Virginie Monceau1, Anna Llach2, David Azria3, André Bridier4, Benoît Petit1, Marianne Mazevet2, Carine Strup-Perrot5, Thi-Hong-Van To1, Lucie Calmels4, Marie-Michèle Germaini2, Sophie Gourgou3, Pascal Fenoglietto3, Céline Bourgier6, Ana-Maria Gomez2, Brigitte Escoubet7, Wolfgang Dörr8, Julia Haagen9, Eric Deutsch10, Eric Morel2, Marie Catherine Vozenin11. 1. INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France. 2. INSERM U769, IFR141, LabEx LERMIT, Faculté de Pharmacie, Châtenay-Malabry, France. 3. Department of Radiation Oncology, CRLC Val d'Aurelle, Montpellier, France. 4. Département de radiothérapie, Institut Gustave Roussy, Villejuif, France. 5. IRSN-PRP-HOM-SRBE-LRTI, Fontenay-aux Roses, France. 6. INSERM U1030, LabEx LERMIT, Villejuif, France; Department of Radiation Oncology, CRLC Val d'Aurelle, Montpellier, France; Département de radiothérapie, Institut Gustave Roussy, Villejuif, France. 7. Département de Physiologie, Explorations Fonctionnelles, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, France; Université Paris Diderot, France; INSERM U872, Paris, France. 8. Department of Radiotherapy and Radiation Oncology, Technical University, Dresden, Germany; Department of Radiation Oncology & Christian Doppler Laboratory for Medical Radiation Research in Radiooncology Medical University, Vienna, Austria. 9. Department of Radiotherapy and Radiation Oncology, Technical University, Dresden, Germany. 10. INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France; Département de radiothérapie, Institut Gustave Roussy, Villejuif, France. 11. INSERM U1030, LabEx LERMIT, Villejuif, France; Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre, France; Laboratoire de Radio-oncologie, CHUV, Lausanne, Switzerland. Electronic address: Marie-Catherine.vozenin@chuv.ch.
Abstract
BACKGROUND: Cardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancer patients and in experimental models in order to identify novel therapeutic target. METHODS: The size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes. RESULTS: In patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca(2+) transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals. CONCLUSION: Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart.
BACKGROUND:Cardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancerpatients and in experimental models in order to identify novel therapeutic target. METHODS: The size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes. RESULTS: In patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca(2+) transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals. CONCLUSION:Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart.
Authors: Mónika Gabriella Kovács; Zsuzsanna Z A Kovács; Zoltán Varga; Gergő Szűcs; Marah Freiwan; Katalin Farkas; Bence Kővári; Gábor Cserni; András Kriston; Ferenc Kovács; Péter Horváth; Imre Földesi; Tamás Csont; Zsuzsanna Kahán; Márta Sárközy Journal: Int J Mol Sci Date: 2021-11-30 Impact factor: 5.923
Authors: Carmen Bergom; Jason Rubenstein; J Frank Wilson; Aimee Welsh; El-Sayed H Ibrahim; Phillip Prior; Aronne M Schottstaedt; Daniel Eastwood; Mei-Jie Zhang; Adam Currey; Lindsay Puckett; Jennifer L Strande; Julie A Bradley; Julia White Journal: Front Oncol Date: 2020-10-16 Impact factor: 6.244