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.
Highlights
The extremely complex tumor microenvironment is composed of an expanding population of transformed cells; it includes stromal cells such as smooth muscle cells, fibroblasts and macrophages [1]
To test this hypothesis we evaluated the transmigration of THP1 cells (Human leukemia monocyte THP1 cell line) derived macrophages towards MDA-MB-231 and MCF-7 human breast cancer cells that were previously exposed to hypoxic conditions for 3 and 6 hrs
Quantitative analysis revealed that the extent of macrophage transmigration positively correlated with the duration for which breast cancer cells were exposed to hypoxia
Summary
The extremely complex tumor microenvironment is composed of an expanding population of transformed cells; it includes stromal cells such as smooth muscle cells, fibroblasts and macrophages [1]. Together these stromal cells act as prominent modifiers of tumor growth and progression [2]. The propensity of tumors to progress does not solely emanate from oncogenic transformations occurring within cancer cells. It is a cumulative manifestation of ongoing dynamic interactions between tumor cells and surrounding stromal cells [3]. Counteracting the infiltration of TAM by antagonizing the key chemokine mediator of macrophage recruitment i.e. CCL5 markedly reduced tumor infiltrate and reduced tumor growth, thereby emphasizing the importance of recruitment of TAMs during tumor progression [18]
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