Colon cancer is a leading cause of cancer related deaths in the United States. Exposure to a number of hazardous environmental agents and consumption of the Western diet are known to contribute to the pathogenesis of malignant colon cancer. While chronic inflammation is known to be a major promoter of tumor development the role of gut microflora in contributing to the colon cancer is unknown. Our laboratory has identified leukotriene B4 receptor, BLT1 as a major regulator of inflammation and host response to infections. In a mouse model of spontaneous intestinal cancer (ApcMin/+), we have made the observation that absence of BLT1 greatly enhances intestinal tumor development. This has led to the central hypothesis that Absence of BLT1 enhances colon tumor development by defective immune surveillance and/or altered microbial gut homeostasis. This apparently paradoxical result that loss of a proinflammatory mediator increases inflammation and tumor development suggests that the ever changing micro environment of intestine can have a major influence on the development of colorectal cancer. The current proposal will test this hypothesis in three specific aims.
In aim 1, we will examine the mechanisms of leukotriene B4 pathway mediated protection of intestinal cancers in ApcMin/+ mice.
Aim 2 will establish the immune functions in tumor bearing mice in the context of BLT1+/+ and BLT1-/- mice.
Aim 3 will test the novel concept that defective host response and altered gut microbiota are responsible for rapid development of colon tumors in BLT1-/- mice. These studies will provide a comprehensive model system to examine the interplay of inflammation and infections to the development of colon cancer. Since the mouse ApcMin/+ model is highly related to human colon cancers the result will have direct and immediate impact for the treatment of human colon cancer.
Leukotrienes are involved in the pathophysiology of many acute and chronic inflammatory diseases such as systemic anaphylaxis, asthma, atherosclerosis and arthritis. The novel finding that leukotriene B4-leukotriene B4 receptor1 axis may have a protective function in the development of colon cancer offers a unique opportunity to understand the role of these mediators in tumor development. Understanding the precise function of distinct leukotriene B4 receptors in mice and defining the role of these receptors in host defense and shaping the gut microflora will provide novel approaches to the treatment of colon cancer.
