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

Khuloud Bajbouj; Abeer Al-Ali; Jasmin Shafarin; Lina Sahnoon; Ahmad Sawan; Ahmed Shehada; Walaaeldin Elkhalifa; Maha Saber-Ayad; Jibran Sualeh Muhammad; Adel B Elmoselhi; Salman Y Guraya; Mawieh Hamad

doi:10.3389/fonc.2022.918340

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

Front Oncol. 2022 Jun 7:12:918340. doi: 10.3389/fonc.2022.918340. eCollection 2022.

Authors

Khuloud Bajbouj^{1

2}, Abeer Al-Ali², Jasmin Shafarin², Lina Sahnoon², Ahmad Sawan¹, Ahmed Shehada¹, Walaaeldin Elkhalifa¹, Maha Saber-Ayad^{1

2

3}, Jibran Sualeh Muhammad^{1

2}, Adel B Elmoselhi^{1

2

4}, Salman Y Guraya^{1

2}, Mawieh Hamad^{2

5}

Affiliations

¹ College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
² Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
³ Medical Pharmacology Department, Cairo University, Cairo, Egypt.
⁴ Department of Physiology, Michigan State University, East Lansing, MI, United States.
⁵ College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.

Abstract

Background: Numerous 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 methods: Publicly 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 discussions: The 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.

Conclusion: Our findings demonstrate that vitamin D mediates its antitumor effects in BC cells by inhibiting and curtailing their potential for VM formation.

Keywords: breast cancer; invasion; metalloproteinases; vasculogenic mimicry; vitamin D.