[HTML][HTML] Macrophages are recruited to hypoxic tumor areas and acquire a pro-angiogenic M2-polarized phenotype via hypoxic cancer cell derived cytokines …

C Tripathi, BN Tewari, RK Kanchan, KS Baghel… - Oncotarget, 2014 - ncbi.nlm.nih.gov
C Tripathi, BN Tewari, RK Kanchan, KS Baghel, N Nautiyal, R Shrivastava, H Kaur…
Oncotarget, 2014ncbi.nlm.nih.gov
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 …
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.
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