title: Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: role of MCP-1.
abstract: Tumor-associated macrophages are associated with poor prognosis in certain cancers. Monocyte chemoattractant protein 1 (MCP-1) is thought to be the most important chemokine for recruitment of macrophages to the tumor microenvironment. However, its role on tumorigenesis in a genetic mouse model of colon cancer has not been explored. We examined the role of MCP-1 on tumor-associated macrophages, inflammation, and intestinal tumorigenesis. Male Apc(Min/+), Apc(Min/+)/MCP-1(-/-) or wild-type mice were euthanized at 18 wk of age and intestines were analyzed for polyp burden, apoptosis, proliferation, β-catenin, macrophage number and phenotype, markers for cytotoxic T lymphocytes and regulatory T cells, and inflammatory mediators. MCP-1 deficiency decreased overall polyp number by 20% and specifically large polyp number by 45% (P < 0.05). This was consistent with an increase in apoptotic cells (P < 0.05), but there was no change detected in proliferation or β-catenin. MCP-1 deficiency decreased F4/80-positive cells in both the polyp tissue and surrounding intestinal tissue (P < 0.05) as well as expression of markers associated with M1 (IL-12 and IL-23) and M2 macrophages (IL-13, CD206, TGF-β, and CCL17) (P < 0.05). MCP-1 knockout was also associated with increased cytotoxic T lymphocytes and decreased regulatory T cells (P < 0.05). In addition, MCP-1(-/-) offset the increased mRNA expression of IL-1β and IL-6 in intestinal tissue and IL-1β and TNF-α in polyp tissue (P < 0.05), and prevented the decrease in SOCS1 expression (P < 0.05). We demonstrate that MCP-1 is an important mediator of tumor growth and immune regulation that may serve as an important biomarker and/or therapeutic target in colon cancer.
authors.affiliation: Dept. of Pathology, Microbiology and Immunology, School of Medicine, Univ. of South Carolina, Columbia, SC 29209, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: McClellan
authors.forename: J Mark
authors.initials: JM
authors.lastname: Davis
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Steiner
authors.forename: Reilly T
authors.initials: RT
authors.lastname: Enos
authors.forename: Seung H
authors.initials: SH
authors.lastname: Jung
authors.forename: James A
authors.initials: JA
authors.lastname: Carson
authors.forename: Maria M
authors.initials: MM
authors.lastname: Pena
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Carnevale
authors.forename: Franklin G
authors.initials: FG
authors.lastname: Berger
authors.forename: E Angela
authors.initials: EA
authors.lastname: Murphy
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003110:Colonic Neoplasms / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000503:physiopathology*; D018664:Interleukin-12 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D053759:Interleukin-23 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007417:Intestinal Polyps / Q000503:physiopathology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D018932:Chemokine CCL2; D053583:Interleukin-1beta; D053759:Interleukin-23; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12