Phenotypic skewing of macrophages in vitro by secreted factors from colorectal cancer cells

Macrophages are cells with many important functions in both innate and adaptive immune responses and have been shown to play a complex role in tumor progression since they harbour both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. In many human cancers, infiltrating macrophages have been associated with a poor patient prognosis, and therefore suggested to be mainly of an M2 phenotype. However, we and others have previously shown that increased macrophage density in colorectal cancer (CRC) instead is correlated with an improved prognosis. It is an intriguing question if the different roles played by macrophages in various cancers could be explained by variations in the balance between M1 and M2 macrophage attributes, driven by tumor- or organ-specific factors in the tumor microenvironment of individual cancers. Here, we utilized an in vitro cell culture system of macrophage differentiation to compare differences and similarities in the phenotype (morphology, antigen-presentation, migration, endocytosis, and expression of cytokine and chemokine genes) between M1/M2 and tumor activated macrophages (TAMs), that could explain the positive role of macrophages in CRC. We found that secreted factors from CRC cells induced TAMs of a "mixed" M1/M2 phenotype, which in turn could contribute to a "good inflammatory response". This suggests that re-education of macrophages might allow for important therapeutic advances in the treatment of human cancer.This study was supported by grants from the Swedish Cancer Society (Grant no. CAN 2011/839, Palmqvist) (www.cancerfonden.se); Swedish Research Council (Grant no. B03488901, Palmqvist) (www.vr.se); Cutting-Edge Research Grant from the County Council of Västerbotten, Sweden (Grant no. VLL-132981, Palmqvist); Cancer Research Foundation in Northern Sweden (Grant no. AMP 10-655, Edin) (www.cancerforskningsfonden.se); and Tore Nilssons Foundation (Edin) (www.torenilssonsstiftelse.nu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.