title: TGF-β signaling in myeloid cells is required for tumor metastasis.
abstract: TGF-β is overexpressed in advanced human cancers. It correlates with metastasis and poor prognosis. However, TGF-β functions as both a tumor suppressor and a tumor promoter. Here, we report for the first time that genetic deletion of Tgfbr2 specifically in myeloid cells (Tgfbr2(MyeKO)) significantly inhibited tumor metastasis. Reconstitution of tumor-bearing mice with Tgfbr2(MyeKO) bone marrow recapitulated the inhibited metastasis phenotype. This effect is mediated through decreased production of type II cytokines, TGF-β1, arginase 1, and inducible nitric oxide synthase, which promoted IFN-γ production and improved systemic immunity. Depletion of CD8 T cells diminished the metastasis defect in the Tgfbr2(MyeKO) mice. Consistent with animal studies, myeloid cells from patients with advanced-stage cancer showed increased TGF-β receptor II expression. Our studies show that myeloid-specific TGF-β signaling is an essential component of the metastasis-promoting puzzle of TGF-β. This is in contrast to the previously reported tumor-suppressing phenotypes in fibroblasts, epithelial cells, and T cells.
authors: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
authors: Yanli
authors: Y
authors: Pang
authors: Sudheer Kumar
authors: SK
authors: Gara
authors: Bhagelu R
authors: BR
authors: Achyut
authors: Zhaoyang
authors: Z
authors: Li
authors: Hannah H
authors: HH
authors: Yan
authors: Chi-Ping
authors: CP
authors: Day
authors: Jonathan M
authors: JM
authors: Weiss
authors: Giorgio
authors: G
authors: Trinchieri
authors: John C
authors: JC
authors: Morris
authors: Li
authors: L
authors: Yang
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D009362:Neoplasm Metastasis; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D019001:Nitric Oxide Synthase; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C544448:Arg1 protein, mouse; D001119:Arginase
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