Mariano F Zacarias-Fluck1, Beatriz Morancho2, Rocio Vicario2, Antonio Luque Garcia2, Marta Escorihuela2, Josep Villanueva2, Isabel T Rubio2, Joaquín Arribas2. 1. Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (JA). jarribas@vhio.net. 2. Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (JA).
Abstract
BACKGROUND: Oncogene-induced senescence (OIS) is a tumor suppressor mechanism. However, senescent cells remain viable and display a distinct secretome (also known as senescence-associated secretory phenotype [SASP] or senescence messaging secretome, [SMS]) that, paradoxically, includes protumorigenic factors. OIS can be triggered by ectopic overexpression of HER2, a receptor tyrosine kinase and the driving oncogene in a subtype of human breast cancer. However, cellular senescence has not been characterized in HER2-positive tumors. METHODS: Using an approach based on their inability to proliferate, we isolated naturally occurring senescent cells from a variety of tumor models including HER2-positive cells, transgenic mice (n = 3), and patient-derived xenografts (PDXs) (n = 6 mice per group from one PDX derived from one patient). Using different biochemical and cell biological techniques, we characterized the secretome of these senescent cells. All statistical tests were two-sided. RESULTS: We found that senescent cells arise constantly in different models of advanced breast cancers overexpressing HER2 and constitute approximately 5% of tumor cells. In these models, IL-6 and other cytokines were expressed mainly, if not exclusively, by the naturally occurring senescent cells (95.1% and 45.0% of HCC1954 cells and cells from a HER2-positive PDX expressing a senescent marker expressed IL-6, respectively). Furthermore, inhibition of IL-6 impaired the growth of the HER2-positive PDX (mean tumor volume at day 101, control vs anti-huIL-6 treated, 332.2mm(3) [95% confidence interval {CI} = 216.6 to 449.8] vs 114.4mm(3) [95% CI = 12.79 to 216.0], P = .005). CONCLUSIONS: Senescent cells can contribute to the growth of tumors by providing cytokines not expressed by proliferating cells, but required by these to thrive.
BACKGROUND: Oncogene-induced senescence (OIS) is a tumor suppressor mechanism. However, senescent cells remain viable and display a distinct secretome (also known as senescence-associated secretory phenotype [SASP] or senescence messaging secretome, [SMS]) that, paradoxically, includes protumorigenic factors. OIS can be triggered by ectopic overexpression of HER2, a receptor tyrosine kinase and the driving oncogene in a subtype of humanbreast cancer. However, cellular senescence has not been characterized in HER2-positive tumors. METHODS: Using an approach based on their inability to proliferate, we isolated naturally occurring senescent cells from a variety of tumor models including HER2-positive cells, transgenic mice (n = 3), and patient-derived xenografts (PDXs) (n = 6 mice per group from one PDX derived from one patient). Using different biochemical and cell biological techniques, we characterized the secretome of these senescent cells. All statistical tests were two-sided. RESULTS: We found that senescent cells arise constantly in different models of advanced breast cancers overexpressing HER2 and constitute approximately 5% of tumor cells. In these models, IL-6 and other cytokines were expressed mainly, if not exclusively, by the naturally occurring senescent cells (95.1% and 45.0% of HCC1954 cells and cells from a HER2-positive PDX expressing a senescent marker expressed IL-6, respectively). Furthermore, inhibition of IL-6 impaired the growth of the HER2-positive PDX (mean tumor volume at day 101, control vs anti-huIL-6 treated, 332.2mm(3) [95% confidence interval {CI} = 216.6 to 449.8] vs 114.4mm(3) [95% CI = 12.79 to 216.0], P = .005). CONCLUSIONS: Senescent cells can contribute to the growth of tumors by providing cytokines not expressed by proliferating cells, but required by these to thrive.
Authors: Elizabeth Ferreira Martinez; Ney Soares de Araújo; Vera Cavalcanti de Araújo Journal: J Cell Commun Signal Date: 2015-06-12 Impact factor: 5.782
Authors: L A Maciel-Barón; S L Morales-Rosales; A A Aquino-Cruz; F Triana-Martínez; S Galván-Arzate; A Luna-López; V Y González-Puertos; N E López-Díazguerrero; C Torres; Mina Königsberg Journal: Age (Dordr) Date: 2016-02-11
Authors: Annette T Byrne; Denis G Alférez; Frédéric Amant; Daniela Annibali; Joaquín Arribas; Andrew V Biankin; Alejandra Bruna; Eva Budinská; Carlos Caldas; David K Chang; Robert B Clarke; Hans Clevers; George Coukos; Virginie Dangles-Marie; S Gail Eckhardt; Eva Gonzalez-Suarez; Els Hermans; Manuel Hidalgo; Monika A Jarzabek; Steven de Jong; Jos Jonkers; Kristel Kemper; Luisa Lanfrancone; Gunhild Mari Mælandsmo; Elisabetta Marangoni; Jean-Christophe Marine; Enzo Medico; Jens Henrik Norum; Héctor G Palmer; Daniel S Peeper; Pier Giuseppe Pelicci; Alejandro Piris-Gimenez; Sergio Roman-Roman; Oscar M Rueda; Joan Seoane; Violeta Serra; Laura Soucek; Dominique Vanhecke; Alberto Villanueva; Emilie Vinolo; Andrea Bertotti; Livio Trusolino Journal: Nat Rev Cancer Date: 2017-01-20 Impact factor: 60.716