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

Cancer Discov. 2013 Aug;3(8):936-51. doi: 10.1158/2159-8290.CD-12-0527. Epub 2013 May 9.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arginase / genetics
  • Arginase / metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Epithelial Cells / metabolism
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, Knockout
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism*
  • Neoplasm Metastasis*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • Protein Serine-Threonine Kinases / genetics*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction*
  • T-Lymphocytes / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology

Substances

  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Nitric Oxide Synthase
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Arg1 protein, mouse
  • Arginase