PDF(Pubmed)
Abstract：
The identification of new effective therapeutic options for non-small-cell lung cancer (NSCLC) represents a crucial challenge in oncology. Recent studies indicate that cancer-associated fibroblasts (CAFs) participate in tumor progression by establishing a favorable microenvironment that promotes cancer progression. Therefore, the development of strategies inhibiting the interplay between CAFs and cancer cells is considered a winning approach for the development of effective anti-cancer drugs. Among other factors, the signal transducer and activator of transcription-3 (STAT3) has been reported as a key mediator of CAF oncogenic actions, representing a promising therapeutic target. Here, we applied an aptamer-based conjugate (named Gint4.T-STAT3), containing a STAT3 siRNA linked to an aptamer binding and inhibiting the platelet-derived growth factor receptor (PDGFR)β, to obtain STAT3-specific silencing and interfere with CAF pro-tumorigenic functions. We demonstrated that this molecule effectively delivers the STAT3 siRNA in NSCLC cells, and blocks CAF-induced cancer cell growth and migration and reduced spheroid dimension. In addition, we found that Gint4.T-STAT3 alters CAF phenotype, thus functioning as a double-acting molecule able to inhibit the entire tumor bulk. Our data provide a proof of principle for the targeting of CAF pro-tumor functions through an aptamer-based drug, and can open innovative horizons in NSCLC therapy.
摘要：
鉴定非小细胞肺癌（NSCLC）的新的有效治疗选择代表了肿瘤学的关键挑战。最近的研究表明，癌症相关成纤维细胞（CAF）通过建立促进癌症进展的有利微环境来参与肿瘤进展。因此,开发抑制CAFs与癌细胞相互作用的策略被认为是开发有效抗癌药物的成功途径.除其他因素外，信号转导和转录激活因子-3（STAT3）已被报道为CAF致癌作用的关键介质，代表一个有希望的治疗目标。这里,我们应用了一种基于适体的缀合物（名为Gint4。T-STAT3),含有与结合并抑制血小板衍生生长因子受体（PDGFR）β的适体连接的STAT3siRNA，获得STAT3特异性沉默并干扰CAF促瘤功能。我们证明了该分子在NSCLC细胞中有效递送STAT3siRNA，并阻止CAF诱导的癌细胞生长和迁移，并减少球体尺寸。此外,我们发现了Gint4.T-STAT3改变CAF表型,因此作为一种能够抑制整个肿瘤体积的双作用分子发挥作用。我们的数据为通过基于适体的药物靶向CAF促肿瘤功能提供了原理证明，并可以在非小细胞肺癌治疗中开辟创新视野。
