Expression of Hypoxia-Inducible Factor 1α and Cathepsin D in Pituitary Adenomas

Abstract

Hypoxia-inducible factor (HIF)-1alpha is a crucial transcription factor involved in the adaptive response to hypoxia, whereas cathepsin D, which regulates angiostatin in several cancer cell lines, has been reported to be upregulated by HIF-1alpha. In order to determine the involvement of angiogenesis in pituitary adenomas, we studied the expression of both HIF-1alpha and cathepsin D in tissues from 58 patients (39 women, 19 men, ranging in age from 20 to 78 yr), sorted by histological group, and assayed by double immunohistochemistry. HIF-1alpha immunoreactivity, confined to the nucleoplasm, was present in both tumor and vascular endothelial cells. There was no difference in microvascular density (p = 0.7761) by histotype. ACTH-producing adenomas showed the lowest level of HIF-1alpha, whereas prolactin (PRL)-producing adenomas and HIF-1alpha-positive microvessels showed the highest (p < 0.001). In contrast, the lowest expression of cathepsin D was observed in PRL-producing adenomas, whereas the highest expression was detected in ACTH-producing adenomas (p < 0.0001). Imaging analysis with fluorescence double immunohistochemistry showed that HIF-1alpha-negative tumor cells did not express significantly higher levels of cathepsin D. In these poorly vascularized tumors, the hypoxic marker HIF-1alpha may not downregulate cathepsin D. The mechanisms of tumor angiogenesis and cell invasion in pituitary adenomas may differ from those in other tumor cells.