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Lookup NU author(s): Dr Judith Bulmer
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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)2D 3), 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-1α-hydroxylase (1α-hydroxylase), in a collection of 12 dysgerminomas. RT-PCR analyses indicated that mRNA for 1α-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 1α-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 1α-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 1α-hydroxylase associated with these tumors. We further postulate that this autocrine/paracrine action of 1α-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.
Author(s): Evans KN, Taylor H, Zehnder D, Kilby MD, Bulmer JN, Shah F, Adams JS, Hewison M
Publication type: Article
Publication status: Published
Journal: American Journal of Pathology
ISSN (print): 0002-9440
ISSN (electronic): 1525-2191
Publisher: American Society for Investigative Pathology
PubMed id: 15331405
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