Lung cancer is the most common cause of cancer-related deaths worldwid. The ultimate goal of my research is to investigate and elucidate the functions and mechanisms underlying the interplay between secreted tumor cell factors and inflammatory response in metastatogenesis and tumorigenesis. My research will focus on the identification of secreted tumor cell factors which can activate inflammatoty cells and elucidation of the molecular mechanisms by which these tumor cell factors activate the inflammatory cells. Tumor cells release many factors including growth factors, cytokines, chemokines, and enzymes that regulate tumor growth, angiogenesis, invasion, and/or metastasis. Inflammatory populations, long been known to its infiltration into the tumor cells and already suggested its important roles for metastatogenesis, respond to these stimuli from tumor cells and activated. Activated inflammatory cells produce numerous cytokines which recruit and activate more myeloid cells such as macrophages. Some inflammatory cells generate massive amounts of reactive oxygen (ROS) and nitrogen species which possess bactericidal and proinflammatory activity, but can also cause oxidative DNA-damage and mutagenesis as well as general tissue damage. Macrophages, major component of this inflammatory populations, are involved in clearance of damaged tissues and dead cells, but once clearance has been completed, the inflammation should be resolved. However, repeated exposure to secreted factors by tumor cells can promote the persistent activation of inflammatory cells that can further aid for tumor progression, promotion and metastasis. Despite the evident link between secreted factors by tumor cells and activation of inflammatory response on metastatogenesis and tumorigenesis, the mechanistic understanding of tumor microenvironment is incomplete. Here, I propose that this vicious cycle of secreted tumor cell factors, activation of inflammatory cells and re-stimulation of tumor growth and angiogenesis is a major and critical contributor to metastatogenesis and/or tumorigenesis. To accomplish this work, I will pursue the following specific aims: 1) Evaluate the direct functional relationship between compounds released from tumor cells and macrophages; 2) Identify the TLR2-activating compound(s) from tumor cells; 3) Determine the functions and mechanisms of TLR2-mediated signaling in metastatogenesis and tumorigenesis; and 4) Examine the roles of TLR2- activating factor(s) in metastatogenesis and tumorigenesis. ? ? ?
