Newly-identified Pathways Relating Vitamin D to Carcinogenesis: A Review

Abstract

Background: The epidemiological relationship between vitamin D levels and cancer has been thoroughly investigated. Published data from large studies appear to corroborate a significant relationship between higher serum vitamin D concentrations and improved survival. Mechanistic reviews on commonly-studied cancers -including breast cancer, colon cancer and melanoma -focus predominantly on data from older studies. In outlining avenues for future research, we believe there is utility in summarizing novel findings introduced to the literature. Materials and Methods: In this narrative review, we used MEDLINE, PUBMED and Cochrane databases to identify mechanistic studies published from January 1, 2015 onwards exploring this topic. Results: Twenty-five mechanistic studies were included in this review. It was found that vitamin D plays a critical role in both direct (i.e. tumor gene expression, proliferation, invasiveness, sensitivity to chemotherapy etc.) and indirect (i.e. effects on the tumor microenvironment and immunomodulation) tumor suppression mechanisms. Conclusion: These newly-identified pathways warrant further research, with the hopes that we may understand how and when vitamin D supplementation can be integrated into precision medicine therapeutics for cancers of the breast, colon and skin. Cancer care providers should consider recommendations to screen for vitamin D deficiency in this population.

Cross-talk of Aryl Hydrocarbon Receptor (AHR)- and Vitamin D Receptor (VDR)-signaling in Human Keratinocytes

“…It is well established that 1,25(OH) 2 D 3 exerts its cancerinhibiting activity in many cell types through various direct (e.g., regulation of the cell cycle, induction of apoptosis, inhibition of angiogenesis and tumor-invasiveness,metastasis and -proliferation) and indirect (e.g., regulation of immuno-modulation, effect on tumor microenvironment) mechanisms (95,118). Although AHR-activated CYP1A1 is associated with pro-carcinogen transformation and cancer development, some studies documented a contribution to cancer prevention (27).…”

“…Notably, it has been shown that 1,25(OH) 2 D 3 modulates the cell cycle through checkpoint regulation (118). Binding to the promoter region of genes encoding p21 and p27 results in cyclin dependent kinase (CDK) inhibition and cell cycle arrest in the G 1 phase via decreased cyclin D1 expression (95,118).…”

“…Notably, it has been shown that 1,25(OH) 2 D 3 modulates the cell cycle through checkpoint regulation (118). Binding to the promoter region of genes encoding p21 and p27 results in cyclin dependent kinase (CDK) inhibition and cell cycle arrest in the G 1 phase via decreased cyclin D1 expression (95,118). Interestingly, ligand-dependent AHR activation was also found to increase p21 and p27 expression in addition to CYP1A1, resulting in G 1 phase cell cycle arrest (119,120).…”

“…Indirect anti-cancer effects of 1,25(OH) 2 D 3 mainly concern the tumor microenvironment. They include modulation of immune mediators [e.g., DNA methylation of CpG regions, production of Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)], cancer-associated metabolic cascades (e.g., Inhibition of estrogenic signaling through down-regulation of CYP19A1, suppression of 27hydroxycholesterol (27HC) and CYP27A1), and homeostatic processes in surrounding tissues (e.g., down-regulation of pyruvate carboxylase, up-regulation of CYP3A4, reduction of AMP hydrolysis and adenosine production) (118). Interestingly, some of these effects may also be related to key players of AHR signaling.…”

Combinations of Calcitriol with Anticancer Treatments for Breast Cancer: An Update

“…In particular, BC cells have shown higher VDR protein levels compared to benign breast tissue [ 39 ]. Through this transcription factor, calcitriol exerts many anticancer effects, including growth inhibition, induction of cell differentiation, anti-inflammatory activity, cell cycle arrest, oncogenes downregulation, and many others that place calcitriol as a natural endogenous cancer-preventive antineoplastic factor [ 40 , 41 ]. This has been the basis of the vast number of studies designed to study calcitriol and its analogs as pharmacological options in the oncological setting [ 42 ].…”