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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.

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.
AuthorsChakrapani Tripathi, Brij Nath Tewari, Ranjana Kumari Kanchan, Khemraj Singh Baghel, Naveen Nautiyal, Richa Shrivastava, Harbeer Kaur, Madan Lal Bramha Bhatt, Smrati Bhadauria
JournalOncotarget (Oncotarget) Vol. 5 Issue 14 Pg. 5350-68 (Jul 30 2014) ISSN: 1949-2553 [Electronic] United States
PMID25051364 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Chemokine CCL11
  • Oncostatin M
Topics
  • Animals
  • Breast Neoplasms (blood supply, metabolism, pathology)
  • Cell Hypoxia (physiology)
  • Cell Line, Tumor
  • Chemokine CCL11 (metabolism)
  • Female
  • Humans
  • MCF-7 Cells
  • Macrophages (pathology)
  • Mammary Neoplasms, Experimental (metabolism, pathology)
  • Mice
  • Mice, Inbred BALB C
  • Neovascularization, Pathologic (metabolism, pathology)
  • Oncostatin M (metabolism)
  • Phenotype
  • Random Allocation
  • Tumor Microenvironment

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