Toward Tumor Fight and Tumor Microenvironment Remodeling: PBA Induces Cell Cycle Arrest and Reduces Tumor Hybrid Cells' Pluripotency in Bladder Cancer.

Autor: Rubio C; Biomedical Biomedical Research Institute I+12, University Hospital '12 de Octubre', Av Córdoba s/n, 28041 Madrid, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº40, 28040 Madrid, Spain., Avendaño-Ortiz J; TumorImmunology Laboratory and Innate Immunity Group, Institute for Health Research (IdiPAZ), 28029 Madrid, Spain., Ruiz-Palomares R; Biomedical Biomedical Research Institute I+12, University Hospital '12 de Octubre', Av Córdoba s/n, 28041 Madrid, Spain., Karaivanova V; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº40, 28040 Madrid, Spain., Alberquilla O; Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28029 Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), 28029 Madrid, Spain.; Advanced Therapy Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD/UAM), 28040 Madrid, Spain., Sánchez-Domínguez R; Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), 28029 Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), 28029 Madrid, Spain.; Advanced Therapy Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD/UAM), 28040 Madrid, Spain., Casalvilla-Dueñas JC; TumorImmunology Laboratory and Innate Immunity Group, Institute for Health Research (IdiPAZ), 28029 Madrid, Spain., Montalbán-Hernández K; TumorImmunology Laboratory and Innate Immunity Group, Institute for Health Research (IdiPAZ), 28029 Madrid, Spain., Lodewijk I; Biomedical Biomedical Research Institute I+12, University Hospital '12 de Octubre', Av Córdoba s/n, 28041 Madrid, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº40, 28040 Madrid, Spain., Rodríguez-Izquierdo M; Uro-Oncology Unit, 12 de Octubre University Hospital, Av Córdoba s/n, 28041 Madrid, Spain., Munera-Maravilla E; Biomedical Biomedical Research Institute I+12, University Hospital '12 de Octubre', Av Córdoba s/n, 28041 Madrid, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº40, 28040 Madrid, Spain., Nunes SP; Biomedical Biomedical Research Institute I+12, University Hospital '12 de Octubre', Av Córdoba s/n, 28041 Madrid, Spain.; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº40, 28040 Madrid, Spain.; Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network) Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal., Suárez-Cabrera C; Biomedical Biomedical Research Institute I+12, University Hospital '12 de Octubre', Av Córdoba s/n, 28041 Madrid, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº40, 28040 Madrid, Spain., Pérez-Crespo M; Biomedical Biomedical Research Institute I+12, University Hospital '12 de Octubre', Av Córdoba s/n, 28041 Madrid, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº40, 28040 Madrid, Spain., Martínez VG; Biomedical Biomedical Research Institute I+12, University Hospital '12 de Octubre', Av Córdoba s/n, 28041 Madrid, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº40, 28040 Madrid, Spain., Morales L; Biomedical Biomedical Research Institute I+12, University Hospital '12 de Octubre', Av Córdoba s/n, 28041 Madrid, Spain.; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº40, 28040 Madrid, Spain., Pérez-Escavy M; Biomedical Biomedical Research Institute I+12, University Hospital '12 de Octubre', Av Córdoba s/n, 28041 Madrid, Spain.; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº40, 28040 Madrid, Spain., Alonso-Sánchez M; Biomedical Biomedical Research Institute I+12, University Hospital '12 de Octubre', Av Córdoba s/n, 28041 Madrid, Spain.; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº40, 28040 Madrid, Spain., Lozano-Rodríguez R; TumorImmunology Laboratory and Innate Immunity Group, Institute for Health Research (IdiPAZ), 28029 Madrid, Spain., Cueto FJ; TumorImmunology Laboratory and Innate Immunity Group, Institute for Health Research (IdiPAZ), 28029 Madrid, Spain., Aguirre LA; TumorImmunology Laboratory and Innate Immunity Group, Institute for Health Research (IdiPAZ), 28029 Madrid, Spain., Guerrero-Ramos F; Uro-Oncology Unit, 12 de Octubre University Hospital, Av Córdoba s/n, 28041 Madrid, Spain., Paramio JM; Biomedical Biomedical Research Institute I+12, University Hospital '12 de Octubre', Av Córdoba s/n, 28041 Madrid, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº40, 28040 Madrid, Spain., López-Collazo E; TumorImmunology Laboratory and Innate Immunity Group, Institute for Health Research (IdiPAZ), 28029 Madrid, Spain.; CIBER of Respiratory Diseases (CIBERES), 28029 Madrid, Spain., Dueñas M; Biomedical Biomedical Research Institute I+12, University Hospital '12 de Octubre', Av Córdoba s/n, 28041 Madrid, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain.; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Avenida Complutense nº40, 28040 Madrid, Spain.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2022 Jan 07; Vol. 14 (2). Date of Electronic Publication: 2022 Jan 07.
DOI: 10.3390/cancers14020287
Abstrakt: Bladder cancer (BC) is the second most frequent cancer of the genitourinary system. The most successful therapy since the 1970s has consisted of intravesical instillations of Bacillus Calmette-Guérin (BCG) in which the tumor microenvironment (TME), including macrophages, plays an important role. However, some patients cannot be treated with this therapy due to comorbidities and severe inflammatory side effects. The overexpression of histone deacetylases (HDACs) in BC has been correlated with macrophage polarization together with higher tumor grades and poor prognosis. Herein we demonstrated that phenylbutyrate acid (PBA), a HDAC inhibitor, acts as an antitumoral compound and immunomodulator. In BC cell lines, PBA induced significant cell cycle arrest in G1, reduced stemness markers and increased PD-L1 expression with a corresponding reduction in histone 3 and 4 acetylation patterns. Concerning its role as an immunomodulator, we found that PBA reduced macrophage IL-6 and IL-10 production as well as CD14 downregulation and the upregulation of both PD-L1 and IL-1β. Along this line, PBA showed a reduction in IL-4-induced M2 polarization in human macrophages. In co-cultures of BC cell lines with human macrophages, a double-positive myeloid-tumoral hybrid population (CD11b + EPCAM + ) was detected after 48 h, which indicates BC cell-macrophage fusions known as tumor hybrid cells (THC). These THC were characterized by high PD-L1 and stemness markers ( SOX2 , NANOG , miR-302 ) as compared with non-fused (CD11b - EPCAM + ) cancer cells. Eventually, PBA reduced stemness markers along with BMP4 and IL-10 . Our data indicate that PBA could have beneficial properties for BC management, affecting not only tumor cells but also the TME.
Databáze: MEDLINE
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