title: Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis.
abstract: Macrophages are important drivers in the development of inflammation-associated colon cancers, but the mechanistic underpinnings for their contributions are not fully understood. Furthermore, Toll-like receptors have been implicated in colon cancer, but their relevant cellular sites of action are obscure. In this study, we show that the endoplasmic reticulum chaperone gp96 is essential in tumor-associated macrophages (TAM) to license their contributions to inflammatory colon tumorigenesis. Mice where gp96 was genetically deleted in a macrophage-specific manner exhibited reduced colitis and inflammation-associated colon tumorigenesis. Attenuation of colon cancer in these mice correlated strikingly with reduced mutation rates of β-catenin, increased efficiency of the DNA repair machinery, and reduced expression of proinflammatory cytokines, including interleukin (IL)-17 and IL-23 in the tumor microenvironment. The genotoxic nature of TAM-associated inflammation was evident by increased expression of genes in the DNA repair pathway. Our work deepens understanding of how TAM promote oncogenesis by altering the molecular oncogenic program within epithelial cells, and it identifies gp96 as a lynchpin chaperone needed in TAM to license their function and impact on expression of critical inflammatory cytokines in colon tumorigenesis.
authors: Authors' Affiliations: Departments of Microbiology and Immunology and Pathology and Laboratory Medicine; Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina; and Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut.
authors: Crystal
authors: C
authors: Morales
authors: Saleh
authors: S
authors: Rachidi
authors: Feng
authors: F
authors: Hong
authors: Shaoli
authors: S
authors: Sun
authors: Xinshou
authors: X
authors: Ouyang
authors: Caroline
authors: C
authors: Wallace
authors: Yongliang
authors: Y
authors: Zhang
authors: Elizabeth
authors: E
authors: Garret-Mayer
authors: Jennifer
authors: J
authors: Wu
authors: Bei
authors: B
authors: Liu
authors: Zihai
authors: Z
authors: Li
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002471:Cell Transformation, Neoplastic; D003092:Colitis / Q000378:metabolism; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism*; D003433:Crosses, Genetic; D016207:Cytokines / Q000378:metabolism; D004260:DNA Repair; D018450:Disease Progression; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D007249:Inflammation; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000378:metabolism
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D053759:Interleukin-23; D008562:Membrane Glycoproteins; C053387:endoplasmin