Co-targeting triple-negative breast cancer cells and endothelial cells by metronomic chemotherapy inhibits cell regrowth and migration via downregulation of the FAK/VEGFR2/VEGF axis and autophagy/apoptosis activation
High-dose standard-of-care chemotherapy is the only option for triple-negative breast cancer (TNBC) patients, which eventually die due to metastatic tumors. Recently, metronomic chemotherapy (mCHT) showed advantages in treating TNBCs leading us to investigate the anti-metastatic and anti-angiogenic...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.998274/full |
| _version_ | 1797987932522414080 |
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| author | Arianna Scagliotti Laura Capizzi Marina Elena Cazzaniga Marina Elena Cazzaniga Alice Ilari Marco De Giorgi Nicoletta Cordani Matteo Gallazzi Antonino Bruno Antonino Bruno Giuseppe Pelosi Giuseppe Pelosi Adriana Albini Marialuisa Lavitrano Emanuela Grassilli Maria Grazia Cerrito |
| author_facet | Arianna Scagliotti Laura Capizzi Marina Elena Cazzaniga Marina Elena Cazzaniga Alice Ilari Marco De Giorgi Nicoletta Cordani Matteo Gallazzi Antonino Bruno Antonino Bruno Giuseppe Pelosi Giuseppe Pelosi Adriana Albini Marialuisa Lavitrano Emanuela Grassilli Maria Grazia Cerrito |
| author_sort | Arianna Scagliotti |
| collection | DOAJ |
| description | High-dose standard-of-care chemotherapy is the only option for triple-negative breast cancer (TNBC) patients, which eventually die due to metastatic tumors. Recently, metronomic chemotherapy (mCHT) showed advantages in treating TNBCs leading us to investigate the anti-metastatic and anti-angiogenic potential of metronomic 5-Fluorouracil plus Vinorelbine (5-FU+VNR) on endothelial cells (ECs) and TNBCs in comparison to standard treatment (STD). We found that 10-fold lower doses of 5-FU+VNR given mCHT vs. STD inhibits cell proliferation and survival of ECs and TNBC cells. Both schedules strongly affect ECs migration and invasion, but in TNBC cells mCHT is significantly more effective than STD in impairing cell migration and invasion. The two treatments disrupt FAK/VEGFR/VEGF signaling in both ECs and TNBC cells. mCHT, and to a much lesser extent STD treatment, induces apoptosis in ECs, whereas it switches the route of cell death from apoptosis (as induced by STD) to autophagy in TNBC cells. mCHT-treated TNBCs-derived conditioned medium also strongly affects ECs’ migration, modulates different angiogenesis-associated proteins, and hampers angiogenesis in matrix sponge in vivo. In conclusion, mCHT administration of 5-FU+VNR is more effective than STD schedule in controlling cell proliferation/survival and migration/invasion of both ECs and TNBC cells and has a strong anti-angiogenic effect. Our data suggest that the stabilization of tumor growth observed in TNBC patients treated with mCHT therapy schedule is likely due not only to direct cytotoxic effects but also to anti-metastatic and anti-angiogenic effects. |
| first_indexed | 2024-04-11T07:55:45Z |
| format | Article |
| id | doaj.art-5f272eaaf6e9491ca96069aa45a0c264 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T07:55:45Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-5f272eaaf6e9491ca96069aa45a0c2642022-12-22T04:35:57ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-11-011210.3389/fonc.2022.998274998274Co-targeting triple-negative breast cancer cells and endothelial cells by metronomic chemotherapy inhibits cell regrowth and migration via downregulation of the FAK/VEGFR2/VEGF axis and autophagy/apoptosis activationArianna Scagliotti0Laura Capizzi1Marina Elena Cazzaniga2Marina Elena Cazzaniga3Alice Ilari4Marco De Giorgi5Nicoletta Cordani6Matteo Gallazzi7Antonino Bruno8Antonino Bruno9Giuseppe Pelosi10Giuseppe Pelosi11Adriana Albini12Marialuisa Lavitrano13Emanuela Grassilli14Maria Grazia Cerrito15School of Medicine and Surgery, University of Milano-Bicocca, Monza, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, Monza, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, Monza, ItalyPhase 1 Research Center, Azienda Socio Sanitaria Territoriale (ASST) di Monza, Monza, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, Monza, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, Monza, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, Monza, ItalyLaboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, ItalyLaboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, ItalyLaboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry and Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, ItalyIstituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, ItalyDepartment of Oncology and Hemato-Oncology, University of Milan, Milan, ItalyIRCCS European Institute of Oncology (IEO), Milan, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, Monza, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, Monza, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, Monza, ItalyHigh-dose standard-of-care chemotherapy is the only option for triple-negative breast cancer (TNBC) patients, which eventually die due to metastatic tumors. Recently, metronomic chemotherapy (mCHT) showed advantages in treating TNBCs leading us to investigate the anti-metastatic and anti-angiogenic potential of metronomic 5-Fluorouracil plus Vinorelbine (5-FU+VNR) on endothelial cells (ECs) and TNBCs in comparison to standard treatment (STD). We found that 10-fold lower doses of 5-FU+VNR given mCHT vs. STD inhibits cell proliferation and survival of ECs and TNBC cells. Both schedules strongly affect ECs migration and invasion, but in TNBC cells mCHT is significantly more effective than STD in impairing cell migration and invasion. The two treatments disrupt FAK/VEGFR/VEGF signaling in both ECs and TNBC cells. mCHT, and to a much lesser extent STD treatment, induces apoptosis in ECs, whereas it switches the route of cell death from apoptosis (as induced by STD) to autophagy in TNBC cells. mCHT-treated TNBCs-derived conditioned medium also strongly affects ECs’ migration, modulates different angiogenesis-associated proteins, and hampers angiogenesis in matrix sponge in vivo. In conclusion, mCHT administration of 5-FU+VNR is more effective than STD schedule in controlling cell proliferation/survival and migration/invasion of both ECs and TNBC cells and has a strong anti-angiogenic effect. Our data suggest that the stabilization of tumor growth observed in TNBC patients treated with mCHT therapy schedule is likely due not only to direct cytotoxic effects but also to anti-metastatic and anti-angiogenic effects.https://www.frontiersin.org/articles/10.3389/fonc.2022.998274/fullmetronomic chemotherapytriple negative breast cancer (TNBC)endothelial cellsangiogenesisFAK-VEGFR2-VEGF-axis |
| spellingShingle | Arianna Scagliotti Laura Capizzi Marina Elena Cazzaniga Marina Elena Cazzaniga Alice Ilari Marco De Giorgi Nicoletta Cordani Matteo Gallazzi Antonino Bruno Antonino Bruno Giuseppe Pelosi Giuseppe Pelosi Adriana Albini Marialuisa Lavitrano Emanuela Grassilli Maria Grazia Cerrito Co-targeting triple-negative breast cancer cells and endothelial cells by metronomic chemotherapy inhibits cell regrowth and migration via downregulation of the FAK/VEGFR2/VEGF axis and autophagy/apoptosis activation Frontiers in Oncology metronomic chemotherapy triple negative breast cancer (TNBC) endothelial cells angiogenesis FAK-VEGFR2-VEGF-axis |
| title | Co-targeting triple-negative breast cancer cells and endothelial cells by metronomic chemotherapy inhibits cell regrowth and migration via downregulation of the FAK/VEGFR2/VEGF axis and autophagy/apoptosis activation |
| title_full | Co-targeting triple-negative breast cancer cells and endothelial cells by metronomic chemotherapy inhibits cell regrowth and migration via downregulation of the FAK/VEGFR2/VEGF axis and autophagy/apoptosis activation |
| title_fullStr | Co-targeting triple-negative breast cancer cells and endothelial cells by metronomic chemotherapy inhibits cell regrowth and migration via downregulation of the FAK/VEGFR2/VEGF axis and autophagy/apoptosis activation |
| title_full_unstemmed | Co-targeting triple-negative breast cancer cells and endothelial cells by metronomic chemotherapy inhibits cell regrowth and migration via downregulation of the FAK/VEGFR2/VEGF axis and autophagy/apoptosis activation |
| title_short | Co-targeting triple-negative breast cancer cells and endothelial cells by metronomic chemotherapy inhibits cell regrowth and migration via downregulation of the FAK/VEGFR2/VEGF axis and autophagy/apoptosis activation |
| title_sort | co targeting triple negative breast cancer cells and endothelial cells by metronomic chemotherapy inhibits cell regrowth and migration via downregulation of the fak vegfr2 vegf axis and autophagy apoptosis activation |
| topic | metronomic chemotherapy triple negative breast cancer (TNBC) endothelial cells angiogenesis FAK-VEGFR2-VEGF-axis |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.998274/full |
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