Spatial profiles of markers of glycolysis, mitochondria, and proton pumps in a rat glioma suggest coordinated programming for proliferation

Abstract

BackgroundIn cancer cells in vitro, the glycolytic pathway and the mitochondrial tricarboxylic acid (TCA) cycle are programmed to produce more precursor molecules, and relatively less ATP, than in differentiated cells. We address the questions of whether and where these changes occur in vivo in glioblastomas grown from C6 cells in rat brain. These gliomas show some spatial organization, notably in the upregulation of membrane proton transporters near the rim.ResultsWe immunolabeled pairs of proteins (as well as DNA) on sections of rat brains containing gliomas, measured the profiles of fluorescence intensity on strips 200 µm wide and at least 3 mm long running perpendicular to the tumor rim, and expressed the intensity in the glioma relative to that outside. On averaged profiles, labeling of a marker of the glycolytic pathway, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), was, as expected, greater in the glioma. Over distances up to 2.5 mm into the glioma, expression of a marker of the TCA cycle, Tom20, a pre-protein receptor on the translocation complex of the mitochondrial outer membrane, was also upregulated. The ratio of upregulation of Tom20 to upregulation of GAPDH was, on average, slightly greater than one. Near the rim (0.4–0.8 mm), GAPDH was expressed less and there was a peak in the mean ratio of 1.16, SEM = 0.001, N = 16 pairs of profiles. An antibody to V-ATPase, which, by pumping protons into vacuoles contributes to cell growth, also indicated upregulation by about 40%. When compared directly with GAPDH, upregulation of V-ATPase was only 0.764, SD = 0.016 of GAPDH upregulation.ConclusionsAlthough there was considerable variation between individual measured profiles, on average, markers of the glycolytic pathway, of mitochondria, and of cell proliferation showed coherent upregulation in C6 gliomas. There is a zone, close to the rim, where mitochondrial presence is upregulated more than the glycolytic pathway, in agreement with earlier suggestions that lactate is taken up by cells near the rim.Electronic supplementary materialThe online version of this article (doi:10.1186/s13104-015-1191-z) contains supplementary material, which is available to authorized users.

A novel Nav1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis

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“…Our finding that the proliferating and invasive tumour periphery was more acidic than the hypoxic core agrees with a number of other studies (Helmlinger et al, 1997;Grillon et al, 2011;Grillon et al, 2015;White et al, 2017;Jardim-Perassi et al, 2019). Low extracellular pH in tumours promotes invasion by increasing activity of low pH-dependent enzymes that degrade the ECM, such as cysteine cathepsins (Gillet et al, 2009;Brisson et al, 2011).…”

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“…Thanks to previous studies, V-ATPase is known to be a key player in gliomagenesis, especially in isocitrate dehydrogenase 1 or 2 ( IDH1 or IDH2 ) wild-type gliomas [ 24 , 25 , 26 , 27 , 28 ]. Moreover, V-ATPase is supposed to participate in the drug resistance that characterizes high-grade gliomas, and it may be involved in the acidification of the glioma environment [ 26 , 29 ]. Finally, the expression of V-ATPase increases proportionally with the tumor’s grade [ 29 ].…”