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

// Chakrapani Tripathi 1,2 , Brij Nath Tewari 4 , Ranjana Kumari Kanchan 1 , Khemraj Singh Baghel 1 , Naveen Nautiyal 1 , Richa Shrivastava 1,2 , Harbeer Kaur 1 , Madan Lal Bramha Bhatt 3 and Smrati Bhadauria 1,2 1 Division of Toxicology, Central Drug Research Institute, (CSIR) Lucknow, India 2 Academy of Scientific Innovative Research, (AcSIR) India 3 Department of Radiotherapy, King George Medical University, Lucknow, India 4 Department of Surgical Oncology, King George Medical University, Lucknow, India Correspondence: Smrati Bhadauria, email: // Keywords : Hypoxia, M2-Polarization, TAM, Tumor-microenvironment, Chemoattract, Pro-angiogenic, Breast Cancer Received : March 4, 2014 Accepted : June 16, 2014 Published : June 17, 2014 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.