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Vitamin D Exerts Significant Antitumor Effects by Suppressing Vasculogenic Mimicry in Breast Cancer Cells
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9210804/ https://www.ncbi.nlm.nih.gov/pubmed/35747793 http://dx.doi.org/10.3389/fonc.2022.918340 |
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author | Bajbouj, Khuloud Al-Ali, Abeer Shafarin, Jasmin Sahnoon, Lina Sawan, Ahmad Shehada, Ahmed Elkhalifa, Walaaeldin Saber-Ayad, Maha Muhammad, Jibran Sualeh Elmoselhi, Adel B. Guraya, Salman Y. Hamad, Mawieh |
author_facet | Bajbouj, Khuloud Al-Ali, Abeer Shafarin, Jasmin Sahnoon, Lina Sawan, Ahmad Shehada, Ahmed Elkhalifa, Walaaeldin Saber-Ayad, Maha Muhammad, Jibran Sualeh Elmoselhi, Adel B. Guraya, Salman Y. Hamad, Mawieh |
author_sort | Bajbouj, Khuloud |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9210804 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92108042022-06-22 Vitamin D Exerts Significant Antitumor Effects by Suppressing Vasculogenic Mimicry in Breast Cancer Cells Bajbouj, Khuloud Al-Ali, Abeer Shafarin, Jasmin Sahnoon, Lina Sawan, Ahmad Shehada, Ahmed Elkhalifa, Walaaeldin Saber-Ayad, Maha Muhammad, Jibran Sualeh Elmoselhi, Adel B. Guraya, Salman Y. Hamad, Mawieh Front Oncol Oncology 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. Frontiers Media S.A. 2022-06-07 /pmc/articles/PMC9210804/ /pubmed/35747793 http://dx.doi.org/10.3389/fonc.2022.918340 Text en Copyright © 2022 Bajbouj, Al-Ali, Shafarin, Sahnoon, Sawan, Shehada, Elkhalifa, Saber-Ayad, Muhammad, Elmoselhi, Guraya and Hamad https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Bajbouj, Khuloud Al-Ali, Abeer Shafarin, Jasmin Sahnoon, Lina Sawan, Ahmad Shehada, Ahmed Elkhalifa, Walaaeldin Saber-Ayad, Maha Muhammad, Jibran Sualeh Elmoselhi, Adel B. Guraya, Salman Y. Hamad, Mawieh Vitamin D Exerts Significant Antitumor Effects by Suppressing Vasculogenic Mimicry in Breast Cancer Cells |
title | Vitamin D Exerts Significant Antitumor Effects by Suppressing Vasculogenic Mimicry in Breast Cancer Cells |
title_full | Vitamin D Exerts Significant Antitumor Effects by Suppressing Vasculogenic Mimicry in Breast Cancer Cells |
title_fullStr | Vitamin D Exerts Significant Antitumor Effects by Suppressing Vasculogenic Mimicry in Breast Cancer Cells |
title_full_unstemmed | Vitamin D Exerts Significant Antitumor Effects by Suppressing Vasculogenic Mimicry in Breast Cancer Cells |
title_short | Vitamin D Exerts Significant Antitumor Effects by Suppressing Vasculogenic Mimicry in Breast Cancer Cells |
title_sort | vitamin d exerts significant antitumor effects by suppressing vasculogenic mimicry in breast cancer cells |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9210804/ https://www.ncbi.nlm.nih.gov/pubmed/35747793 http://dx.doi.org/10.3389/fonc.2022.918340 |
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