Defective TGF-β signaling in bone marrow-derived cells prevents hedgehog-induced skin tumors

Cancer Res. 2014 Jan 15;74(2):471-483. doi: 10.1158/0008-5472.CAN-13-2134-T. Epub 2013 Nov 26.

Abstract

Hedgehog signaling in cancer cells drives changes in the tumor microenvironment that are incompletely understood. Here, we report that hedgehog-driven tumors exhibit an increase in myeloid-derived suppressor cells (MDSC) and a decrease in T cells, indicative of an immunosuppressive tumor microenvironment. This change was associated with activated TGF-β signaling in several cell types in basal cell carcinomas. We determined that TGF-β signaling in bone marrow-derived cells, not keratinocytes, regulates MDSC and promotes tumor development. Tgfbr2 deficiency in the bone marrow-derived cells also reduced the size of previously developed tumors in mice. We identified CCL2 as the major chemokine attracting MDSCs to tumor, whose expression was Tgfbr2-dependent, whereas its receptor CCR2 was highly expressed in MDSC population. CCL2 alone was sufficient to induce migration of MDSCs. Moreover, the CCR2 inhibitors prevented MDSC migration toward skin cells in vitro, and reduced MDSC accumulation and hedgehog signaling-driven tumor development in mice. Our results reveal a signaling network critical for hedgehog signaling in cancer cells to establish an effective immunosuppressive microenvironment during tumor development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology*
  • Cell Movement
  • Cell Proliferation
  • Chemokine CCL2 / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Hedgehog Proteins / metabolism*
  • Immunosuppressive Agents / chemistry
  • Keratinocytes / cytology
  • Mice
  • Mice, Transgenic
  • Myeloid Cells / cytology
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, CCR2 / metabolism
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction*
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / prevention & control
  • T-Lymphocytes / cytology
  • Tissue Distribution
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • Ccl2 protein, mouse
  • Ccr2 protein, mouse
  • Chemokine CCL2
  • Hedgehog Proteins
  • Immunosuppressive Agents
  • Receptors, CCR2
  • Receptors, Transforming Growth Factor beta
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II