Src 作为子宫内膜异位症的一个新的治疗靶点。

Src as a novel therapeutic target for endometriosis.

机构信息

Department of Preventive Medicine, University of Southern California/Keck School of Medicine, 1450 Biggy Street, Los Angeles, CA 90033, USA.

Department of Genetics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Núcleo de Apoio à Pesquisa (NAP) denominado Centro de Biologia Sistêmica Integrada (CISBi), São Paulo, Brazil.

出版信息

Gynecol Oncol. 2014 Oct;135(1):100-7. doi: 10.1016/j.ygyno.2014.06.016. Epub 2014 Jun 24.

Abstract

BACKGROUND

Endometriosis is a common condition that is associated with an increased risk of developing ovarian carcinoma. Improved in vitro models of this disease are needed to better understand how endometriosis, a benign disease, can undergo neoplastic transformation, and for the development of novel treatment strategies to prevent this progression.

METHODS

We describe the generation and in vitro characterization of novel TERT immortalized ovarian endometriosis epithelial cell lines (EEC16-TERT).

RESULTS

Expression of TERT alone was sufficient to immortalize endometriosis epithelial cells. TERT immortalization induces an epithelial-to-mesenchymal transition and perturbation in the expression of genes involved in the development of ovarian cancer. EEC16-TERT was non-tumorigenic when xenografted into immunocompromised mice but grew in anchorage-independent growth assays in an epidermal growth factor and hydrocortisone dependent manner. Colony formation in agar was abolished by inhibition of Src, and the Src pathway was found to be activated in human endometriosis lesions.

CONCLUSIONS

This new in vitro model system mimics endometriosis and the early stages of neoplastic transformation in the development of endometriosis associated ovarian cancer. We demonstrate the potential clinical relevance of this model by identifying Src activation as a novel pathway in endometriosis that could be targeted therapeutically, perhaps as a novel strategy to manage endometriosis clinically, or to prevent the development of endometriosis-associated ovarian cancer.

摘要

背景

子宫内膜异位症是一种常见疾病,与卵巢癌风险增加相关。需要更好地了解子宫内膜异位症这种良性疾病如何发生肿瘤性转化,从而开发出改进的体外模型,为此需要开发出新型治疗策略以预防这种进展。

方法

我们描述了新型端粒酶逆转录酶(TERT)永生化卵巢子宫内膜异位症上皮细胞系(EEC16-TERT)的生成和体外鉴定。

结果

仅表达 TERT 就足以使子宫内膜异位症上皮细胞永生化。TERT 永生化诱导上皮细胞向间充质转化,并扰乱与卵巢癌发生相关的基因表达。将 EEC16-TERT 异种移植到免疫功能低下的小鼠中时无致瘤性,但以表皮生长因子和氢化可的松依赖性方式在无锚定依赖性生长测定中生长。Src 抑制可消除琼脂中的集落形成,并且在人子宫内膜异位症病变中发现Src 途径被激活。

结论

这种新的体外模型系统模拟了子宫内膜异位症,并模拟了子宫内膜异位症相关卵巢癌发生中肿瘤性转化的早期阶段。我们通过鉴定 Src 激活作为子宫内膜异位症中的一种新途径来证明该模型的潜在临床相关性,这可能是一种治疗子宫内膜异位症的新策略,或者可以预防子宫内膜异位症相关的卵巢癌。

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