Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence
Abstract Background Sunitinib, a receptor tyrosine kinase (RTK) inhibitor that targets multiple receptors such as vascular endothelial growth factor receptors (VEGFRs), was approved for cancer treatment in 2006. However, it was unsuccessful in treating certain cancers, particularly metastatic breast...
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2020-09-01
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Online Access: | http://link.springer.com/article/10.1186/s13058-020-01346-y |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Denian Wang Fei Xiao Zhongxue Feng Min Li Lingmiao Kong Luping Huang Yong’gang Wei Hongyu Li Fei Liu Haili Zhang Wei Zhang |
spellingShingle |
Denian Wang Fei Xiao Zhongxue Feng Min Li Lingmiao Kong Luping Huang Yong’gang Wei Hongyu Li Fei Liu Haili Zhang Wei Zhang Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence Breast Cancer Research Sunitinib Metastatic breast cancer (MBC) Receptor tyrosine kinase (RTK) Cell senescence Metastasis |
author_facet |
Denian Wang Fei Xiao Zhongxue Feng Min Li Lingmiao Kong Luping Huang Yong’gang Wei Hongyu Li Fei Liu Haili Zhang Wei Zhang |
author_sort |
Denian Wang |
title |
Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence |
title_short |
Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence |
title_full |
Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence |
title_fullStr |
Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence |
title_full_unstemmed |
Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence |
title_sort |
sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence |
publisher |
BMC |
series |
Breast Cancer Research |
issn |
1465-542X |
publishDate |
2020-09-01 |
description |
Abstract Background Sunitinib, a receptor tyrosine kinase (RTK) inhibitor that targets multiple receptors such as vascular endothelial growth factor receptors (VEGFRs), was approved for cancer treatment in 2006. However, it was unsuccessful in treating certain cancers, particularly metastatic breast cancer (MBC), and the mechanism underlying this “sunitinib resistance” remains unclear. Herein, we investigated whether the sunitinib-associated inferior survival benefit in MBC was due to sunitinib-induced endothelial cell (EC) injury or EC senescence. Methods 4T1 murine breast cancer cells were used as the main breast tumor model for it produces a highly metastatic solid tumor that can spontaneously metastasize to the lung, which closely mimics highly metastatic human breast cancer. Senescence-associated β-galactosidase (SA-β-Gal, immunohistochemistry [IHC]-staining), P16, P53, and P57 (immunoblotting) were used as markers of cell senescence. A protein array containing 25 senescence-associated chemokines and the transwell chemotaxis assay were used to examine whether sunitinib increases inflammatory chemokine secretion which attracts tumor cells via chemokinesis. Flow cytometry and IHC were used to detect whether the sunitinib-induced senescent ECs recruit cancer-associated inflammatory myeloid cells. Finally, the spontaneous metastatic model was used to monitor whether sunitinib causes the formation of “pre-metastatic niche” which promotes MBC to metastasize to the lungs. Results We demonstrated that sunitinib induced a senescence-like endothelial cell (EC) phenotype. Inflammatory chemokine secretion and VCAM1 expression were significantly increased in senescent ECs, resulting in tumor cell (TC) chemotaxis and TC/EC interactions. Meanwhile, EC senescence caused loosening of EC junctions, facilitating TC transmigration through the endothelial barrier. Sunitinib-induced senescent ECs also recruited cancer-associated myeloid cells to form a “pre-metastatic niche”-like microenvironment. Alterations at the molecular level and in the tissue environment ultimately led to an increase in distant metastasis. Conclusion Although sunitinib was designed to target the EC directly, the increase in tumor metastasis may ironically be due to sunitinib “correctly” playing its role. Our findings suggest that we should carefully weigh the pros and cons before using sunitinib and other antiangiogenic drugs that directly target the ECs. |
topic |
Sunitinib Metastatic breast cancer (MBC) Receptor tyrosine kinase (RTK) Cell senescence Metastasis |
url |
http://link.springer.com/article/10.1186/s13058-020-01346-y |
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doaj-a90d5d42827e45bab86da03abd0e9f2a2021-04-02T15:44:24ZengBMCBreast Cancer Research1465-542X2020-09-0122111310.1186/s13058-020-01346-ySunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescenceDenian Wang0Fei Xiao1Zhongxue Feng2Min Li3Lingmiao Kong4Luping Huang5Yong’gang Wei6Hongyu Li7Fei Liu8Haili Zhang9Wei Zhang10Department of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyDepartment of Intensive Care Unit of Gynecology and Obstetrics, West China Second University Hospital, Sichuan UniversityDepartment of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyDepartment of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyDepartment of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyDepartment of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyDepartment of Liver Surgery, West China Hospital, Sichuan UniversityLiver Transplantation Center, Beijing Friendship Hospital, Capital Medical UniversityDepartment of Liver Surgery, West China Hospital, Sichuan UniversityDepartment of Liver Surgery, West China Hospital, Sichuan UniversityDepartment of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyAbstract Background Sunitinib, a receptor tyrosine kinase (RTK) inhibitor that targets multiple receptors such as vascular endothelial growth factor receptors (VEGFRs), was approved for cancer treatment in 2006. However, it was unsuccessful in treating certain cancers, particularly metastatic breast cancer (MBC), and the mechanism underlying this “sunitinib resistance” remains unclear. Herein, we investigated whether the sunitinib-associated inferior survival benefit in MBC was due to sunitinib-induced endothelial cell (EC) injury or EC senescence. Methods 4T1 murine breast cancer cells were used as the main breast tumor model for it produces a highly metastatic solid tumor that can spontaneously metastasize to the lung, which closely mimics highly metastatic human breast cancer. Senescence-associated β-galactosidase (SA-β-Gal, immunohistochemistry [IHC]-staining), P16, P53, and P57 (immunoblotting) were used as markers of cell senescence. A protein array containing 25 senescence-associated chemokines and the transwell chemotaxis assay were used to examine whether sunitinib increases inflammatory chemokine secretion which attracts tumor cells via chemokinesis. Flow cytometry and IHC were used to detect whether the sunitinib-induced senescent ECs recruit cancer-associated inflammatory myeloid cells. Finally, the spontaneous metastatic model was used to monitor whether sunitinib causes the formation of “pre-metastatic niche” which promotes MBC to metastasize to the lungs. Results We demonstrated that sunitinib induced a senescence-like endothelial cell (EC) phenotype. Inflammatory chemokine secretion and VCAM1 expression were significantly increased in senescent ECs, resulting in tumor cell (TC) chemotaxis and TC/EC interactions. Meanwhile, EC senescence caused loosening of EC junctions, facilitating TC transmigration through the endothelial barrier. Sunitinib-induced senescent ECs also recruited cancer-associated myeloid cells to form a “pre-metastatic niche”-like microenvironment. Alterations at the molecular level and in the tissue environment ultimately led to an increase in distant metastasis. Conclusion Although sunitinib was designed to target the EC directly, the increase in tumor metastasis may ironically be due to sunitinib “correctly” playing its role. Our findings suggest that we should carefully weigh the pros and cons before using sunitinib and other antiangiogenic drugs that directly target the ECs.http://link.springer.com/article/10.1186/s13058-020-01346-ySunitinibMetastatic breast cancer (MBC)Receptor tyrosine kinase (RTK)Cell senescenceMetastasis |