Tumor-associated macrophages (TAMs) depend on ZEB1 for their cancer-promoting roles

EMBO J. 2017 Nov 15;36(22):3336-3355. doi: 10.15252/embj.201797345. Epub 2017 Oct 16.

Abstract

Accumulation of tumor-associated macrophages (TAMs) associates with malignant progression in cancer. However, the mechanisms that drive the pro-tumor functions of TAMs are not fully understood. ZEB1 is best known for driving an epithelial-to-mesenchymal transition (EMT) in cancer cells to promote tumor progression. However, a role for ZEB1 in macrophages and TAMs has not been studied. Here we describe that TAMs require ZEB1 for their tumor-promoting and chemotherapy resistance functions in a mouse model of ovarian cancer. Only TAMs that expressed full levels of Zeb1 accelerated tumor growth. Mechanistically, ZEB1 expression in TAMs induced their polarization toward an F4/80low pro-tumor phenotype, including direct activation of Ccr2 In turn, expression of ZEB1 by TAMs induced Ccl2, Cd74, and a mesenchymal/stem-like phenotype in cancer cells. In human ovarian carcinomas, TAM infiltration and CCR2 expression correlated with ZEB1 in tumor cells, where along with CCL2 and CD74 determined poorer prognosis. Importantly, ZEB1 in TAMs was a factor of poorer survival in human ovarian carcinomas. These data establish ZEB1 as a key factor in the tumor microenvironment and for maintaining TAMs' tumor-promoting functions.

Keywords: EMT; TAMs; ZEB1; macrophages; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation, B-Lymphocyte / metabolism
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology*
  • Cell Count
  • Cell Differentiation / drug effects
  • Chemokine CCL2 / pharmacology
  • Colony-Stimulating Factors / pharmacology
  • Disease Models, Animal
  • Disease Progression
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Macrophage Activation / drug effects
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Macrophages / pathology*
  • Matrix Metalloproteinase 9 / metabolism
  • Mice, Inbred C57BL
  • Models, Biological
  • Monocytes / drug effects
  • Monocytes / pathology
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Phenotype
  • Receptors, CCR2 / metabolism
  • Survival Analysis
  • Up-Regulation / drug effects
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism*

Substances

  • Antigens, Differentiation, B-Lymphocyte
  • Ccr2 protein, mouse
  • Chemokine CCL2
  • Colony-Stimulating Factors
  • Histocompatibility Antigens Class II
  • Receptors, CCR2
  • ZEB1 protein, human
  • ZEB1 protein, mouse
  • Zinc Finger E-box-Binding Homeobox 1
  • invariant chain
  • Matrix Metalloproteinase 9