Tumor Necrosis Factor-α (TNFα) Stimulates Triple-Negative Breast Cancer Stem Cells to Promote Intratumoral Invasion and Neovasculogenesis in the Liver of a Xenograft Model
TNBC represents the most aggressive breast cancer subtype. Although cancer stem cells (CSCs) are a minor fraction of all cancer cells, they are highly cancerous when compared to their non-stem counterparts, playing a major role in tumor recurrence and metastasis. Angiogenic stimuli and the tumor env...
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MDPI AG
2022-10-01
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| Series: | Biology |
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| Online Access: | https://www.mdpi.com/2079-7737/11/10/1481 |
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| author | Harini Narasimhan Francesca Ferraro Andreas Bleilevens Ralf Weiskirchen Elmar Stickeler Jochen Maurer |
| author_facet | Harini Narasimhan Francesca Ferraro Andreas Bleilevens Ralf Weiskirchen Elmar Stickeler Jochen Maurer |
| author_sort | Harini Narasimhan |
| collection | DOAJ |
| description | TNBC represents the most aggressive breast cancer subtype. Although cancer stem cells (CSCs) are a minor fraction of all cancer cells, they are highly cancerous when compared to their non-stem counterparts, playing a major role in tumor recurrence and metastasis. Angiogenic stimuli and the tumor environment response are vital factors in cancer metastasis. However, the causes and effects of tumor angiogenesis are still poorly understood. In this study, we demonstrate TNFα effects on primary triple-negative breast cancer stem cells (BCSCs). TNFα stimulation increased the mesenchymality of BCSCs in an intermediate epithelial-to-mesenchymal transition (EMT) state, enhanced proliferation, self-renewal, and invasive capacity. TNFα-treatment elicited BCSC signaling on endothelial networks in vitro and increased the network forming capacity of the endothelial cells. Our findings further demonstrate that TNFα stimulation in BCSCs has the ability to instigate distinct cellular communication within the tumor microenvironment, inducing intra-tumoral stromal invasion. Further, TNFα-treatment in BCSCs induced a pre-metastatic niche through breast-liver organ crosstalk by inducing vascular cell adhesion molecule-1 (VCAM-1) enriched neovasculogenesis in the liver of tumor-bearing mice. Overall, TNFα is an important angiogenic target to be considered in breast cancer progression to attenuate any angiogenic response in the tumor environment that could lead to secondary organ metastasis. |
| first_indexed | 2024-03-09T20:40:00Z |
| format | Article |
| id | doaj.art-94129cc1e49f4a2c85475bed40d823b3 |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-09T20:40:00Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-94129cc1e49f4a2c85475bed40d823b32023-11-23T23:00:16ZengMDPI AGBiology2079-77372022-10-011110148110.3390/biology11101481Tumor Necrosis Factor-α (TNFα) Stimulates Triple-Negative Breast Cancer Stem Cells to Promote Intratumoral Invasion and Neovasculogenesis in the Liver of a Xenograft ModelHarini Narasimhan0Francesca Ferraro1Andreas Bleilevens2Ralf Weiskirchen3Elmar Stickeler4Jochen Maurer5Department of Obstetrics and Gynecology, University Hospital Aachen, D-52074 Aachen, GermanyDepartment of Obstetrics and Gynecology, University Hospital Aachen, D-52074 Aachen, GermanyDepartment of Obstetrics and Gynecology, University Hospital Aachen, D-52074 Aachen, GermanyInstitute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC) RWTH University Hospital Aachen, D-52074 Aachen, GermanyDepartment of Obstetrics and Gynecology, University Hospital Aachen, D-52074 Aachen, GermanyDepartment of Obstetrics and Gynecology, University Hospital Aachen, D-52074 Aachen, GermanyTNBC represents the most aggressive breast cancer subtype. Although cancer stem cells (CSCs) are a minor fraction of all cancer cells, they are highly cancerous when compared to their non-stem counterparts, playing a major role in tumor recurrence and metastasis. Angiogenic stimuli and the tumor environment response are vital factors in cancer metastasis. However, the causes and effects of tumor angiogenesis are still poorly understood. In this study, we demonstrate TNFα effects on primary triple-negative breast cancer stem cells (BCSCs). TNFα stimulation increased the mesenchymality of BCSCs in an intermediate epithelial-to-mesenchymal transition (EMT) state, enhanced proliferation, self-renewal, and invasive capacity. TNFα-treatment elicited BCSC signaling on endothelial networks in vitro and increased the network forming capacity of the endothelial cells. Our findings further demonstrate that TNFα stimulation in BCSCs has the ability to instigate distinct cellular communication within the tumor microenvironment, inducing intra-tumoral stromal invasion. Further, TNFα-treatment in BCSCs induced a pre-metastatic niche through breast-liver organ crosstalk by inducing vascular cell adhesion molecule-1 (VCAM-1) enriched neovasculogenesis in the liver of tumor-bearing mice. Overall, TNFα is an important angiogenic target to be considered in breast cancer progression to attenuate any angiogenic response in the tumor environment that could lead to secondary organ metastasis.https://www.mdpi.com/2079-7737/11/10/1481triple-negative breast cancercancer stem cellsTNFαEMTseed-and-soil theory |
| spellingShingle | Harini Narasimhan Francesca Ferraro Andreas Bleilevens Ralf Weiskirchen Elmar Stickeler Jochen Maurer Tumor Necrosis Factor-α (TNFα) Stimulates Triple-Negative Breast Cancer Stem Cells to Promote Intratumoral Invasion and Neovasculogenesis in the Liver of a Xenograft Model Biology triple-negative breast cancer cancer stem cells TNFα EMT seed-and-soil theory |
| title | Tumor Necrosis Factor-α (TNFα) Stimulates Triple-Negative Breast Cancer Stem Cells to Promote Intratumoral Invasion and Neovasculogenesis in the Liver of a Xenograft Model |
| title_full | Tumor Necrosis Factor-α (TNFα) Stimulates Triple-Negative Breast Cancer Stem Cells to Promote Intratumoral Invasion and Neovasculogenesis in the Liver of a Xenograft Model |
| title_fullStr | Tumor Necrosis Factor-α (TNFα) Stimulates Triple-Negative Breast Cancer Stem Cells to Promote Intratumoral Invasion and Neovasculogenesis in the Liver of a Xenograft Model |
| title_full_unstemmed | Tumor Necrosis Factor-α (TNFα) Stimulates Triple-Negative Breast Cancer Stem Cells to Promote Intratumoral Invasion and Neovasculogenesis in the Liver of a Xenograft Model |
| title_short | Tumor Necrosis Factor-α (TNFα) Stimulates Triple-Negative Breast Cancer Stem Cells to Promote Intratumoral Invasion and Neovasculogenesis in the Liver of a Xenograft Model |
| title_sort | tumor necrosis factor α tnfα stimulates triple negative breast cancer stem cells to promote intratumoral invasion and neovasculogenesis in the liver of a xenograft model |
| topic | triple-negative breast cancer cancer stem cells TNFα EMT seed-and-soil theory |
| url | https://www.mdpi.com/2079-7737/11/10/1481 |
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