Regulation of aminopeptidase A in human brain tumor vasculature: Evidence for a role of transforming growth factor-beta

Angiotensin peptides are potent vasoconstrictors, cell growth factors, and neuromodulators in normal and pathological situations. To assess the potent ial role of the angiotensins in brain tumor-associated vessels, the express ion of the enzymes of the angiotensin cascade were evaluated in these tumor s. The production of these bioactive peptides is dependent on the activitie s of exopeptidases, including several aminopeptidases and carboxypeptidases , producing angiotensin (Ang) I, II, III, IV and Ang 1-7. Human cerebral pa renchymal and glioblastoma cells expressed renin, and tumor vasculature, bu t not glioblastoma cells, expressed angiotensin-converting enzyme. High ami nopeptidase A (APA) activity, but no aminopeptidase N/B activity, was obser ved in human brain tumor vasculature, suggesting a predominant production o f Ang ill. Grafting of rat glioma cells in rat brains yielded tumors with h igh APA and low aminopeptidase N/B activities in tumor vessels, confirming human results. Tumor growth and APA activity in tumor vessels were not affe cted by chronic angiotensin-converting enzyme inhibition. The brain-derived EC219 endothelial cells expressed high APA activity, which was not involve d in endothelial cell proliferation, but was down-regulated by exposure of cells to transforming growth factor-beta (TGF beta) or to TGF beta-secretin g tumor cells, suggesting a role for this peptide in the control of APA act ivity in cerebral vasculature. Thus, APA is a potential marker of chronic d ysfunction, involving loss of TGF beta function, of the metabolic blood-bra in barrier, but not of neovascularization.