Vitamin D Exerts Significant Antitumor Effects by Suppressing Vasculogenic Mimicry in Breast Cancer Cells

Abstract

BackgroundNumerous clinical and experimental observations have alluded to the substantial anti-neoplastic role of vitamin D in breast cancer (BC), primarily by inducing apoptosis and affecting metastasis. Tumor progression and resistance to chemotherapy have been linked to vasculogenic mimicry (VM), which represents the endothelial-independent formation of microvascular channels by cancer cells. However, the effect of vitamin D on VM formation in BC has not been thoroughly investigated. This study examined the impact of 1α,25-dihydroxyvitamin D3 (calcitriol), the active form of vitamin D, on the expression of major factors involved in BC migration, invasion, and VM formation.Experimental MethodsPublicly available transcriptomic datasets were used to profile the expression status of the key VM markers in vitamin D-treated BC cells. The in silico data were validated by examining the expression and activity of the key factors that are involved in tumor progression and MV formation in hormone-positive MCF-7 and aggressive triple‐negative MDA-MB-231 BC cells after treatment with calcitriol.Results and DiscussionsThe bioinformatics analysis showed that tumor VM formation-enriched pathways were differentially downregulated in vitamin D-treated cells when compared with control counterparts. Treatment of BC cells with calcitriol resulted in increased expression of tissue inhibitors of metalloproteinases (TIMPs 1 and 2) and decreased content and gelatinolytic activity of matrix metalloproteinases (MMPs 2 and 9). Furthermore, calcitriol treatment reduced the expression of several pro-MV formation regulators including vascular endothelial growth factor (VEGF), tumor growth factor (TGF-β1), and amphiregulin. Eventually, this process resulted in a profound reduction in cell migration and invasion following the treatment of BC cells with calcitriol when compared to the controls. Finally, the formation of VM was diminished in the aggressive triple‐negative MDA-MB-231 cancer cell line after calcitriol treatment.ConclusionOur findings demonstrate that vitamin D mediates its antitumor effects in BC cells by inhibiting and curtailing their potential for VM formation.

Endothelium-Dependent Induction of Vasculogenic Mimicry in Human Triple-Negative Breast Cancer Cells Is Inhibited by Calcitriol and Curcumin

“…Also, calcitriol exerts potent anti-inflammatory activity, partially through downregulating JAK-STAT pathway activation and inflammatory cytokine production, processes known to be involved in carcinogenesis and VM [ 16 , 17 ]; however, calcitriol’s effects upon VM has not been explored. Regarding this, while this article was under peer review, Khuloud Bajbouj et al, reported that calcitriol differentially downregulated VM-related pathways and the expression of key VM markers in calcitriol-treated breast cancer cells by an in silico analysis of transcriptomic databases [ 18 ]. The same research group also showed that a very high concentration of calcitriol (10 μM) stimulated the expression of tissue inhibitors of MMPs (TIMPs) and decreased that of MMPs, lowering the formation of VM in MDA-MB-231 cells [ 18 ].…”

“…Regarding this, while this article was under peer review, Khuloud Bajbouj et al, reported that calcitriol differentially downregulated VM-related pathways and the expression of key VM markers in calcitriol-treated breast cancer cells by an in silico analysis of transcriptomic databases [ 18 ]. The same research group also showed that a very high concentration of calcitriol (10 μM) stimulated the expression of tissue inhibitors of MMPs (TIMPs) and decreased that of MMPs, lowering the formation of VM in MDA-MB-231 cells [ 18 ]. The effects of curcumin, those of nanomolar calcitriol concentrations, and those exerted by the combination of these compounds on VM development in breast cancer, as well as the mechanisms potentially involved, do, however, remain unknown, which were the originating concepts of our research question.…”

Prognostic role of plasma vitamin D and its association with disease characteristics in germ cell tumours

“…Studies evaluating the function of vitamin D proposed that the metastatic cascade is affected by the vitamin D plasma serum level ( 35 – 38 ); therefore, we hypothesize that there might be an association between the site and/or presence of metastases and the vitamin D plasma level in germ cell tumor patients. Positive association between low vitamin D level and promotion of bone metastasis as well as lung metastases in mice with breast tumor models was well described ( 36 , 39 ); thus, potential correlation between clinic-pathological variables in testicular germ cell tumor and vitamin D plasma level might be present as well.…”

Pan-cancer dissection of vasculogenic mimicry characteristic to provide potential therapeutic targets

“…EMT can cause tumor cells to lose epithelial markers and acquire mesenchymal characteristics, giving tumor cells phenotypic plasticity, thereby enhance the motility and invasiveness of tumor cells and facilitate VM formation ( Xiao et al, 2023 ). In addition, various cytokines have been identified as contributing to the formation of VM, such as IL6, IL8, IL17, VEGF and TGF-β ( Yang et al, 2016 ; Sharma et al, 2018 ; Bajbouj et al, 2022 ; Hu et al, 2022 ). Most of the them work by activating the biological process of EMT.…”