Increased expression of 25-hydroxyvitamin D-1α-hydroxylase in dysgerminomas: A novel form of humoral hypercalcemia of malignancy

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 D 3 (1,25(OH) 2 D 3 ). Dysgerminomas are a notable exception to this rule, previous reports having described hypercalcemia with elevated serum 1,25(OH) 2 D 3 . 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) 2 D 3 , 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) 2 D 3 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) 2 D 3 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) 2 D 3 and a form of HHM which is distinct from that seen with PTHrP-secreting tumors.