Inflammation and cancer: Divergent roles for leukotriene B4 receptor-1 and chemokine decoy receptor D6

Cancer is a much-dreaded disease considering the high rates of mortality and morbidity. In spite of several decades of research, the etiology of several cancers remains elusive. Often cancers are caused by multiple factors. Genetic mutations in cancer cells are fundamental for a normal cell to become cancerous. Recently, a major focus has been on the role of tumor microenvironment.; Inflammation induced by infections, irritants and other stimuli can play important roles in the initiation, promotion and progression of cancers. Several inflammatory mediators are thought to play critical roles in inflammatory diseases including carcinogenesis. Chemokines and leukotrienes are potent chemoattractant molecules involved in diverse physiological and pathological conditions. Hence targeting the receptors for these molecules can become powerful tools for cancer medicine. We focused our attention in elucidating the potential role of leukotriene B4 receptor-1 (BLT1), the high affinity receptor for one of the most potent chemoattractants, leukotriene B4 and a chemokine decoy receptor D6 involved in chemokine scavenging.; Chapter II of this dissertation describes in detail our studies on the role of pulmonary inflammation mediated by leukotriene B4 receptor-1 in lung carcinogenesis using genetically engineered mice. By adopting a two stage (initiation and promotion) lung carcinogenesis model, we found that BLT1 deficient mice have smaller and fewer tumors than BLT1 sufficient mice. We found that BLT1 deficient mice mounted reduced pulmonary inflammation in response to the pneumotoxicant butylated hydroxytoluene and harbored reduced mutations.; Chapter III of this dissertation describes the generation of two new compound mutant mice, one with a deficiency of BLT1 and the other with a deficiency of D6 in the Min background. The Min mice spontaneously develop multiple intestinal neoplasia due to the mutation in the tumor suppressor gene Adenomatous polyposis coli (Apc). Surprisingly, BLT1 deficient Min mice died earlier with an increased tumor burden, notably in the colon. In contrast, D6 deficient Min mice survived for longer time points.; These studies indicate that chemokine and leukotriene mediators play divergent roles in the pathogenesis of lung and colon cancers. Further study is essential to determine the potential mechanisms for the diverse phenotypes in two distinct organ systems.