TGF-β signaling in myeloid cells is required for tumor metastasis

Yanli Pang, Sudheer Kumar Gara, Bhagelu R Achyut, Zhaoyang Li, Hannah H Yan, Chi-Ping Day, Jonathan M Weiss, Giorgio Trinchieri, John C Morris, Li Yang

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)936-51
Number of pages16
JournalCancer Discovery
Volume3
Issue number8
DOIs
StatePublished - Aug 2013

Keywords

  • Animals
  • Arginase
  • Cell Line, Tumor
  • Disease Models, Animal
  • Epithelial Cells
  • Fibroblasts
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, Knockout
  • Myeloid Cells
  • Neoplasm Metastasis
  • Nitric Oxide Synthase
  • Protein-Serine-Threonine Kinases
  • Receptors, Transforming Growth Factor beta
  • Signal Transduction
  • T-Lymphocytes
  • Transforming Growth Factor beta
  • Tumor Microenvironment
  • Journal Article
  • Research Support, N.I.H., Extramural

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