New Roles for Vitamin D Superagonists: From COVID to Cancer

Abstract

Vitamin D is a potent steroid hormone that induces widespread changes in gene expression and controls key biological pathways. Here we review pathophysiology of vitamin D with particular reference to COVID-19 and pancreatic cancer. Utility as a therapeutic agent is limited by hypercalcemic effects and attempts to circumvent this problem have used vitamin D superagonists, with increased efficacy and reduced calcemic effect. A further caveat is that vitamin D mediates multiple diverse effects. Some of these (anti-fibrosis) are likely beneficial in patients with COVID-19 and pancreatic cancer, whereas others (reduced immunity), may be beneficial through attenuation of the cytokine storm in patients with advanced COVID-19, but detrimental in pancreatic cancer. Vitamin D superagonists represent an untapped resource for development of effective therapeutic agents. However, to be successful this approach will require agonists with high cell-tissue specificity.

Keywords: COVID-19; pancreatic cancer; pancreatic stellate cell; paricalcitol; superagonist; vitamin D.

Figure 1

Signaling pathways in late phase ARDS in patients with COVID-19; role of vitamin D Disease progression is influenced by stromal/inflammatory infiltrate. Epithelial cells are colored blue, lung stellate cells (yellow), lymphocytes (green), and myeloid cells: macrophages M1, M2 and neutrophils (grey). SARS-CoV-2 infected alveolar type II epithelial (ATE2) cells release IL8, recruiting inflammatory cells, with neutrophil secretion of IL-6 contributing to the cytokine storm. Lung fibrosis occurs via two pathways. Macrophages and lung stellate cells secrete angiotensin II, promoting myofibroblast formation and increasing ECM formation with hyaline membrane disease. ATE2 cells secrete TGF-β, which drives the myofibroblast phenotype. Predicted effects of vitamin D are labeled in red A–J as described in Table 6 , where labels indicate: B: Increased ACE/Ang II/AT1R signaling; C: Down-regulation of TGF-β-SMAD-dependent transcription; D: Inhibition of pro-inflammatory chemokine release; E: Increased antimicrobial peptides, defensins and cathelicidin; F: Maintains epithelial cell tight-junction integrity; G: Increased Treg activity; J: Decreased Neutrophil activity and increased NET formation. VDA effects D and E are likely more relevant in early stage COVID-19 respiratory tract infections.

Figure 2

Reciprocal signaling pathways between PDAC and myofibroblasts (myCAFs) and role of vitamin D, modified from (169, 176, 177). Cells are colored as in Figure 1 . Epithelial (PDAC) cells are blue and stromal cells, (PSCs) are yellow. Two broad pathways are shown: a PDAC-derived secretome, including TGF-β and Sonic hedgehog (SHH), upper and mechano-signaling via ECM/β-1 integrin and FAK (lower part of figure). TGF-β drives a myofibroblast phenotype. SHH signals via GLI to promote dysplasia. Ligands derived from myCAFs (including IGF1, AXL, TYRO3 and TGFα) support tumor growth and inhibit apoptosis. Predicted effects of vitamin D are labeled A-J as described in Table 6 , where labels indicate: A Pro-Differentiation and Anti-Proliferation; C Inhibition of fibrosis and down-regulation of TGF-β-SMAD-dependent transcription of pro-fibrotic genes and H Promotion of autophagy in PDAC cells and CAFs with provision of alanine to PDAC cells (178, 179).

Figure 3

Reciprocal signaling pathways within PDAC and iCAFs, modified from (170, 180) and role of vitamin D. Tumor cell interactions with immune cells (tumor associated macrophages (TAM), neutrophils and T cells are also indicated. Cells are colored as in Figures 1 and 2 . Stromal/inflammatory signaling pathways influence PDAC progression. Growth of PDAC cells is driven by cytokines and growth factors: LIF, IL-6 and SAA1 (derived from iCAFs), IL-4 (from TH2) and TGFα from TAMs. PDAC cells secrete IL-1α or TGF to drive an iCAF or myo-CAF phenotype. VDAs have direct effects upon cancer, stromal and immune cells and indirect effects upon intercellular signaling pathways. Predicted effects of vitamin D are labeled A-J as described in Table 6 , where labels indicate: D Inhibition of cytokine and pro-inflammatory chemokine release; E Increased macrophage production of cathelicidin and cleavage product (LL-37), associated with a cancer stem cell phenotype; G Suppression of immunity: increased Treg activity, activation of Th2 and suppression of Th1 cells; I Anti-tumor M1 phenotype conversion into immune-suppressive, pro-tumor M2 macrophages, and J Decreased neutrophil activity and increased formation of NETs. The role of vitamin D in NET formation remains controversial and is discussed above. All figures, tables, and images will be published under a Creative Commons CC-BY license, and permission must be obtained for use of copyrighted material from other sources (including re-published/adapted/modified/partial figures and images from the internet). It is the responsibility of the authors to acquire the licenses, follow any citation instructions requested by third-party rights holders, and cover any supplementary charges.