Abstract 411: Absence of leukotriene B4 receptor-1 promotes colon tumorigenesis in the ApcMin/+ mice by modulating gut microbiota

Leukotriene B4, a potent lipid mediator of inflammation acts through the G-protein coupled receptor, BLT1. The BLT1-/- mice displayed substantial protection in inflammatory disease models of arthritis, asthma and atherosclerosis. To examine the role of BLT1 in progression of cancers known to be promoted by inflammation, we crossed the BLT1-/- mice onto mice with a heterozygous mutation in the adenomatous polyposis coli (ApcMin/+) gene. The BLT1-/-ApcMin/+ mice demonstrated an increase in the rate of spontaneous intestinal tumor development and accelerated mortality. Unlike ApcMin/+ mice that develop mostly small intestinal tumors the BLT1-/-ApcMin/+ mice developed large colonic adenomas. Tumors from the BLT1-/-ApcMin/+ mice showed increased rates of proliferation, decrease in apoptosis and an increase in the expression of tumor promoting inflammatory markers such as TNF-α and CXCL1 and COX2 when compared to tumors from the ApcMin/+ mice. Microarray analysis of transcriptome showed that the paradoxical increase in inflammation in tumors from the BLT1-/-ApcMin/+ mice is coincidental with defective host response to infections. The expression of angiogenins, a class of antibacterial proteins was significantly reduced in tumors from BLT1-/-ApcMin/+ mice. Further, analysis of gut flora (by 16S ribosomal DNA sequences) identified major differences in microbiome colonizing the BLT1-/-ApcMin/+ and ApcMin/+ mice. BLT1-/-ApcMin/+ mice rederived and raised under germ-free conditions are completely protected from colon cancer development. To examine the role of Toll-like receptor mediated signaling events involved in tumor promotion in the absence of BLT1, we developed BLT1/MyD88 double deficient mice. The BLT1-/-MyD88-/- mice were highly susceptible to lethal neonatal infections indicating the cooperative interactions between TLR and leukotriene pathways in host response. These BLT1-/-MyD88-/- mice could be rescued by treatment with a broad-spectrum antibiotic. The MyD88-/-ApcMin/+ mice are highly protected from intestinal cancers. The BLT1-/-MyD88-/-ApcMin/+ mice are also highly protected indicating that BLT1-mediated host defense acts upstream of MyD88-mediated tumor promoting inflammation. While both BLT1 and MyD88 are important in host defense only the MyD88 but not BLT1 activated pathways are required to initiate tumor promoting inflammation. These results identify novel roles for gut microbiota in promoting colon cancer and for BLT1 in preventing the colon cancer development by shaping the gut microbiome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 411. doi:10.1158/1538-7445.AM2011-411