Abstract
In colon cancer, the prognostic value of macrophages is controversial, and it is still unknown how hypoxia modulates macrophage–cancer cell crosstalk. To unravel this, co-cultures of human primary macrophages and colon cancer cells were performed at 20% and 1% O2, followed by characterization of both cellular components. Different colon cancer patient cohorts were analyzed for hypoxia and immune markers, and their association with patient overall survival was established. A positive correlation between HIF1A and CD68 in colon cancer patients was identified but, unexpectedly, in cases with higher macrophage infiltration, HIF1A expression was associated with a better prognosis, in contrast to breast, gastric, and lung cancers. Under hypoxia, co-cultures’ secretome indicated a shift towards a pro-inflammatory phenotype. These alterations occurred along with increased macrophage phagocytic activity and decreased SIRPα expression. Cancer cells were more invasive and exhibited higher CD47 expression. We hypothesize that the better prognosis associated with HIF1AHighCD68High tumors could occur due to macrophagic pro-inflammatory pressure. Indeed, we found that tumors HIF1AHighCD68High expressed increased levels of CD8A, which is positively correlated with HIF1A. In conclusion, we show that in colon cancer, hypoxia drives macrophages into a pro-inflammatory phenotype, concomitant with increased infiltration of anti-tumor immune cells, favoring better disease outcome.
Highlights
It is recognized that the non-malignant component of the tumor microenvironment (TM)has a pivotal role in both tumorigenesis and tumor progression
The Cancer Genome Atlas (TCGA) compiles expression data from normal and cancer colon tissues, we focused our analysis in HIF1A
Since TCGA compiles expression data from normal and cancer colon tissues, we focused our analysis in HIF1A in CD68High and CD68Low populations, in both tissues, assuming that CD68High degree of macrophagic infiltration
Summary
It is recognized that the non-malignant component of the tumor microenvironment (TM)has a pivotal role in both tumorigenesis and tumor progression. It is recognized that the non-malignant component of the tumor microenvironment (TM). Cancers 2020, 12, 818 achieved without knowing how the different TM components influence each other’s behavior, driving disease outcomes. Macrophages are abundant in the TM, and their high infiltration is associated, in several malignancies, with poor prognosis and therapy resistance [2]. Due to their plasticity, macrophages can polarize into pro-inflammatory and anti-tumor or into anti-inflammatory and pro-tumor [3], being, interesting therapeutic targets. It is known that a pro-inflammatory environment is a driving force for the tumorigenic process, driving mutagenesis, while in the context of an established tumor, the pro-inflammatory environment could favor the elimination of already-transformed cells [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
