TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases
Breast cancer (BCa) cells disseminating to the bone can remain dormant and resistant to treatments for many years until relapsing as bone metastases. The tyrosine kinase receptor TIE2 induces the dormancy of hematopoietic stem cells, and could also induce the dormancy of BCa cells. However, TIE2 is...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/4/868 |
| _version_ | 1797571534963867648 |
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| author | Florian Drescher Patricia Juárez Danna L. Arellano Nicolás Serafín-Higuera Felipe Olvera-Rodriguez Samanta Jiménez Alexei F. Licea-Navarro Pierrick G.J. Fournier |
| author_facet | Florian Drescher Patricia Juárez Danna L. Arellano Nicolás Serafín-Higuera Felipe Olvera-Rodriguez Samanta Jiménez Alexei F. Licea-Navarro Pierrick G.J. Fournier |
| author_sort | Florian Drescher |
| collection | DOAJ |
| description | Breast cancer (BCa) cells disseminating to the bone can remain dormant and resistant to treatments for many years until relapsing as bone metastases. The tyrosine kinase receptor TIE2 induces the dormancy of hematopoietic stem cells, and could also induce the dormancy of BCa cells. However, TIE2 is also a target for anti-angiogenic treatments in ongoing clinical trials, and its inhibition could then restart the proliferation of dormant BCa cells in bone. In this study, we used a combination of patient data, in vitro, and in vivo models to investigate the effect of TIE2 in the dormancy of bone metastases. In BCa patients, we found that a higher <i>TIE2</i> expression is associated with an increased time to metastases and survival. In vitro, TIE2 decreased cell proliferation as it increased the expression of cyclin-dependent kinase inhibitors <i>CDKN1A</i> and <i>CDKN1B</i> and arrested cells in the G<sub>0</sub>/G<sub>1</sub> phase. Expression of <i>TIE2</i> also increased the resistance to the chemotherapeutic 5-Fluorouracil. In mice, <i>TIE2</i> expression reduced tumor growth and the formation of osteolytic bone metastasis. Together, these results show that TIE2 is sufficient to induce dormancy in vitro and in vivo, and could be a useful prognostic marker for patients. Our data also suggest being cautious when using TIE2 inhibitors in the clinic, as they could awaken dormant disseminated tumor cells. |
| first_indexed | 2024-03-10T20:41:35Z |
| format | Article |
| id | doaj.art-05fbd344051e4742a9d05b77f1e827bd |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T20:41:35Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-05fbd344051e4742a9d05b77f1e827bd2023-11-19T20:35:12ZengMDPI AGCancers2072-66942020-04-0112486810.3390/cancers12040868TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone MetastasesFlorian Drescher0Patricia Juárez1Danna L. Arellano2Nicolás Serafín-Higuera3Felipe Olvera-Rodriguez4Samanta Jiménez5Alexei F. Licea-Navarro6Pierrick G.J. Fournier7Biomedical Innovation Department, Centro de Investigación Científica y de Educación Superior de Ensenada (CICESE), Ensenada, Baja California 22860, MexicoBiomedical Innovation Department, Centro de Investigación Científica y de Educación Superior de Ensenada (CICESE), Ensenada, Baja California 22860, MexicoBiomedical Innovation Department, Centro de Investigación Científica y de Educación Superior de Ensenada (CICESE), Ensenada, Baja California 22860, MexicoUnidad de Ciencias de la Salud, Facultad de Odontología, Universidad Autónoma de Baja California, Mexicali, Baja California 21040, MexicoDepartamento de Biología Molecular y Bioprocesos, Instituto de Biotecnología Universidad Nacional Autónoma de Mexico, Cuernavaca, Morelos 62210, MexicoBiomedical Innovation Department, Centro de Investigación Científica y de Educación Superior de Ensenada (CICESE), Ensenada, Baja California 22860, MexicoBiomedical Innovation Department, Centro de Investigación Científica y de Educación Superior de Ensenada (CICESE), Ensenada, Baja California 22860, MexicoBiomedical Innovation Department, Centro de Investigación Científica y de Educación Superior de Ensenada (CICESE), Ensenada, Baja California 22860, MexicoBreast cancer (BCa) cells disseminating to the bone can remain dormant and resistant to treatments for many years until relapsing as bone metastases. The tyrosine kinase receptor TIE2 induces the dormancy of hematopoietic stem cells, and could also induce the dormancy of BCa cells. However, TIE2 is also a target for anti-angiogenic treatments in ongoing clinical trials, and its inhibition could then restart the proliferation of dormant BCa cells in bone. In this study, we used a combination of patient data, in vitro, and in vivo models to investigate the effect of TIE2 in the dormancy of bone metastases. In BCa patients, we found that a higher <i>TIE2</i> expression is associated with an increased time to metastases and survival. In vitro, TIE2 decreased cell proliferation as it increased the expression of cyclin-dependent kinase inhibitors <i>CDKN1A</i> and <i>CDKN1B</i> and arrested cells in the G<sub>0</sub>/G<sub>1</sub> phase. Expression of <i>TIE2</i> also increased the resistance to the chemotherapeutic 5-Fluorouracil. In mice, <i>TIE2</i> expression reduced tumor growth and the formation of osteolytic bone metastasis. Together, these results show that TIE2 is sufficient to induce dormancy in vitro and in vivo, and could be a useful prognostic marker for patients. Our data also suggest being cautious when using TIE2 inhibitors in the clinic, as they could awaken dormant disseminated tumor cells.https://www.mdpi.com/2072-6694/12/4/868breast cancerbone metastasisdormancyTIE2chemotherapy resistancecancer relapse |
| spellingShingle | Florian Drescher Patricia Juárez Danna L. Arellano Nicolás Serafín-Higuera Felipe Olvera-Rodriguez Samanta Jiménez Alexei F. Licea-Navarro Pierrick G.J. Fournier TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases Cancers breast cancer bone metastasis dormancy TIE2 chemotherapy resistance cancer relapse |
| title | TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases |
| title_full | TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases |
| title_fullStr | TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases |
| title_full_unstemmed | TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases |
| title_short | TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases |
| title_sort | tie2 induces breast cancer cell dormancy and inhibits the development of osteolytic bone metastases |
| topic | breast cancer bone metastasis dormancy TIE2 chemotherapy resistance cancer relapse |
| url | https://www.mdpi.com/2072-6694/12/4/868 |
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