Hypoxia and HIFs in Ewing sarcoma: new perspectives on a multi-facetted relationship

Abstract

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.

Keywords: ARNT; Ewing sarcoma; HIF-1-a; HIF-1-b; hypoxia.

Fig. 1

Hypoxia-related and non hypoxia-related upregulation of HIF-1-a might contribute independently to EWSR1::FLI1 regulation

Fig. 2

Elevated HIF-1-a and GLUT1 expression correlates with worse overall survival in EwS patients. Kaplan–Meier survival analyses in 156 EwS patients based on HIF-1-a and GLUT1 expression levels (cut-off defined as best percentile, log-rank test). Microarray data were retrieved from the Gene Expression Omnibus (accession codes: GSE63157, GSE34620, GSE12102, GSE17618) and normalized using Robust Multiarray Average (RMA) using custom brainarray chip-description files (v20). Batch effects were removed with ComBat. Tumor purity was assessed using the ESTIMATE algorithm. Only samples with a tumor purity > 60% corresponding to The Cancer Genome Atlas (TCGA) standard were included in survival analyses