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
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Chakrapani Tripathi1,2, Brij Nath Tewari4, Ranjana Kumari Kanchan1, Khemraj Singh Baghel1, Naveen Nautiyal1, Richa Shrivastava1,2, Harbeer Kaur1, Madan Lal Bramha Bhatt3 and Smrati Bhadauria1,2
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
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
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.
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