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The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling

Chemotherapy is one of the most common strategies for tumor treatment but often associated with post-therapy tumor recurrence. While chemotherapeutic drugs are known to induce tumor cell senescence, the roles and mechanisms of senescence in tumor recurrence remain unclear. In this study, we used dox...

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Autores principales: Zhang, Na, Ji, Jiafei, Zhou, Dandan, Liu, Xuan, Zhang, Xinglin, Liu, Yingqi, Xiang, Weifang, Wang, Meida, Zhang, Lian, Wang, Guannan, Huang, Baiqu, Lu, Jun, Zhang, Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830992/
https://www.ncbi.nlm.nih.gov/pubmed/33467780
http://dx.doi.org/10.3390/ijms22020849
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author Zhang, Na
Ji, Jiafei
Zhou, Dandan
Liu, Xuan
Zhang, Xinglin
Liu, Yingqi
Xiang, Weifang
Wang, Meida
Zhang, Lian
Wang, Guannan
Huang, Baiqu
Lu, Jun
Zhang, Yu
author_facet Zhang, Na
Ji, Jiafei
Zhou, Dandan
Liu, Xuan
Zhang, Xinglin
Liu, Yingqi
Xiang, Weifang
Wang, Meida
Zhang, Lian
Wang, Guannan
Huang, Baiqu
Lu, Jun
Zhang, Yu
author_sort Zhang, Na
collection PubMed
description Chemotherapy is one of the most common strategies for tumor treatment but often associated with post-therapy tumor recurrence. While chemotherapeutic drugs are known to induce tumor cell senescence, the roles and mechanisms of senescence in tumor recurrence remain unclear. In this study, we used doxorubicin to induce senescence in breast cancer cells, followed by culture of breast cancer cells with conditional media of senescent breast cancer cells (indirect co-culture) or directly with senescent breast cancer cells (direct co-culture). We showed that breast cancer cells underwent the epithelial–mesenchymal transition (EMT) to a greater extent and had stronger migration and invasion ability in the direct co-culture compared with that in the indirect co-culture model. Moreover, in the direct co-culture model, non-senescent breast cancer cells facilitated senescent breast cancer cells to escape and re-enter into the cell cycle. Meanwhile, senescent breast cancer cells regained tumor cell characteristics and underwent EMT after direct co-culture. We found that the Notch signaling was activated in both senescent and non-senescent breast cancer cells in the direct co-culture group. Notably, the EMT process of senescent and adjacent breast cancer cells was blocked upon inhibition of Notch signaling with N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester (DAPT) in the direct co-cultures. In addition, DAPT inhibited the lung metastasis of the co-cultured breast cancer cells in vivo. Collectively, data arising from this study suggest that both senescent and adjacent non-senescent breast cancer cells developed EMT through activating Notch signaling under conditions of intratumoral heterogeneity caused by chemotherapy, which infer the possibility that Notch inhibitors used in combination with chemotherapeutic agents may become an effective treatment strategy.
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spelling pubmed-78309922021-01-26 The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling Zhang, Na Ji, Jiafei Zhou, Dandan Liu, Xuan Zhang, Xinglin Liu, Yingqi Xiang, Weifang Wang, Meida Zhang, Lian Wang, Guannan Huang, Baiqu Lu, Jun Zhang, Yu Int J Mol Sci Article Chemotherapy is one of the most common strategies for tumor treatment but often associated with post-therapy tumor recurrence. While chemotherapeutic drugs are known to induce tumor cell senescence, the roles and mechanisms of senescence in tumor recurrence remain unclear. In this study, we used doxorubicin to induce senescence in breast cancer cells, followed by culture of breast cancer cells with conditional media of senescent breast cancer cells (indirect co-culture) or directly with senescent breast cancer cells (direct co-culture). We showed that breast cancer cells underwent the epithelial–mesenchymal transition (EMT) to a greater extent and had stronger migration and invasion ability in the direct co-culture compared with that in the indirect co-culture model. Moreover, in the direct co-culture model, non-senescent breast cancer cells facilitated senescent breast cancer cells to escape and re-enter into the cell cycle. Meanwhile, senescent breast cancer cells regained tumor cell characteristics and underwent EMT after direct co-culture. We found that the Notch signaling was activated in both senescent and non-senescent breast cancer cells in the direct co-culture group. Notably, the EMT process of senescent and adjacent breast cancer cells was blocked upon inhibition of Notch signaling with N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester (DAPT) in the direct co-cultures. In addition, DAPT inhibited the lung metastasis of the co-cultured breast cancer cells in vivo. Collectively, data arising from this study suggest that both senescent and adjacent non-senescent breast cancer cells developed EMT through activating Notch signaling under conditions of intratumoral heterogeneity caused by chemotherapy, which infer the possibility that Notch inhibitors used in combination with chemotherapeutic agents may become an effective treatment strategy. MDPI 2021-01-15 /pmc/articles/PMC7830992/ /pubmed/33467780 http://dx.doi.org/10.3390/ijms22020849 Text en © 2021 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Na
Ji, Jiafei
Zhou, Dandan
Liu, Xuan
Zhang, Xinglin
Liu, Yingqi
Xiang, Weifang
Wang, Meida
Zhang, Lian
Wang, Guannan
Huang, Baiqu
Lu, Jun
Zhang, Yu
The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling
title The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling
title_full The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling
title_fullStr The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling
title_full_unstemmed The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling
title_short The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling
title_sort interaction of the senescent and adjacent breast cancer cells promotes the metastasis of heterogeneous breast cancer cells through notch signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830992/
https://www.ncbi.nlm.nih.gov/pubmed/33467780
http://dx.doi.org/10.3390/ijms22020849
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