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-Hydroxylase in Dysgerminomas
From the Division of Medical Sciences,* Institute of Biomedical Research, The University of Birmingham, Birmingham, United Kingdom; the Division of Clinical and Molecular Endocrinology, Case Western Reserve University School of Medicine, Cleveland, Ohio; the Department of Fetal Medicine, Division of Reproduction and Child Health, Birmingham Women’s Hospital, Birmingham, United Kingdom; Department of Pathology, Royal Victoria Infirmary, the School of Clinical and Laboratory Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom; the Department of Medicine,¶ Fairview Health System, Cleveland, Ohio; and the Department of Endocrinology, Diabetes, and Metabolism,|| Cedars-Sinai Medical Center, Los Angeles, California
Humoral hypercalcemia of malignancy (HHM) is a common paraneoplastic disorder usually associated with increased synthesis of parathyroid hormone-related peptide (PTHrP). Unlike non-cancer forms of hypercalcemia, HHM does not routinely involve increased circulating levels of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Dysgerminomas are a notable exception to this rule, previous reports having described hypercalcemia with elevated serum 1,25(OH)2D3. To investigate the etiology of this form of HHM we have characterized expression and activity of the enzyme that catalyzes synthesis of 1,25(OH)2D3, 25-hydroxyvitamin D-1
-hydroxylase (1-hydroxylase), in a collection of 12 dysgerminomas. RT-PCR analyses indicated that mRNA for 1-hydroxylase was increased 222-fold in dysgerminomas compared to non-tumor ovarian tissue. Parallel enzyme assays in tissue homogenates showed that dysgerminomas produced fivefold higher levels of 1,25(OH)2D3 compared to normal ovarian tissue. Immunolocalization studies indicated that 1-hydroxylase was expressed by both tumor cells and by macrophages within the inflammatory cell infiltrate associated with dysgerminomas. The immunological nature of the increased 1,25(OH)2D3 production observed in dysgerminomas was further emphasized by correlation between expression of 1-hydroxylase and the endotoxin recognition factors CD14 and toll-like receptor 4 (TLR4). These data suggest that inflammatory mechanisms associated with dysgerminomas are the underlying cause of the increased expression and activity of 1-hydroxylase associated with these tumors. We further postulate that this autocrine/paracrine action of 1-hydroxylase may lead to increased circulating levels of 1,25(OH)2D3 and a form of HHM which is distinct from that seen with PTHrP-secreting tumors.
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