Abstract
Simple SummaryInflammation and oxidative stress are important host defense responses. However, while the host response can be cytotoxic and kill tumor cells, tumor cells can also alter and exploit the host immune environment to further their survival. Thus, the host response can impact both tumor suppression and progression. Modulating the tumor–host response interaction to favor tumor suppression would be highly desirable. D-mannose has been found to have anti-inflammatory properties and can block signaling related to myeloperoxidase (MPO), a highly oxidizing pro-inflammatory enzyme secreted in host defense. However, the effect of D-mannose on host immune response in the glioma microenvironment has not been explored. We found that D-mannose slowed glioma growth by increasing MPO activity and oxidative stress in the glioma microenvironment. Our findings revealed that D-mannose may be able to shift the host immune response toward tumor suppression and could be a potential new therapeutic direction for these difficult-to-treat tumors. Host immune response in the tumor microenvironment plays key roles in tumorigenesis. We hypothesized that D-mannose, a simple sugar with anti-inflammatory properties, could decrease oxidative stress and slow glioma progression. Using a glioma stem cell model in immunocompetent mice, we induced gliomas in the brain and tracked MPO activity in vivo with and without D-mannose treatment. As expected, we found that D-mannose treatment decreased the number of MPO+ cells and slowed glioma progression compared to PBS-treated control animals with gliomas. Unexpectedly, instead of decreasing MPO activity, D-mannose increased MPO activity in vivo, revealing that D-mannose boosted the MPO activity per MPO+ cell. On the other hand, D-glucose had no effect on MPO activity. To better understand this effect, we examined the effect of D-mannose on bone marrow-derived myeloid cells. We found that D-mannose modulated MPO activity via two mechanisms: directly via N-glycosylation of MPO, which boosted the MPO activity of each molecule, and indirectly by increasing H2O2 production, the main substrate for MPO. This increased host immune response acted to reduce tumor size, suggesting that increasing MPO activity such as through D-mannose administration may be a potential new therapeutic direction for glioma treatment.
Highlights
Glioblastoma (GBM) is the most malignant subtype of high-grade glioma
We found that the mean light intensity was significantly lower in the brains of the D-mannose-treated group than those in the PBS-treated group (Figure 1A,B; p = 0.0042), demonstrating the presence of fewer
We found that the mean light intensity was significantly lower in the brains of the D-mannose-treated group than those in the PBS-treated group (Figure 1A,B; p = 0.0042), demonstrating the presence loufcfiefewrearsel-uecxipferreasssein-egxpglrieosmsiangcegllsioamftaercDel-lsmaafntenroDse-mtreaantnmoesne tt.rWeaetmtheennt.uWseedthTe2n-wuesiegdhtTe2dMweRigihmteadginMgRtoimmeaagsinugre tloesimoneassiuzere(tulemsioornasnidzeas(stoucmiaotredanpdareanscshoycimataeldabpnaorermncahlyitmieas)l faobunrowrmeeaklistiaefst)erfotuurmworeeinkds uacftteiornt,uwmhoirchinsdhuocwtieodn,smwhalilcehr slehsoiownesdinsmthaellDer-mleasnionnossein-trtehaeteDdgmraonunpotshea-tnretahtoesdegirnotuhpe tPhBanS-tthreoasteedinmthiceeP(BFSig-turereat1eCd)m
Summary
Glioblastoma (GBM) is the most malignant subtype of high-grade glioma. It is composed of highly malignant cells that can exhibit widespread infiltration into adjacent and distant brain regions. The most important source of reactive oxygen species and oxidative stress is the isoforms of nicotinamide adenine dinucleotide phosphate dehydrogenase (NADPH) oxidase. NADPH oxidases are a family of transmembrane proteins and include oxygen- and NADPH-dependent oxidoreductases that produce H2O2 in various cell types and tissues, often in response to growth factor and immune mediators [7]. MPO has been found in mature macrophages in atherosclerosis [9], in brain tissue showing Alzheimer-type pathology [10] or Parkinson’s disease [11], and in multiple sclerosis lesions [12], but it is released in the tumor immune microenvironment [13]. MPO and MPO-mediated products likely play a role in the glioma immune microenvironment
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.
