Macrophages are recruited to hypoxic tumor areas and acquire a pro-angiogenic M2-polarized phenotype via hypoxic cancer cell derived cytokines Oncostatin M and Eotaxin

Oncotarget. 2014 Jul 30;5(14):5350-68. doi: 10.18632/oncotarget.2110.

Abstract

TAMs, a unique and distinct M2-skewed myeloid population of tumor stroma, exhibiting pro-tumor functions is fast emerging as a potential target for anti-cancer immunotherapy. Macrophage-recruitment and M2-polarization represent key TAMs-related phenomenon that are amenable to therapeutic intervention. However successful translation of these approaches into effective therapeutic regimen requires better characterization of tumor-microenvironment derived signals that regulate macrophage recruitment and their polarization. Owing to hypoxic milieu being a persistent feature of tumor-microenvironment and a major contributor to malignancy and treatment resistance, the current study was planned with an aim to decipher tumor cell responses to hypoxia vis-a-vis macrophage homing and phenotype switching. Here, we show that hypoxia-primed cancer cells chemoattract and polarize macrophages to pro-angiogenic M2-polarized subtype via Eotaxin and Oncostatin M. Concordantly, hypoxic regions of human breast-cancer specimen exhibited elevated Eotaxin and Oncostatin M levels with concurrently elevated M2-macrophage content. Blockade of Eotaxin/Oncostatin M not only prevented hypoxic breast-cancer cells from recruiting and polarizing macrophages towards an M2-polarized phenotype and retarded tumor progression in 4T1/BALB/c-syngenic-mice-model of breast-cancer but also enhanced the efficacy of anti-angiogenic Bevacizumab. The findings established these two cytokines as novel targets for devising effective anticancer therapy particularly for tumors that are refractory or develop resistance to anti-angiogenic therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / blood supply*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Hypoxia / physiology
  • Cell Line, Tumor
  • Chemokine CCL11 / metabolism*
  • Female
  • Humans
  • MCF-7 Cells
  • Macrophages / pathology*
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Oncostatin M / metabolism*
  • Phenotype
  • Random Allocation
  • Tumor Microenvironment

Substances

  • Chemokine CCL11
  • Oncostatin M