Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell Carcinomas
Cancer angiogenesis is required to support energetic demand and metabolic stress, particularly during conditions of hypoxia. Coupled to neo-vasculogenesis, cancer cells rewire metabolic programs to sustain growth, survival and long-term maintenance. Thyroid hormone (TH) signaling regulates growth an...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/11/2743 |
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| author | Caterina Miro Annarita Nappi Annunziata Gaetana Cicatiello Emery Di Cicco Serena Sagliocchi Melania Murolo Valentina Belli Teresa Troiani Sandra Albanese Sara Amiranda Ann Marie Zavacki Mariano Stornaiuolo Marcello Mancini Domenico Salvatore Monica Dentice |
| author_facet | Caterina Miro Annarita Nappi Annunziata Gaetana Cicatiello Emery Di Cicco Serena Sagliocchi Melania Murolo Valentina Belli Teresa Troiani Sandra Albanese Sara Amiranda Ann Marie Zavacki Mariano Stornaiuolo Marcello Mancini Domenico Salvatore Monica Dentice |
| author_sort | Caterina Miro |
| collection | DOAJ |
| description | Cancer angiogenesis is required to support energetic demand and metabolic stress, particularly during conditions of hypoxia. Coupled to neo-vasculogenesis, cancer cells rewire metabolic programs to sustain growth, survival and long-term maintenance. Thyroid hormone (TH) signaling regulates growth and differentiation in a variety of cell types and tissues, thus modulating hyper proliferative processes such as cancer. Herein, we report that TH coordinates a global program of metabolic reprogramming and induces angiogenesis through up-regulation of the <i>VEGF-A</i> gene, which results in the enhanced proliferation of tumor endothelial cells. In vivo conditional depletion of the TH activating enzyme in a mouse model of cutaneous squamous cell carcinoma (SCC) reduces the concentration of TH in the tumoral cells and results in impaired VEGF-A production and attenuated angiogenesis. In addition, we found that TH induces the expression of the glycolytic genes and fosters lactate production, which are key traits of the Warburg effect. Taken together, our results reveal a <i>TH–VEGF-A–HIF1α</i> regulatory axis leading to enhanced angiogenesis and glycolytic flux, which may represent a target for SCC therapy. |
| first_indexed | 2024-03-10T10:48:43Z |
| format | Article |
| id | doaj.art-5324953aa67d43b8884b02711587cc85 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T10:48:43Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5324953aa67d43b8884b02711587cc852023-11-21T22:24:59ZengMDPI AGCancers2072-66942021-06-011311274310.3390/cancers13112743Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell CarcinomasCaterina Miro0Annarita Nappi1Annunziata Gaetana Cicatiello2Emery Di Cicco3Serena Sagliocchi4Melania Murolo5Valentina Belli6Teresa Troiani7Sandra Albanese8Sara Amiranda9Ann Marie Zavacki10Mariano Stornaiuolo11Marcello Mancini12Domenico Salvatore13Monica Dentice14Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, ItalyDepartment of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, ItalyDepartment of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, ItalyDepartment of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, ItalyDepartment of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, ItalyDepartment of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, ItalyLaboratorio di Oncologia Molecolare, Dipartimento di Medicina di Precisione, University of Campania Luigi Vanvitelli, 81100 Caserta, ItalyLaboratorio di Oncologia Molecolare, Dipartimento di Medicina di Precisione, University of Campania Luigi Vanvitelli, 81100 Caserta, ItalyInstitute of Biostructures and Bioimaging of the National Research Council, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, ItalyHarvard Medical School, Brigham and Women’s Hospital, Boston, MA 01451, USADepartment of Pharmacy, University of Naples Federico II, 80131 Naples, ItalyInstitute of Biostructures and Bioimaging of the National Research Council, 80131 Naples, ItalyCEINGE–Biotecnologie Avanzate Scarl, 80131 Naples, ItalyDepartment of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, ItalyCancer angiogenesis is required to support energetic demand and metabolic stress, particularly during conditions of hypoxia. Coupled to neo-vasculogenesis, cancer cells rewire metabolic programs to sustain growth, survival and long-term maintenance. Thyroid hormone (TH) signaling regulates growth and differentiation in a variety of cell types and tissues, thus modulating hyper proliferative processes such as cancer. Herein, we report that TH coordinates a global program of metabolic reprogramming and induces angiogenesis through up-regulation of the <i>VEGF-A</i> gene, which results in the enhanced proliferation of tumor endothelial cells. In vivo conditional depletion of the TH activating enzyme in a mouse model of cutaneous squamous cell carcinoma (SCC) reduces the concentration of TH in the tumoral cells and results in impaired VEGF-A production and attenuated angiogenesis. In addition, we found that TH induces the expression of the glycolytic genes and fosters lactate production, which are key traits of the Warburg effect. Taken together, our results reveal a <i>TH–VEGF-A–HIF1α</i> regulatory axis leading to enhanced angiogenesis and glycolytic flux, which may represent a target for SCC therapy.https://www.mdpi.com/2072-6694/13/11/2743thyroid hormonesdeiodinasesangiogenesissquamous cell carcinoma |
| spellingShingle | Caterina Miro Annarita Nappi Annunziata Gaetana Cicatiello Emery Di Cicco Serena Sagliocchi Melania Murolo Valentina Belli Teresa Troiani Sandra Albanese Sara Amiranda Ann Marie Zavacki Mariano Stornaiuolo Marcello Mancini Domenico Salvatore Monica Dentice Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell Carcinomas Cancers thyroid hormones deiodinases angiogenesis squamous cell carcinoma |
| title | Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell Carcinomas |
| title_full | Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell Carcinomas |
| title_fullStr | Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell Carcinomas |
| title_full_unstemmed | Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell Carcinomas |
| title_short | Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell Carcinomas |
| title_sort | thyroid hormone enhances angiogenesis and the warburg effect in squamous cell carcinomas |
| topic | thyroid hormones deiodinases angiogenesis squamous cell carcinoma |
| url | https://www.mdpi.com/2072-6694/13/11/2743 |
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