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Ferroptosis Inducers Kill Mesenchymal Stem Cells Affected by Neuroblastoma
SIMPLE SUMMARY: Bone marrow metastasis represents poor prognosis in neuroblastoma, and bone marrow mesenchymal stem cells play an important role in this progression. There is no effective way to intervene in bone marrow mesenchymal stem cells. We attempt to find one way to effectively kill these cel...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954189/ https://www.ncbi.nlm.nih.gov/pubmed/36831642 http://dx.doi.org/10.3390/cancers15041301 |
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author | Li, Xiangze Wang, Qi Xu, Chencheng Zhang, Lei Zhou, Jiquan Lv, Jingchun Xu, Min Jiang, Dapeng |
author_facet | Li, Xiangze Wang, Qi Xu, Chencheng Zhang, Lei Zhou, Jiquan Lv, Jingchun Xu, Min Jiang, Dapeng |
author_sort | Li, Xiangze |
collection | PubMed |
description | SIMPLE SUMMARY: Bone marrow metastasis represents poor prognosis in neuroblastoma, and bone marrow mesenchymal stem cells play an important role in this progression. There is no effective way to intervene in bone marrow mesenchymal stem cells. We attempt to find one way to effectively kill these cells. We found that ferroptosis induction might be an recommended approach. Our findings provide new strategies for therapy of neuroblastoma patients with bone marrow metastasis. ABSTRACT: Bone marrow (BM) is the most common site of neuroblastoma (NB) metastasis, and its involvement represents poor patient prognosis. In accordance with the “seed and soil” theory of tumor metastasis, BM provides a favorable environment for NB metastasis while bone marrow mesenchymal stem cells (BMSCs) have been recognized as a central part of tumor stroma formation. Yet, there is currently no effective method for intervening these BMSCs. We found that BMSCs affected by NB (NB-BMSCs) could significantly promote NB growth and migration. Additionally, tumor cell-endowed BMSCs showed stronger resistance to several chemotherapeutic agents. Surprisingly, NB-BMSCs were more sensitive to ferroptosis than normal BMSCs. NB-BMSCs had lower levels of intracellular free iron while synthesizing more iron-sulfur clusters and heme. Moreover, the Xc(−)/glutathione/glutathione peroxidase 4 (Xc(−)/GSH/GPX4) pathway of the anti-ferroptosis system was significantly downregulated. Accordingly, ferroptosis inducers erastin and RAS-selective lethal 3 (RSL3) could significantly kill NB-BMSCs with limited effects on normal BMSCs. BMSCs from NB patients with BM metastasis also showed poor anti-ferroptosis ability compared with those from NB patients without BM metastasis. In vivo studies suggested that co-injection of mice with BMSCs and NB cells could significantly promote the growth of tumor tissues compared with injecting NB cells alone. However, treatment with erastin or RSL3 resulted in the opposite effect to some extent. Our results revealed that NB-BMSCs were vulnerable to ferroptosis from downregulation of the Xc(−)/GSH/GPX4 pathway. Ferroptosis inducers could effectively kill NB-BMSCs, but not normal BMSCs. This study provides possible new ideas for the treatment of tumor-associated BMSCs in NB patients. |
format | Online Article Text |
id | pubmed-9954189 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99541892023-02-25 Ferroptosis Inducers Kill Mesenchymal Stem Cells Affected by Neuroblastoma Li, Xiangze Wang, Qi Xu, Chencheng Zhang, Lei Zhou, Jiquan Lv, Jingchun Xu, Min Jiang, Dapeng Cancers (Basel) Article SIMPLE SUMMARY: Bone marrow metastasis represents poor prognosis in neuroblastoma, and bone marrow mesenchymal stem cells play an important role in this progression. There is no effective way to intervene in bone marrow mesenchymal stem cells. We attempt to find one way to effectively kill these cells. We found that ferroptosis induction might be an recommended approach. Our findings provide new strategies for therapy of neuroblastoma patients with bone marrow metastasis. ABSTRACT: Bone marrow (BM) is the most common site of neuroblastoma (NB) metastasis, and its involvement represents poor patient prognosis. In accordance with the “seed and soil” theory of tumor metastasis, BM provides a favorable environment for NB metastasis while bone marrow mesenchymal stem cells (BMSCs) have been recognized as a central part of tumor stroma formation. Yet, there is currently no effective method for intervening these BMSCs. We found that BMSCs affected by NB (NB-BMSCs) could significantly promote NB growth and migration. Additionally, tumor cell-endowed BMSCs showed stronger resistance to several chemotherapeutic agents. Surprisingly, NB-BMSCs were more sensitive to ferroptosis than normal BMSCs. NB-BMSCs had lower levels of intracellular free iron while synthesizing more iron-sulfur clusters and heme. Moreover, the Xc(−)/glutathione/glutathione peroxidase 4 (Xc(−)/GSH/GPX4) pathway of the anti-ferroptosis system was significantly downregulated. Accordingly, ferroptosis inducers erastin and RAS-selective lethal 3 (RSL3) could significantly kill NB-BMSCs with limited effects on normal BMSCs. BMSCs from NB patients with BM metastasis also showed poor anti-ferroptosis ability compared with those from NB patients without BM metastasis. In vivo studies suggested that co-injection of mice with BMSCs and NB cells could significantly promote the growth of tumor tissues compared with injecting NB cells alone. However, treatment with erastin or RSL3 resulted in the opposite effect to some extent. Our results revealed that NB-BMSCs were vulnerable to ferroptosis from downregulation of the Xc(−)/GSH/GPX4 pathway. Ferroptosis inducers could effectively kill NB-BMSCs, but not normal BMSCs. This study provides possible new ideas for the treatment of tumor-associated BMSCs in NB patients. MDPI 2023-02-18 /pmc/articles/PMC9954189/ /pubmed/36831642 http://dx.doi.org/10.3390/cancers15041301 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Li, Xiangze Wang, Qi Xu, Chencheng Zhang, Lei Zhou, Jiquan Lv, Jingchun Xu, Min Jiang, Dapeng Ferroptosis Inducers Kill Mesenchymal Stem Cells Affected by Neuroblastoma |
title | Ferroptosis Inducers Kill Mesenchymal Stem Cells Affected by Neuroblastoma |
title_full | Ferroptosis Inducers Kill Mesenchymal Stem Cells Affected by Neuroblastoma |
title_fullStr | Ferroptosis Inducers Kill Mesenchymal Stem Cells Affected by Neuroblastoma |
title_full_unstemmed | Ferroptosis Inducers Kill Mesenchymal Stem Cells Affected by Neuroblastoma |
title_short | Ferroptosis Inducers Kill Mesenchymal Stem Cells Affected by Neuroblastoma |
title_sort | ferroptosis inducers kill mesenchymal stem cells affected by neuroblastoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954189/ https://www.ncbi.nlm.nih.gov/pubmed/36831642 http://dx.doi.org/10.3390/cancers15041301 |
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