文章：

ASPH是软骨肉瘤的转移因子及治疗靶点

ASPH Is a Metastatic Factor and Therapeutic Target in Chondrosarcoma

原文发布日期：12 March 2025

DOI: 10.3390/cancers17060951

类型: Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

背景：软骨肉瘤是一种高度侵袭性的原发性恶性骨肿瘤，目前尚无有效的全身性治疗方法。本研究评估了天冬氨酸β-羟化酶作为潜在治疗靶点的可能性。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明确。本研究旨在分析传统型软骨肉瘤中ASPH的表达情况，评估其作为生物标志物的价值，并验证抑制ASPH是否能在临床前模型中减缓肿瘤进展。 方法：构建包含传统型软骨肉瘤组织的组织芯片，采用免疫组化技术定量分析ASPH表达。在两种ASPH表达完整的软骨肉瘤细胞系及ASPH敲除细胞系中，评估了特异性抑制ASPH活性的小分子抑制剂的作用。检测指标包括细胞活力、侵袭能力及基质金属蛋白酶表达水平。通过小鼠异种移植软骨肉瘤模型，评估SMI对肿瘤生长、肿瘤内MMP活性及肺转移负荷的影响。 结果：较高的ASPH评分与更高的死亡和转移风险相关。体外实验显示，SMI能显著抑制软骨肉瘤细胞增殖、侵袭及MMPs分泌，而ASPH敲除后这些效应消失。在体内实验中，全身给予SMI可抑制异种移植瘤的生长、降低肿瘤内MMP活性与含量，并减轻肺转移负荷。 结论：本研究证实ASPH可作为软骨肉瘤的生物标志物及转移表型的影响因子。针对ASPH的全身性小分子抑制剂治疗在临床前模型中能有效抑制肿瘤进展，表明靶向ASPH治疗可能成为表达ASPH的软骨肉瘤的新型治疗策略。

原文链接：

ASPH Is a Metastatic Factor and Therapeutic Target in Chondrosarcoma