seeking a more thorough understanding of cancer can contrast with and reinforce the knowledge we have about the spread of cancer cells to other regions of the body. The melanoma cancer model has been validated to study cancer metastasis. It will be studied in our system in the context of generating a lymphangiogenic response. It has recently become appreciated that creation of new lymphatic vessels can provide an escape route for cancer cells en route to other parts of the body. Also, macrophages that are normally recruited to tumors can play role in lymphangiogenesis. It has been proposed that this occurs by two distinct mechanisms: 1) Direct macrophage incorporation into existing lymphatic vessels and 2) Macrophage production of VEGF-C which stimulates lymphangiogenesis. Through mice that are deficient in a protein tyrosine kinase, (Bmx -/-), we plan to determine the function of Bmx in the bone marrow and more broadly the contribution of bone marrow derived cells to tumor lymphangiogenesis. Our preliminary results indicate Bmx in the bone marrow is critical for migration in an inflammatory response. We will determine if these effects are ultimately mediated by a defect in lymphatic cell migration, monocyte/macrophage migration, or perhaps a combination of both. We plan to study the interactions between cancer cells, macrophages, lymphatic endothelium and the functional outcomes when Bmx is deleted in these cell types. Specifically, we want to investigate if Bmx affects the migratory and/or proliferative capacity of these cells and the clinical outcomes/significance of decreased or increased tumor lymphangiogenesis (measured by mice morbidity and mortality). We will measure migration in vivo by using green fluorescent protein (GFP) reporter mice which will allow us to determine the contribution of bone marrow derived cells to lymphatic vessels in Bmx-/- mice. We plan to combine this in vivo method with other in vivo and in vitro assays to determine the mechanism of macrophage contribution to lymphangiogenesis. Ultimately novel inhibitor molecules against Bmx may be effective in cancer therapy.
