RESUMEN
Hypoxia develops during the growth of solid tumors and influences tumoral activity in multiple ways. Low oxygen tension is also present in the bone microenvironment where Ewing sarcoma (EwS) - a highly aggressive pediatric cancer - mainly arises. Hypoxia inducible factor 1 subunit alpha (HIF-1-a) is the principal molecular mediator of the hypoxic response in cancer whereas EWSR1::FLI1 constitutes the oncogenic driver of EwS. Interaction of the two proteins has been shown in EwS. Although a growing body of studies investigated hypoxia and HIFs in EwS, their precise role for EwS pathophysiology is not clarified to date. This review summarizes and structures recent findings demonstrating that hypoxia and HIFs play a role in EwS at multiple levels. We propose to view hypoxia and HIFs as independent protagonists in the story of EwS and give a perspective on their potential clinical relevance as prognostic markers and therapeutic targets in EwS treatment.
Asunto(s)
Sarcoma de Ewing , Humanos , Niño , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Proteínas de Fusión Oncogénica/genética , Proteínas/metabolismo , Proteína EWS de Unión a ARN/genética , Proteína EWS de Unión a ARN/metabolismo , Hipoxia/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Microambiente TumoralAsunto(s)
Biomarcadores de Tumor , Neoplasias Óseas/etiología , Ribonucleósido Difosfato Reductasa/genética , Sarcoma de Ewing/etiología , Animales , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/terapia , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Terapia Molecular Dirigida , Pronóstico , Piridinas/farmacología , Ribonucleósido Difosfato Reductasa/metabolismo , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/terapia , Tiosemicarbazonas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward. HSCs from challenged mice demonstrated multiple cellular and molecular features of accelerated aging and developed clinically relevant blood and bone marrow phenotypes not normally observed in aged laboratory mice but commonly seen in elderly humans. In vivo HSC self-renewal divisions were absent or extremely rare during both challenge and recovery periods. The progressive, irreversible attrition of HSC function demonstrates that temporally discrete inflammatory events elicit a cumulative inhibitory effect on HSCs. This work positions early/mid-life inflammation as a mediator of lifelong defects in tissue maintenance and regeneration.