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In Ewing sarcoma (EwS), a highly aggressive pediatric cancer, low oxygen tension is also evident in the bone microenvironment where EwS primarily arises. This review focuses on how hypoxia inducible factor subunits, especially HIF-1-α, interact with the oncogenic driver EWSR1::FLI1. It organizes emerging evidence supporting multifaceted roles of hypoxia and HIFs in EwS and highlights clinical relevance as prognostic markers and therapeutic targets.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/hypoxia-and-hifs-in-ewing-sarcoma-new-perspectives-on-a-multi-facetted-relationship/385593/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/hypoxia-and-hifs-in-ewing-sarcoma-new-perspectives-on-a-multi-facetted-relationship/385593.png","ImageObject",300,407,{"name":92,"@type":93},"Logic","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the significance of hypoxia in solid tumors and in Ewing sarcoma specifically?","Question",{"text":112,"@type":113},"Hypoxia develops during solid tumor growth and influences tumor activity through multiple pathways. In Ewing sarcoma, low oxygen tension is present in the bone microenvironment where the cancer mainly originates.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What roles do HIF proteins play in cellular adaptation to hypoxia?",{"text":117,"@type":113},"HIF proteins are key transcription factors that initiate the cellular adaptation to hypoxia. They require dimerization (including HIF-1-b and oxygen-regulated subunits like HIF-1-α) to bind hypoxia response elements and regulate multiple functional pathways.",{"name":119,"@type":110,"acceptedAnswer":120},"How might HIF-1α be regulated beyond hypoxia?",{"text":121,"@type":113},"HIF-1α can be upregulated in normoxia through growth factors and oncogenic signaling pathways such as PI3K/AKT and Ras/Raf/MAPK, and through loss of tumor suppressors like PTEN. This concept is referred to as pseudohypoxia.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},385593,1790500406,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},1099513958762,"https://ap-avatar.wpscdn.com/avatar/1000023916a998db790?x-image-process=image/resize,m_fixed,w_180,h_180&k=1784791008015729253","Ceranski etal. Molecular Cancer (2023) 22:49 [https://doi.org/10.1186/s12943-023-01750-w](https://doi.org/10.1186/s12943-023-01750-w)  \nMolecular Cancer  \n REVIEW Open Access  \nHypoxia and HIFs in Ewing sarcoma: new perspectives on a multi-facetted relationship  \nA. Katharina Ceranski1,2, Martha J. Carreño‑Gonzalez 1,2, Anna C. Ehlers 1,2, Maria Vittoria Colombo1,2,3,4,5, Florencia Cidre‑Aranaz1,2 and Thomas G. P. Grünewald 1,2,6*  \nAbstract  \nHypoxia 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 pro‑ teins 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 demon‑ strating that hypoxia and HIFs play a role in EwS at multiple levels. We propose to view hypoxia and HIFs as independ‑ ent protagonists in the story of EwS and give a perspective on their potential clinical relevance as prognostic markers and therapeutic targets in EwS treatment.  \nKeywords Ewing sarcoma, hypoxia, HIF‑1‑a, HIF‑1‑b, ARNT  \nIntroduction  \nCancer is characterized on the one hand by irregular intracellular processes, and on the other hand by aberrant extracellular processes such as an altered interplay between cancerous cells and the tumor microenvironment (TME) [1–3]. One of the key aspects of the TMEis hypoxia, which is generally defined as tissue oxygen  \n*Correspondence:  \nThomas G. P. Grünewald  \nt.gruenewald@kitz‑heidelberg.de  \n1 Hopp‑Children’s Cancer Center (KiTZ), Heidelberg, Germany  \n2 Division of Translational Pediatric Sarcoma Research (B410), German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany  \n3 Regenerative Medicine Technologies Laboratory, Laboratories for Translational Research (LRT), Ente Ospedaliero Cantonale (EOC), Via F. Chiesa 5, CH‑6500 Bellinzona, Switzerland  \n4 Department of Surgery, Service of Orthopaedics and Traumatology, EOC, Lugano, Switzerland  \n5 Department of Chemistry, Materials and Chemical Engineering“Giulio Natta”, Politecnico Di Milano, Via Mancinelli 7, 20131 Milan, Italy  \n6 Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany  \nconcentration below the level needed for normal cell function [4]. Hypoxia will develop in most solid tumors because of increased cellular proliferation and oxygen need as well as of insufficient vessel formation and blood supply [5]. Studies identified the hypoxia inducible factor (HIF) protein family as key transcription factors that initiate the cellular adaptation to hypoxia [5–7]. To act as a transcription factor, the constitutively expressed subunit HIF-1-b and one of the three oxygen-dependently expressed subunits HIF-1-a/HIF-2-a/HIF-3-a must dimerize and bind to hypoxia response elements (HREs) in the target gene sequences [5, 6]. Thereby, HIFs regulate a multitude of functional pathways that can impact tumor activity, such as tumor vascularization via vascular endothelial growth factor (VEGF) [6], tumor metabolism via solute carrier family 2 member 1 (SLC2A1, better known as GLUT-1) [8] and Aldolase-C expression [9], and tumor motility and invasiveness via loss of E-cadherin and activation of Wnt/beta-catenin signaling [10, 11].  \n© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide ","cbCaimzu5e660zXl","https://ap.wps.com/l/cbCaimzu5e660zXl","pdf",1595157,15,"English","# Introduction\n## Hypoxia in the tumor microenvironment\n## HIF proteins as transcriptional mediators\n## Hypoxia-driven pathways affecting tumor activity\n# Licensing and open-access information","[{\"question\":\"What is the significance of hypoxia in solid tumors and in Ewing sarcoma specifically?\",\"answer\":\"Hypoxia develops during solid tumor growth and influences tumor activity through multiple pathways. In Ewing sarcoma, low oxygen tension is present in the bone microenvironment where the cancer mainly originates.\"},{\"question\":\"What roles do HIF proteins play in cellular adaptation to hypoxia?\",\"answer\":\"HIF proteins are key transcription factors that initiate the cellular adaptation to hypoxia. They require dimerization (including HIF-1-b and oxygen-regulated subunits like HIF-1-α) to bind hypoxia response elements and regulate multiple functional pathways.\"},{\"question\":\"How might HIF-1α be regulated beyond hypoxia?\",\"answer\":\"HIF-1α can be upregulated in normoxia through growth factors and oncogenic signaling pathways such as PI3K/AKT and Ras/Raf/MAPK, and through loss of tumor suppressors like PTEN. This concept is referred to as pseudohypoxia.\"}]","Hypoxia and HIFs in Ewing sarcoma - new perspectives on a multi-facetted relationship | PDF",1790270137,38]