ASPH Is a Metastatic Factor and Therapeutic Target in Chondrosarcoma.

IF 4.5 2区 医学 Q1 ONCOLOGY
Cancers Pub Date : 2025-03-12 DOI:10.3390/cancers17060951
Xiaojuan Sun, Jesse Hart, Ross Taliano, Janine Molino, Joseph H Schwab, Sjoerd Nota, Katsuya Nagaoka, Songhua Zhang, Mark Olsen, Rolf Carlson, Jack Wands, Richard M Terek
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引用次数: 0

Abstract

Background: Chondrosarcoma (CS) is a highly aggressive primary malignant bone tumor for which there are no effective systemic treatments. We assessed aspartate β-hydroxylase (ASPH) as a potential treatment target. ASPH is a transforming cell surface receptor, but its role in chondrosarcoma has not been evaluated. Our goals were to analyze the expression of ASPH in conventional chondrosarcoma, evaluate its utility as a biomarker, and determine if ASPH inhibition diminishes tumor progression in a preclinical model. Methods: An annotated tissue microarray was constructed with conventional chondrosarcoma tissues. ASPH expression was quantified with immunohistochemistry. A small molecule inhibitor (SMI) designed to inhibit ASPH activity was evaluated in two CS cell lines with intact ASPH expression and after knockout. Cell viability, invasion, and matrix metalloproteinase (MMP) expression were measured. A mouse xenograft chondrosarcoma model was used to evaluate the effect of the SMI on tumor growth, MMP activity in tumors, and lung metastatic burden. Results: Higher ASPH scores were associated with a greater risk of death and metastasis. The SMI decreased CS cell proliferation, invasion, and secretion of MMPs in vitro, and the effects were lost after ASPH knockout. In vivo, systemic administration of the SMI decreased tumor growth, MMP activity and content in xenograft tumors, and lung metastatic burden. Conclusions: These data validate ASPH as a biomarker in CS and as a factor in the metastatic phenotype. Systemic treatment with an SMI directed against ASPH inhibits tumor progression in a preclinical model, suggesting that ASPH-targeted therapy may be a new treatment strategy for chondrosarcoma expressing ASPH.

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来源期刊
Cancers
Cancers Medicine-Oncology
CiteScore
8.00
自引率
9.60%
发文量
5371
审稿时长
18.07 days
期刊介绍: Cancers (ISSN 2072-6694) is an international, peer-reviewed open access journal on oncology. It publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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