ABSTRACT
Calcitriol (1,25-dihydroxycholecalciferol, vitamin D3), the major active form of vitamin D, is anti-proliferative in tumor cells and tumor-derived endothelial cells The actions of calcitriol are mediated, in part by vitamin D receptor (VDR), which is expressed in many tissues including endothelial cells. Chung et al (Chung et al. 2009) examined the role of VDR in mediating the effects of calcitriol on the tumor vasculature using in vivo tumor model established in either VDR wild type (WT) or VDR-knockout (KO) mice. These researchers found that calcitriol treatment produced growth inhibition of tumor-derived endothelial cells expressing VDR, but those from VDR-KO mice were relatively resistant. These researchers also demonstrated that blood vessels in VDR-KO mice were enlarged and had less pericyte coverage compared to WT. There was increased expression of HIF-1a, VEGF, Ang-1 and PDGF-BB levels by tumors from VDR-KO mice. Collectively, these results suggest that calcitriol attenuation of tumor angiogenesis is VDR dependent; loss of VDR may lead to abnormal tumor angiogenesis. Levine and Teegarden (Levine and Teegarden 2004) showed that 1,25-dihydroxycholecalciferol altered the angiogenic phenotype of the cells. The VEGF promoter was activated by 1,25-dihydroxycholecalciferol in a dose-dependent leading to the induction of VEGF mRNA expression, and secretion of VEGF protein. Thus, these data provide evidence that 1,25-dihydroxycholecalciferol modulates angiogenesis in normal and disease states. Since 1,25-dihydroxycholecalciferol affects multiple cellular signaling pathways and modulate a variety of cellular processes including proliferation, differentiation, and apoptosis in multiple cell types, it is possible that complex signaling could also affect angiogenesis (Krishnan et al. 2003). Research in chondrocytes and osteoblasts demonstrated that in addition to inducing proliferation and growth, 1,25-dihydroxycholecalciferol increases VEGF mRNA and secretion, subsequently increasing angiogenesis in bone, which is critical to normal bone development, maintenance, and fracture healing. VEGF secretion was also enhanced by 1,25-dihydroxycholecalciferol treatment of vascular smooth muscle cells, the primary source of circulating VEGF (Levine and Teegarden 2004). Conversely, 1,25-dihydroxycholecalciferol suppresses angiogenesis, tumor size and number, and VEGF staining in several animal models of cancer (BenShoshan et al. 2007; Chung et al. 2009; Gonzalez-Pardo et al. 2010). In this case, 1,25-dihydroxycholecalciferol suppresses endothelial cell migration. Therefore, the suppression of angiogenesis in some animal models of cancer may be partially explained by reduction of the proliferating tumor cell population, thus decreasing the source of VEGF. There is evidence that 1,25-dihydroxycholecalciferol regulates angiogenesis and VEGF production, although the exact targets of 1,25-dihydroxycholecalciferol remains unclear. The effects of 1,25-dihydroxycholecalciferol on VEGF, and therefore angiogenesis, may depend on the cell type and model system studied.
