Stromal cell oxidation: A mechanism by which tumors obtain vitamin C

Human tumors may contain high concentrations of ascorbic acid, but little i s known about how they acquire the vitamin. Certain specialized cells can t ransport ascorbic acid directly through a sodium ascorbate cotransporter, b ut in most cells, vitamin C enters through the facilitative glucose transpo rters (GLUTs) in the form of dehydroascorbic acid, which is then reduced in tracellularly and retained as ascorbic acid. Mice with established hematopo ietic and epithelial cell xenografts were studied for the accumulation of i njected ascorbic acid and dehydroascorbic acid. Most hematopoietic and epit helial tumor cell lines can only transport vitamin C in the oxidized form ( dehydroascorbic acid) in vitro; however, when grown as xenografts in mice, they rapidly accumulated vitamin C after administration of radiolabeled asc orbic acid, The involvement of the GLUTs in vitamin C uptake by the xenogra fted tumors was demonstrated by competitive inhibition with D-glucose but n ot L-glucose, Because the malignant cells were not capable of directly tran sporting ascorbic acid, we reasoned that the ascorbic acid was oxidized to dehydroascorbic acid in the tumor microenvironment. Tumor accumulation of v itamin C in animals injected,vith ascorbic acid was inhibited by coadminist ration of superoxide dismutase, implying a role for superoxide anion in the oxidation of ascorbic acid. Whereas the epithelial cancer cell lines could not generate superoxide anion in culture, the minced xenograft tumors did. Our studies show the transport of dehydroascorbic acid by GLUTs is a means by which tumors acquire vitamin C and indicate the oxidation of ascorbic a cid by superoxide anion produced by cells in the tumor stroma as a mechanis m for generating the transportable form of the vitamin.