Functional expression of membrane alanyl-aminopeptidase (CD13/APN) promotes tumor cell proliferation and neoangiogenesis in malignant gliomas.

Malignant gliomas are characterized by marked neovascularization and increased tumor cell proliferation. Recently, membrane alanyl-aminopeptidase (CD13/APN) has been identified to play a crucial role in neoangiogenesis. In this study, we show that among various central nervous system tumors, malignant astrocytomas are unique in their high expression levels of functionally active CD13/APN. CD13/APN was found in both tumor cells and tumor vessels of malignant astrocytomas, while in low-grade astrocytomas only endothelial cells of tumor vessels expressed CD13/APN. Inhibitors of the enzymatic activity of CD13/APN significantly reduced the proliferation of U87MG and U138MG malignant glioma cells. Inhibition of CD13/APN mRNA expression by siRNA in glioma cells co-cultured with human umbilical vein endothelial cells (HUVEC) effectively decreased blood vessel formation. Pro-angiogenic factors like bFGF and VEGF induced CD13/APN expression in glioma cells. Treatment of U87MG and U138MG cells with CD13/APN inhibitors resulted in an increased mRNA expression of VEGF and VEGF receptor 2 (VEGF-R2) in these cells. Taken together, these findings provide evidence that CD13/APN promotes tumor cell proliferation and blood vessel formation in malignant astrocytomas. Remarkably, inhibition of CD13/APN induces an angiogenic expression profile via an autocrine feed-back mechanism involving the VEGF/VEGF-R2 system in malignant gliomas.

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