Biological Significance of Lowered Tissue Oxygen Pressure in Pituitary Adenomas: A Review Article
1Department of Neurosurgery, Nippon Medical School Second Hospital
2Department of Neurosurgery, Nippon Medical School
3Clinical Neuroscience, Nippon Medical School Graduate School of Medicine
Hypoxia, the disruption of oxygen homeostasis induced by low oxygen supply, is critical in the development and progression of a large number of tumors. Various solid tumors are basically in a hypoxic condition, when growth exceeds vascular supply. Under such conditions, cellular oxygen concentration redirects cellular biosynthetic pathways to promote adaptation and enable survival. Recently, a transcriptional factor called hypoxia-inducible factor (HIF)-1α has been shown to play a crucial role in the regulation of many genes involved in the hypoxia adaptive pathway, especially vascular endothelial growth factor (VEGF). Under hypoxic conditions, many tumor cells promote angiogenesis via HIF-1α. Meanwhile pituitary tumors are solid tumors in which the regional oxygen saturation is lower than that of normal pituitary gland and the vasculature is usually poor. Despite expression of HIF-1α was confined in pituitary adenomas, its function driving to angiogenesis, apoptotic induction, and cell invasion, even though these issues have been extended in the other malignant tumors in recent years, has not yet been discussed. We have investigated the expression of microvascular density, HIF-1α, and VEGF in primary human pituitary adenomas focusing on the co-localization, and subsequently in vitro study, elucidated gene profiling regulated by HIF-1α.
Our previous studies indicated that HIF-1α immunoreactivity was confined to the nucleoplasm, but was present in both tumor cells and vascular endothelial cells. There was no difference in microvascular density by histotype. ACTH-producing adenomas showed the lowest level of HIF-1α, whereas PRL-producing adenomas and HIF-1α-positive microvessels showed the highest (p<0.001). There was no significant correlation in the expression levels of HIF-1α mRNA and VEGF mRNA in pituitary adenomas. Both of HIF-1α and VEGF proteins expressed in pituitary adenoma and they were, in part, co-localized. Transfection with specific siRNA duplexes knocked down HIF1-α mRNA and protein expression in hypoxia-exposed cells by approximately 80%. Microarray analysis indicated that HIF1-α down-regulated caspase-10, but up-regulated of laminin β2 (4.26 folds), SAP90 (3.34 folds), and BNIP3 (3.24 folds).
Conclusively in these poorly vascularized tumors, HIF-1α may not mainly regulate the VEGF expression in pituitary adenoma. In vitro studies strongly suggest that HIF 1-α exerts an antiapoptotic role in HP-75 in hypoxia mediated by down-regulation of caspase-10 and that hypoxia can potentially enhance the cell invasion properties of a pituitary adenoma cell line through elevated expression of laminin β-2. The mechanism of tumor angiogenesis and cell invasion in pituitary adenomas may differ from that in the other cancer cells.
日医大医会誌 2005; 1(3), 110-116
HP-75, hypoxia, hypoxia inducible factor, pituitary adenoma
Daizo Yoshida, Department of Neurosurgery, Nippon Medical School Second Hospital, 2-297-2 Kosugi-cho, Nakahara-ku, Kawasaki, Kanagawa 221-0063, Japan