title: Mast cell 5-lipoxygenase activity promotes intestinal polyposis in APCDelta468 mice.
abstract: Arachidonic acid metabolism has been implicated in colon carcinogenesis, but the role of hematopoietic 5-lipoxygenase (5LO) that may impact tumor immunity in development of colon cancer has not been explored. Here we show that tissue-specific deletion of the 5LO gene in hematopoietic cells profoundly attenuates polyp development in the APC(Δ468) murine model of colon polyposis. In vitro analyses indicated that mast cells in particular utilized 5LO to limit proliferation of intestinal epithelial cells and to mobilize myeloid-derived suppressor cells (MDSCs). Mice lacking hemapoietic expression of 5LO exhibited reduced recruitment of MDSCs to the spleen, mesenteric lymph nodes, and primary tumor site. 5LO deficiency also reduced the activity in MDSCs of arginase-1, which is thought to be critical for MDSC function. Together, our results establish a pro-tumorigenic role of hematopoietic 5LO in the immune microenvironment and suggest 5LO inhibition as an avenue for future investigation in treatment of colorectal polyposis and cancer.
authors.affiliation: Department of Surgery, Mount Sinai Hospital, University of Illinois College of Medicine, Chicago, Illinois, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Cheon
authors.forename: Khashayarsha
authors.initials: K
authors.lastname: Khazaie
authors.forename: Mohammad W
authors.initials: MW
authors.lastname: Khan
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Strouch
authors.forename: Seth B
authors.initials: SB
authors.lastname: Krantz
authors.forename: Joseph
authors.initials: J
authors.lastname: Phillips
authors.forename: Nichole R
authors.initials: NR
authors.lastname: Blatner
authors.forename: Laura M
authors.initials: LM
authors.lastname: Hix
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Dennis
authors.forename: Mohammed R
authors.initials: MR
authors.lastname: Salabat
authors.forename: Michael
authors.initials: M
authors.lastname: Heiferman
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Grippo
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
authors.forename: Elias
authors.initials: E
authors.lastname: Gounaris
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002469:Cell Separation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D017491:Genes, APC; D044483:Intestinal Polyposis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008407:Mast Cells / Q000201:enzymology*; D051379:Mice; D008817:Mice, Mutant Strains
chemical_list: D001094:Arachidonate 5-Lipoxygenase