Biological actions of extra-renal 25-hydroxyvitamin D-1α-hydroxylase and implications for chemoprevention and treatment

The Vitamin D-activating enzyme 25-hydroxyvitamin D-1α-hydroxylase (1α-hydroxylase) is now known to be expressed in a much wider range of tissues that previously thought, suggesting a role for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), which is more in keeping with a cytokine than a hormone. In this capacity, the function of 1α-hydroxylase in tumors is far from clear. Studies from several groups including ours have shown altered expression of 1α-hydroxylase in different types of neoplasm including breast, prostate and colon cancers. However, functional analysis of Vitamin D metabolism in cancer is complicated by the heterogenous composition of tumors. Immunohistochemical analysis of breast tumors has shown that 1α-hydroxylase is expressed by both epithelial cells and by tumor-infiltrating macrophages, suggesting an immunomodulatory component to 1,25(OH)2D3 production in some types of cancer. The demonstration of 1α-hydroxylase activity in tumors and their equivalent normal tissues has implications for both the treatment and prevention of cancers. For example, in tumors chemotherapy options may include the use of non-1α-hydroxylated Vitamin D analogs to increase local concentrations of active metabolites without systemic side-effects. The role of 1α-hydroxylase in protection against cancer is likely to be more complicated and may involve anti-tumor immune responses.