The Role of Classical and Novel Forms of Vitamin D in the Pathogenesis and Progression of Nonmelanoma Skin Cancers

Abstract

Nonmelanoma skin cancers including basal and squamous cell carcinomas (SCC and BCC) represent a significant clinical problem due to their relatively high incidence, imposing an economic burden to healthcare systems around the world. It is accepted that ultraviolet radiation (UVR: λ = 290-400 nm) plays a crucial role in the initiation and promotion of BCC and SCC with UVB (λ = 290-320 nm) having a central role in this process. On the other hand, UVB is required for vitamin D3 (D3) production in the skin, which supplies >90% of the body's requirement for this prohormone. Prolonged exposure to UVB can also generate tachysterol and lumisterol. Vitamin D3 itself and its canonical (1,25(OH)₂D3) and noncanonical (CYP11A1-intitated) D3 hydroxyderivatives show photoprotective functions in the skin. These include regulation of keratinocyte proliferation and differentiation, induction of anti-oxidative responses, inhibition of DNA damage and induction of DNA repair mechanisms, and anti-inflammatory activities. Studies in animals have demonstrated that D3 hydroxyderivatives can attenuate UVB or chemically induced epidermal cancerogenesis and inhibit growth of SCC and BCC. Genomic and non-genomic mechanisms of action have been suggested. In addition, vitamin D3 itself inhibits hedgehog signaling pathways which have been implicated in many cancers. Silencing of the vitamin D receptor leads to increased propensity to develop UVB or chemically induced epidermal cancers. Other targets for vitamin D compounds include 1,25D3-MARRS, retinoic orphan receptors α and γ, aryl hydrocarbon receptor, and Wnt signaling. Most recently, photoprotective effects of lumisterol hydroxyderivatives have been identified. Clinical trials demonstrated a beneficial role of vitamin D compounds in the treatment of actinic keratosis. In summary, recent advances in vitamin D biology and pharmacology open new exciting opportunities in chemoprevention and treatment of skin cancers.

Keywords: Basal cell carcinoma; RORα; RORγ; Squamous cell carcinoma; Ultraviolet radiation; VDR; Vitamin D.

Fig. 13.1

Ultraviolet B as the double-edge sword in skin health UVB not only induces skin cancers but also is necessary for phototransformation of 7DHC (7-dehydrocholesterol) to vitamin D3. BCC basal cell carcinoma, SCC invasive squamous cell carcinoma. (Reprinted from [208] with permission from Elsevier)

Fig. 13.2

Detection of CYP11A1-derived 7DHC and D3 hdroxyderivatives in the human epidermis and serum LC-MS spectra were measured on fractions with retention times corresponding to either 22(OH)7DHC or 20,22(OH)₂7DHC or 20(OH)D3, 22(OH)D3, or 25(OH)D3 that were pre-purified on a Waters C18 column (250 × 4.6 mm, 5 μm particle size) with a gradient of acetonitrile in water as described in [202]. Arrows indicate the retention times of the corresponding standards. Inserts show the mass spectra corresponding to the retention time of detected compound. In the outer panel, extracted ion chromatograms are shown for human epidermis (a and d), serum (b and e), and the pig adrenal (c and f). The work is reprinted from [202] under the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) with small modifications

Fig. 13.3

Detection of novel lumisterol hdroxyderivatives in the human epidermis and serum LC-MS spectra were measured on fractions with retention times corresponding to either of the hydroxyderivatives listed that were pre-purified on a Waters C18 column as described in [202]. Arrows indicate the retention times of the corresponding standards. Inserts show the mass spectra corresponding to the retention time of the detected compound. The work is reprinted from [202] under the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) with small modifications

Fig. 13.4

UVB-induced phototransformation of 7DHC, its hydroxyderivatives, and 7DHP to the corresponding secosteroidal, lumisterol, and tachysterol compounds Shown is the metabolism of 7DHC by CYP11A1, the skin, and the subsequent transformations to the corresponding photoproducts after exposure to UVB. (?) – the enzyme transforming 7DHC to 20(OH)7DHC remains to be identified, since none of the products of 7DHC hydroxylation by CYP11A1 has its retention time. Because of the similarity of 20(OH)7DHC and 20-hydroxycholesterol, it is likely to be the same enzyme that transforms cholesterol into 20-hydroxychaolesterol, which is also detectable in the epidermis. (Reprinted from [208] with permission from Elsevier)

Fig. 13.5

Crystal structures of 20(OH)D3, 1,20(OH)D3, and 1,25(OH)2D3 in complexes with the VDR ligand-binding domain The crystal structures of 20S(OH)D3, in complex with the Danio Rerio VDR (zVDR) LBD, were determined and compared to those of 1,20(OH)₂D3 and 1,25(OH)₂D3 VDR complexes as described previously [119]. The complexes with 20(OH)D3 (PDB ID 5OW9), 1,20(OH)₂D3 (PDB ID 5MX7), and 1,25(OH)₂D3 (PBD ID 2HC4) are shown in cyan, yellow, and salmon, respectively. Hydrogen bonds between the ligands and LBD are represented by purple dashed lines. Details of the interactions mediated by the side chains of 20(OH)D3 are in the second image from the left. Hydrophobic interactions are indicated by gray dashed lines, and hydrogen bonds are depicted as pink dashed lines. Only residues within 4 Å of the ligand are shown by stick representation. The residue numbers correspond to human VDR. The detailed description and analysis are in [119]. (The work is reprinted from [119] under the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) with small modifications)

Fig. 13.6

Immunohistochemical detection of RORα(upper), RORγ (middle), and VDR (lower) in normal skin (left panel), BCC (middle), and SCC (right). Scale bar: 50 μm. Archival formalin-fixed paraffin-embedded sections, after heat-induced antigen retrieval in Trisbased antigen unmasking solution (Vector Laboratories, Inc., Burlingame, CA) and endogenous peroxidase blocking, were incubated over night at 4 °C with primary antibodies (rabbit anti-RORα (provided by Dr. Anton M. Jetten), 1:400; rabbit anti-RORγ (provided by Dr. Anton M. Jetten), 1:50; rat anti-VDR (Abcam, MA1-710; Thermo Fisher Scientific, Waltham, MA)). Next, sections were incubated with secondary antibodies conjugated with HRP (anti-rabbit ImmPRESS antibody (ready to use, Vector Laboratories, Inc., Burlingame, CA) for RORα and RORγ; anti-rat antibody (1:200, Abcam, Cambridge, UK) for VDR), followed by peroxidase substrate ImmPACT NovaRED (Vector Laboratories Inc., Burlingame, CA, USA) application and mounting with permanent mounting media and glass coverslip (Thermo Fisher Scientific, Waltham, MA)

Fig. 13.7