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.

ASPH是软骨肉瘤的转移因子和治疗靶点。
背景:软骨肉瘤(CS)是一种高度侵袭性的原发性骨恶性肿瘤,目前尚无有效的全身治疗方法。我们评估了天冬氨酸β-羟化酶(ASPH)作为潜在的治疗靶点。ASPH是一种转化细胞表面受体,但其在软骨肉瘤中的作用尚未得到评价。我们的目标是分析ASPH在常规软骨肉瘤中的表达,评估其作为生物标志物的效用,并在临床前模型中确定ASPH抑制是否会减少肿瘤进展。方法:用常规软骨肉瘤组织构建带注释的组织微阵列。免疫组织化学定量测定ASPH的表达。一种设计用于抑制ASPH活性的小分子抑制剂(SMI)在两个ASPH完整表达和敲除后的CS细胞系中进行了评估。检测细胞活力、侵袭性和基质金属蛋白酶(MMP)的表达。采用小鼠异种移植软骨肉瘤模型来评估SMI对肿瘤生长、肿瘤中MMP活性和肺转移负担的影响。结果:较高的ASPH评分与较高的死亡和转移风险相关。SMI在体外降低了CS细胞的增殖、侵袭和MMPs的分泌,在敲除ASPH后这种作用消失。在体内,全身给药SMI可降低肿瘤生长、异种移植物肿瘤中MMP的活性和含量,以及肺转移负担。结论:这些数据证实了ASPH是CS的生物标志物,也是转移表型的一个因素。在临床前模型中,针对ASPH的SMI全身治疗可抑制肿瘤进展,表明ASPH靶向治疗可能是表达ASPH的软骨肉瘤的一种新的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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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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