Genetic Deletion of Hematopoietic 5-Lipoxygenase Suppresses Intestinal Polyposis in ApcΔ468 Knockout Mice
Eric C. Cheon*1,2, Matthew J. Strouch2, Seth B. Krantz2, Mohammad K. Khan3, Kristen Dennis3, Nichole R. Blatner3, Elias Gounaris3, Khashayarsha Khazaie3, David J. Bentrem2,4
1Surgery, Mount Sinai Hospital, University of Illinois College of Medicine at Chicago, Chicago, IL; 2Surgery, Northwestern Memorial Hospital and Feinberg School of Medicine, Chicago, IL; 3Gastroenterology, Northwestern Memorial Hospital and Feinberg School of Medicine, Chicago, IL; 4Surgery, Jesse Brown Veterans Affairs Medical Center, Chicago, IL
Purpose : The arachidonic acid pathway enzymes, cyclooxygenase and 5-lipoxygenase (5LO), have both been shown to modulate cell growth. Many studies have investigated the effects of cyclooxygenase inhibition on human colorectal cancer, but the role of 5LO in colon carcinogenesis has not been well studied. Interestingly, 5LO is a major mediator of hematopoietic immune function. However, its role in relation to tumorigenic myeloid-derived suppressor cells (MDSC) is unknown. The aim of this study was to evaluate if 5LO deficiency suppresses intestinal polyp formation and if this suppression is mediated through the hematopoietic system, namely MDSC’s.Methods : We examined the effects of 5LO gene knockouts on ApcΔ468 knockout mice, a model of human familial adenomatous polyposis. APCΔ468/5LO-/- mice were sacrificed and evaluated at 16 weeks. Age-matched APCΔ468/5LO+/+ mice served as controls. Polyp counts and diameters were measured in both groups. MDSC’s were quantified from intestines, mesenteric lymph nodes, and spleens also from both groups, using flow cytometry. To evaluate which compartment’s 5LO deficiency was responsible for polyposis suppression, APCΔ468 mice were lethally irradiated and reconstituted with bone marrow from healthy 5LO+/+ mice (wt BM) or 5LO-/- mice (5LO-/- BM). Polyp counts and MDSC’s were also quantified in both reconstitution groups.Results : 5LO null mutation led to a dramatic reduction in the number and size of intestinal polyps. The APCΔ468/5LO+/+ group developed 79 + 4 polyps with a median polyp diameter of 2.7mm. In contrast, APCΔ468/5LO-/- mice had 46 + 6 polyps with a median diameter of 1.2mm, an approximately 40% and 44% reduction, respectively (P < 0.005). In even greater contrast, the 5LO-/- BM group had a 95% reduction in polyp counts compared to the wt BM group (5 + 1 vs 111 + 14, respectively, P < 0.005). MDSC’s were reduced in the intestines, mesenteric lymph nodes, and spleens of the APCΔ468/5LO-/- and 5LO-/- BM groups compared to their respective controls (P < 0.005).Conclusions : These findings provide direct genetic evidence that hematopoietic 5LO has an important role in tumorigenesis which is partially mediated through MDSC expansion. Our data points to 5LO-selective inhibitors as a potential, novel class of therapeutic agents for colorectal polyposis and cancer.
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