title: Anti-TNF-α treatment modulates SASP and SASP-related microRNAs in endothelial cells and in circulating angiogenic cells.
abstract: Endothelial cell senescence is characterized by acquisition of senescence-associated secretory phenotype (SASP), able to promote inflammaging and cancer progression. Emerging evidence suggest that preventing SASP development could help to slow the rate of aging and the progression of age-related diseases, including cancer. Aim of this study was to evaluate whether and how adalimumab, a monoclonal antibody directed against tumor necrosis factor-α (TNF-α), a major SASP component, can prevent the SASP. A three-pronged approach has been adopted to assess the if adalimumab is able to: i) modulate a panel of classic and novel senescence- and SASP-associated markers (interleukin [IL]-6, senescence associated-β-galactosidase, p16/Ink4a, plasminogen activator inhibitor 1, endothelial nitric oxide synthase, miR-146a-5p/Irak1 and miR-126-3p/Spred1) in human umbilical vein endothelial cells (HUVECs); ii) reduce the paracrine effects of senescent HUVECs' secretome on MCF-7 breast cancer cells, through wound healing and mammosphere assay; and iii) exert significant decrease of miR-146a-5p and increase of miR-126-3p in circulating angiogenic cells (CACs) from psoriasis patients receiving adalimumab in monotherapy.TNF-α blockade associated with adalimumab induced significant reduction in released IL-6 and significant increase in eNOS and miR-126-3p expression levels in long-term HUVEC cultures.A significant reduction in miR-146a-5p expression levels both in long-term HUVEC cultures and in CACs isolated from psoriasis patients was also evident. Interestingly, conditioned medium from senescent HUVECs treated with adalimumab was less consistent than medium from untreated cells in inducing migration- and mammosphere- promoting effects on MCF-7 cells.Our findings suggest that adalimumab can induce epigenetic modifications in cells undergoing senescence, thus contributing to the attenuation of SASP tumor-promoting effects.
authors.affiliation: Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy.|Insititut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain and IRCCS MultiMedica Sesto, San Giovanni, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Prattichizzo
authors.affiliation: Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Angelica
authors.initials: A
authors.lastname: Giuliani
authors.affiliation: Center of Clinical Pathology and Innovative Therapy, National Institute INRCA-IRCCS, Ancona, Italy.
authors.forename: Rina
authors.initials: R
authors.lastname: Recchioni
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, DIMES, University of Bologna, Bologna, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonafè
authors.affiliation: Center of Clinical Pathology and Innovative Therapy, National Institute INRCA-IRCCS, Ancona, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Marcheselli
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, DIMES, University of Bologna, Bologna, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: De Carolis
authors.affiliation: Dermatology Clinic, Department of Clinical and Molecular Medicine, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Campanati
authors.affiliation: Dermatology Clinic, Department of Clinical and Molecular Medicine, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Giuliodori
authors.affiliation: Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Rippo
authors.affiliation: Department of Clinical and Dental Sciences, DISCO, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Brugè
authors.affiliation: Department of Clinical and Dental Sciences, DISCO, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Tiano
authors.affiliation: Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Micucci
authors.affiliation: Insititut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain and IRCCS MultiMedica Sesto, San Giovanni, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ceriello
authors.affiliation: Dermatology Clinic, Department of Clinical and Molecular Medicine, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Offidani
authors.affiliation: Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy.|Center of Clinical Pathology and Innovative Therapy, National Institute INRCA-IRCCS, Ancona, Italy.
authors.forename: Antonio Domenico
authors.initials: AD
authors.lastname: Procopio
authors.affiliation: Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy.|Center of Clinical Pathology and Innovative Therapy, National Institute INRCA-IRCCS, Ancona, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Olivieri
mesh_terms: D000068879:Adalimumab / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D061986:MCF-7 Cells; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D011565:Psoriasis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D017077:Culture Media, Conditioned; C508600:IL6 protein, human; D015850:Interleukin-6; C527111:MIRN126 microRNA, human; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab
keywords: Gerotarget; HUVEC; SASP; miR-126-3p; miR-146a-5p; replicative senescence