title: Myeloid TGF-β signaling contributes to colitis-associated tumorigenesis in mice.
abstract: Myeloid cells have a critical role in maintaining intestinal homeostasis and regulating the development of inflammatory bowel disease and colitis-associated cancer (CAC). However, the signaling pathways that control the function of colonic myeloid cells in these pathological processes are still poorly defined. In this study, we demonstrate that transforming growth factor-β (TGF-β) signaling in colonic myeloid cells is significantly involved in the development of CAC. Myeloid TGF-β receptor II (Tgfbr2)-deficient mice showed reduced susceptibility to chemically induced colitis-associated tumorigenesis, as evidenced by decreases in number and size of tumors. Myeloid Tgfbr2 deficiency markedly decreased the production of interleukin-6 and tumor necrosis factor-α, two proinflammatory cytokines that are essential for colonic tumorigenesis; in addition, a marked increase in the proportions of Foxp3+CD4+ regulatory T cells was observed in the colonic lamina propria in the initial stage of CAC. Loss of myeloid Tgfbr2 was associated with a decrease in the presence of F4/80 positive macrophages and a downregulation of phosphorylated STAT3, proliferative cell nuclear antigen and cyclin D1 expression in colonic adenoma tissues. TGF-β enhanced macrophage recruitment, at least in part, through modulating the expression of the chemokine (C-C motif) receptor 2 (CCR2) ligands in tumor environment and the CCR2 signaling in macrophages. Collectively, these results suggest that myeloid TGF-β signaling modulates intestinal inflammation and significantly promotes tumorigenesis in the development of colitis-associated colon cancer.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200032, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Boshi
authors.initials: B
authors.lastname: Wang
authors.forename: Yingqian
authors.initials: Y
authors.lastname: Xu
authors.forename: Aihui
authors.initials: A
authors.lastname: Ma
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Chao
authors.initials: C
authors.lastname: Ge
authors.forename: Zhaojuan
authors.initials: Z
authors.lastname: Yang
authors.forename: Jinjun
authors.initials: J
authors.lastname: Li
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha