Intracerebral Distribution of the Oncometabolite d-2-Hydroxyglutarate in Mice Bearing Mutant Isocitrate Dehydrogenase Brain Tumors: Implications for Tumorigenesis

Abstract

The prevalence of mutant isocitrate dehydrogenase 1 (IDH1) brain tumors has generated significant efforts to understand the role of the mutated enzyme product d-2-hydroxyglutarate (D2HG), an oncometabolite, in tumorigenesis, as well as means to eliminate it. Glymphatic clearance was proposed as a pathway that could be manipulated to accelerate D2HG clearance and dictated the study design that consisted of two cohorts of mice bearing U87/mutant IDH1 intracerebral tumors that underwent two microdialysis – providing D2HG interstitial fluid concentrations – sampling periods of awake and asleep (activate glymphatic clearance) in a crossover manner. Glymphatic clearance was found not to have a significant effect on D2HG brain tumor interstitial fluid concentrations that were 126.9 ± 74.8 μM awake and 117.6 ± 98.6 μM asleep. These concentrations, although low relative to total brain tumor concentrations of 6.8 ± 3.6 mM, were considered sufficient to be transported by interstitial fluid and taken up into normal cells to cause deleterious effects. A model of D2HG CNS distribution supported this contention and was further supported by in vitro studies that showed D2HG could interfere with immune cell function. The study provides insight into the compartmental distribution of D2HG in the brain, wherein the interstitial fluid serves as a dynamic pathway for D2HG to enter normal cells and contribute to tumorigenesis.

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations

“…For example, we have previously shown that exposure to D-2HG or expression of mutated IDH constructs reduced proliferation of cells, both in-vitro and in-vivo [ 6 ]. Later independent studies largely confirmed these observations and also conversely, reduction of D-2HG levels by mutant IDH inhibitors increased cell proliferation [ 18 , 38 , 40 , 47 , 55 ]. It should be noted, however, that in some preclinical model systems a growth inhibitory effect of IDH-inhibitors was observed [ 39 , 41 ].…”

Low-grade glioma harbors few CD8 T cells, which is accompanied by decreased expression of chemo-attractants, not immunogenic antigens

“…We also evaluated whether T cell numbers are related to IDH mutation status as several reports indicated a causal role for mutated IDH (and D2HG accumulation) in immune suppression 23,24 . IDH1/2 mutation status was available for 35 (100%) LGG samples and 21 (68%) HGG samples used for TIL immune stainings and flow cytometry.…”

“…For example, in a murine model for LGG, the introduction of mutant IDH1 or treatment with 2HG reduced protein levels of CXCL10 likely through decreased production of STAT1 23 , and suppressed the accumulation of T cells at tumor sites. A different study showed that 2HG reduced proliferation of human T cells cultured in vitro 24 . However, we could not conclude on a potential relationship between IDH status and T cell abundance, since either IDH wildtype or IDH mutant sample numbers were too small for LGG and HGG, respectively.…”

Biased measurements by stationary turbidity‐fluorescence instruments due to phototactic zooplankton behavior

“…Optical characteristics of the water, such as transparency, scattering, polarization, and color, serve as key attributes of water bodies in oceanography (Jerlov 1976;Pickard and Emery 2016) and limnology (Wetzel 2001;Cole and Weihe 2016). Methodologies for their quantification have been developed for over 150 years, starting with the Secchi disk, proposed in the mid-19th century (Watson and Zielinski 2013).…”