title: 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.
authors: Division of Toxicology, Central Drug Research Institute, (CSIR) Lucknow, India; Academy of Scientific Innovative Research, (AcSIR) India.
authors: Chakrapani
authors: C
authors: Tripathi
authors: Department of Surgical Oncology, King George Medical University, Lucknow, India.
authors: Brij Nath
authors: BN
authors: Tewari
authors: Division of Toxicology, Central Drug Research Institute, (CSIR) Lucknow, India.
authors: Ranjana Kumari
authors: RK
authors: Kanchan
authors: Division of Toxicology, Central Drug Research Institute, (CSIR) Lucknow, India.
authors: Khemraj Singh
authors: KS
authors: Baghel
authors: Division of Toxicology, Central Drug Research Institute, (CSIR) Lucknow, India.
authors: Naveen
authors: N
authors: Nautiyal
authors: Division of Toxicology, Central Drug Research Institute, (CSIR) Lucknow, India; Academy of Scientific Innovative Research, (AcSIR) India.
authors: Richa
authors: R
authors: Shrivastava
authors: Division of Toxicology, Central Drug Research Institute, (CSIR) Lucknow, India.
authors: Harbeer
authors: H
authors: Kaur
authors: Department of Radiotherapy, King George Medical University, Lucknow, India.
authors: Madan Lal Bramha
authors: ML
authors: Bhatt
authors: Division of Toxicology, Central Drug Research Institute, (CSIR) Lucknow, India; Academy of Scientific Innovative Research, (AcSIR) India.
authors: Smrati
authors: S
authors: Bhadauria
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D054413:Chemokine CCL11 / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008264:Macrophages / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D053683:Oncostatin M / Q000378:metabolism*; D010641:Phenotype; D011897:Random Allocation; D059016:Tumor Microenvironment
chemical_list: D054413:Chemokine CCL11; D053683:Oncostatin M