Cyclic Hypoxia Induces Transcriptomic Changes in Mast Cells Leading to a Hyperresponsive Phenotype after FcεRI Cross-Linking

Abstract

Mast cells (MCs) play important roles in tumor development, executing pro- or antitumoral functions depending on tumor type and tumor microenvironment (TME) conditions. Cyclic hypoxia (cyH) is a common feature of TME since tumor blood vessels fail to provide a continuous supply of oxygen to the tumor mass. Here, we hypothesized that the localization of MCs in cyH regions within solid tumors could modify their transcriptional profile and activation parameters. Using confocal microscopy, we found an important number of MCs in cyH zones of murine melanoma B16-F1 tumors. Applying microarray analysis to examine the transcriptome of murine bone-marrow-derived MCs (BMMCs) exposed to interleaved cycles of hypoxia and re-oxygenation, we identified altered expression of 2512 genes. Functional enrichment analysis revealed that the transcriptional signature of MCs exposed to cyH is associated with oxidative phosphorylation and the FcεRI signaling pathway. Interestingly, FcεRI-dependent degranulation, calcium mobilization, and PLC-γ activity, as well as Tnf-α, Il-4, and Il-2 gene expression after IgE/antigen challenge were increased in BMMCs exposed to cyH compared with those maintained in normoxia. Taken together, our findings indicate that cyH causes an important phenotypic change in MCs that should be considered in the design of inflammation-targeted therapies to control tumor growth.