Background:High dissemination potential and resistance to standard therapy significantly contribute to high mortality associated with ovarian cancer. Cancer stem cells (CSCs) drive tumor progression, metastasis, and recurrence after treatments’ failure. Here, we provide the first evidence of TIMP1 overexpression in ovarian CSCs, suggesting its potential role as a prognostic biomarker.Methods:Different ovarian cancer cell models were used to explore the potential link between TIMP1 and stem-like phenotypes. Experiments included spheroid formation, drug treatments, gene expression, functional assays, and zebrafish xenograft models to assess cell behavior and molecular changes.Results:TIMP1 was overexpressed in CSCs, and its expression was also upregulated in chemoresistant and anoikis-resistant cells. Our database analysis revealed a correlation between TIMP1 expression levels and poor patient prognosis. Overexpression of TIMP1 in ovarian cancer cell lines was able to recapitulate several features of the ovarian cancer stem cell phenotype, including treatment resistance, expression of stem cell markers, and anoikis resistance. TIMP1-overexpressing cells also exhibited enhanced migration potential in vitro and increased metastatic potential in vivo. Moreover, TIMP1 overexpression significantly altered the transcriptome landscape of cells, highlighting its role in modulating critical pathways associated with cell migration and inflammation.Conclusions:This study identifies the pivotal role of TIMP1 in ovarian CSCs and its contribution to therapy resistance, recurrence, and metastasis.
背景：卵巢癌的高死亡率与其高扩散潜力及对标准治疗的抵抗性密切相关。癌症干细胞（CSCs）驱动肿瘤进展、转移以及治疗失败后的复发。本研究首次提供了TIMP1在卵巢癌干细胞中过表达的证据，提示其作为预后生物标志物的潜在作用。 方法：采用多种卵巢癌细胞模型探究TIMP1与干细胞样表型之间的潜在关联。实验包括球体形成、药物处理、基因表达分析、功能实验以及斑马鱼异种移植模型，以评估细胞行为及分子变化。 结果：TIMP1在癌症干细胞中过表达，且在化疗耐药和失巢凋亡耐受细胞中表达上调。数据库分析显示TIMP1表达水平与患者不良预后相关。在卵巢癌细胞系中过表达TIMP1可重现卵巢癌干细胞表型的多个特征，包括治疗抵抗性、干细胞标志物表达及失巢凋亡耐受。过表达TIMP1的细胞在体外表现出增强的迁移能力，在体内则显示出更高的转移潜力。此外，TIMP1过表达显著改变了细胞的转录组景观，突显其在调控细胞迁移和炎症相关关键通路中的作用。 结论：本研究揭示了TIMP1在卵巢癌干细胞中的关键作用及其对治疗抵抗、复发和转移的贡献。
肿瘤(癌症)患者之家