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Keywords:

  • brain tumors;
  • bystander effect;
  • choroid plexus;
  • GLUT1;
  • SVCT2;
  • vitamin C

Abstract

Thumbnail image of graphical abstract

In vitro and in vivo studies suggest that the basolateral membrane of choroid plexus cells, which is in contact with blood vessels, is involved in the uptake of the reduced form of vitamin C, ascorbic acid (AA), through the sodium-vitamin C cotransporter, (SVCT2). Moreover, very low levels of vitamin C were observed in the brains of SVCT2-null mice. The oxidized form of vitamin C, dehydroascorbic acid (DHA), is incorporated through the facilitative glucose transporters (GLUTs). In this study, the contribution of SVCT2 and GLUT1 to vitamin C uptake in human choroid plexus papilloma (HCPP) cells in culture was examined. Both the functional activity and the kinetic parameters of GLUT1 and SVCT2 in cells isolated from HCPP were observed. Finally, DHA uptake by GLUT1 in choroid plexus cells was assessed in the presence of phorbol-12-myristate-13-acetate (PMA)-activated human neutrophils. A marked increase in vitamin C uptake by choroid plexus cells was observed that was associated with superoxide generation and vitamin C oxidation (bystander effect). Thus, vitamin C can be incorporated by epithelial choroid plexus papilloma cells using the basolateral polarization of SVCT2 and GLUT1. This mechanism may be amplified with neutrophil infiltration (inflammation) of choroid plexus tumors.

In choroid plexus papilloma cells, the vitamin C transporters SVCT2 and GLUT1 are polarized to the basolateral epithelial membrane, where SVCT2 is essential for AA flux from the blood vessels into the brain. However, neutrophils, attracted by inflammation or the tumor microenvironment, can oxidize extracellular AA to DHA, thereby enabling its uptake through GLUT1. For the first time, we show the in vivo and in vitro basolateral co-distribution of functional SVCT2 and GLUT1 in epithelial cells. We postulate that patients with choroid plexus papillomas may continue to transport vitamin C from the blood to CSF. However, increased transport of oxidized vitamin C could generate pro-oxidative conditions that may help control tumor growth.