Depletion of Ascorbic Acid Restricts Angiogenesis and Retards Tumor Growth in a Mouse Model

Abstract

Angiogenesis requires the deposition of type IV collagen by endothelial cells into the basement membrane of new blood vessels. Stabilization of type IV collagen triple helix depends on the hydroxylation of proline, which is catalyzed by the iron-containing enzyme prolyl hydroxylase. This enzyme, in turn, requires ascorbic acid to maintain the enzyme-bound iron in its reduced state. We hypothesized that dietary ascorbic acid might be required for tumor angiogenesis and, therefore, tumor growth. Here, we show that, not surprisingly, ascorbic acid is necessary for the synthesis of collagen type IV by human endothelial cells and for their effective migration and tube formation on a basement membrane matrix. Furthermore, ascorbic acid depletion in mice incapable of synthesizing ascorbic acid (Gulo-/-) dramatically restricts the in vivo growth of implanted Lewis lung carcinoma tumors. Histopathological analyses of these tumors reveal poorly formed blood vessels, extensive hemorrhagic foci, and decreased collagen and von Willebrand factor expression. Our data indicate that ascorbic acid plays an essential role in tumor angiogenesis and growth, and that restriction of ascorbic acid or pharmacological inhibition of prolyl hydroxylase may prove to be novel therapeutic approaches to the treatment of cancer.

Keywords

• Ascorbic acid
• tumor
• angiogenesis
• collagen
• prolyl hydroxylase