Dataset Information

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.

SUBMITTER: Ceranski AK

PROVIDER: S-EPMC10010019 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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

Ceranski A Katharina AK Carreño-Gonzalez Martha J MJ Ehlers Anna C AC Colombo Maria Vittoria MV Cidre-Aranaz Florencia F Grünewald Thomas G P TGP

Molecular cancer 20230313 1

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 growi ...[more]

PMID: 36915100

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Project description:Adamantinoma-like Ewing sarcoma (ALES) has traditionally been considered a variant of Ewing sarcoma because it generally harbors EWSR1::FLI1 fusions despite showing diffuse positivity for keratins and p40. However, it has become increasingly recognized that different tumors can have identical translocations, including shared fusions between carcinomas and sarcomas, raising questions as to whether ALES might represent a separate entity. Using methylation profiling, we further explored the relationship between Ewing sarcoma and ALES. The archives of multiple institutions were searched for candidate cases of ALES. DNA methylation profiling was performed and results were compared to corresponding data from conventional Ewing sarcoma. Twelve cases of ALES (5 previously reported) were identified in 10 men and 2 women (aged 20-72 years; median age, 41.5 years). Cases included tumors arising in the parotid gland (3), sinonasal cavity (2), submandibular gland (2), thyroid gland (1), neck (1), gingiva (1), hypopharynx (1), and mandible (1). Histologic review consistently showed sheets and nests of basaloid cells within a fibromyxoid or hyalinized stroma. All tumors were positive for at least 1 keratin and CD99 expression, whereas all 10 cases tested were positive for p63 or p40; S100 protein expression was noted in 2 cases. Cases harbored either EWSR1::FLI1 fusions (n = 6), FUS::FLI1 fusions (n = 1), and/or EWSR1 rearrangements (n = 6). Methylation profiling was successful in 11/12 cases evaluated. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) of DNA methylation data revealed a distinct methylation cluster for all 11 cases, including the tumor with the FUS::FLI1 fusion, which clearly segregated them from the conventional Ewing sarcoma. Follow-up (n = 11, 1-154 months) revealed that 4 patients experienced recurrence and 6 developed metastatic disease. ALES demonstrates a distinct methylation signature from conventional Ewing sarcoma. This finding adds to the distinctive immunoprofile of ALES, suggesting that these 2 tumors should be considered distinct entities rather than histologic extremes of the same disease.

Project description:The therapeutic strategy of Ewing sarcoma (EWS) remains largely unchanged over the past few decades. Hypoxia is reported to have an impact on tumor cell progression and is regarded as a novel potential therapeutic target in tumor treatment. This study aimed at developing a prognostic gene signature based on hypoxia-related genes (HRGs). EWS patients from GSE17674 in the GEO database were analyzed as a training cohort, and differently expressed HRGs between tumor and normal samples were identified. The univariate Cox regression, Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate Cox regression analyses were used in this study. A total of 57 EWS patients from the International Cancer Genome Consortium (ICGC) database were set as the validation cohort. A total of 506 differently expressed HRGs between tumor and normal tissues were identified, among which 52 were associated with the prognoses of EWS patients. Based on 52 HRGs, EWS patients were divided into two molecular subgroups with different survival statuses. In addition, a prognostic signature based on 4 HRGs (WSB1, RXYLT1, GLCE and RORA) was constructed, dividing EWS patients into low- and high-risk groups. The 2-, 3- and 5-years area under the receiver operator characteristic curve of this signature was 0.913, 0.97 and 0.985, respectively. It was found that the survival rates of patients in the high-risk group were significantly lower than those in the low-risk group (p < 0.001). The risk level based on the risk score could serve as an independent clinical factor for predicting the survival probabilities of EWS patients. Additionally, antigen-presenting cell (APC) related pathways and T cell co-inhibition were differently activated in two risk groups, which may result in different prognoses. CTLA4 may be an effective immune checkpoint inhibitor to treat EWS patients. All results were verified in the validation cohort. This study constructed 4-HRGs as a novel prognostic marker for predicting survival in EWS patients.

Dataset Information

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

Publications

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

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