Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients.
Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients.
复制标题
DOI：
10.1038/bjc.2017.270
复制
发表时间：
2017-10-10
影响因子：
8.8
通讯作者：
Alcaraz J
中科院分区：
文献类型：
--
作者：
Gabasa M;Ikemori R;Hilberg F;Reguart N;Alcaraz J
9tedanib是一种临床批准的多激酶受体抑制剂，用于与腺癌(ADC)组织学结合多西紫杉醇联合治疗非小细胞肺癌，其临床疗效是基于对ADC的临床益处，而对鳞癌(SCC)没有报道，鳞癌是两种最常见的组织学肺癌亚型。我们研究了肿瘤相关成纤维细胞(TAFs)在9tedanib对ADC和SCC的不同作用中的潜在作用。由于TAFs在组织切片中大部分处于静止和激活状态，因此我们重点研究了九替丹尼对肺癌中上调的成纤维细胞激活剂转化生长因子-β-1刺激的TAFs的抗纤维化作用。9tedanib剂量依赖性地抑制转化生长因子-β1诱导的一组促纤维化激活标志物在ADCTAFs和对照成纤维细胞中的表达，而在SCC-TAFs中这种抑制作用非常轻微。值得注意的是，9tedanib抑制了ADC中激活的TAFs分泌因子对一组癌细胞的生长和侵袭的刺激作用，但不能抑制SCC中TAFs的分泌，从而支持转化生长因子-β信号和异常的TAF癌串扰在ADC和SCC中是由不同的机制调控的。这些结果表明，9tedanib是一种有效的抑制ADC的纤维化及其相关的促肿瘤作用，而SCC-TAFs对9tedanib较差的抗纤维化反应可能是在这两种亚型中观察到的不同临床益处的原因。我们的研究结果还支持，基于肿瘤-TAF相互作用的临床前模型可能有助于确定SCC-TAFs对九替丹尼抗纤维化反应差的机制，并测试新的联合疗法，以进一步扩大该药物在实体瘤中的治疗效果。
Nintedanib is a clinically approved multikinase receptor inhibitor to treat non-small cell lung cancer with adenocarcinoma (ADC) histology in combination with docetaxel, based on the clinical benefits reported on ADC but not on squamous cell carcinoma (SCC), which are the two most common histologic lung cancer subtypes. We examined the potential role of tumour-associated fibroblasts (TAFs) in the differential effects of nintedanib in ADC and SCC. Because TAFs are largely quiescent and activated in histologic sections, we focused on the antifibrotic effects of nintedanib on TAFs stimulated with the potent fibroblast activator TGF-β1, which is upregulated in lung cancer. Nintedanib dose-dependently inhibited the TGF-β1-induced expression of a panel of pro-fibrotic activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved lung parenchyma, whereas such inhibition was very modest in SCC-TAFs. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by secreted factors from activated TAFs in ADC but not SCC, thereby supporting that TGF-β signalling and aberrant TAF–carcinoma cross-talk is regulated by different mechanisms in ADC and SCC. These results reveal that nintedanib is an effective inhibitor of fibrosis and its associated tumour-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that preclinical models based on carcinoma–TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumours.
登录
查看更多内容
影响因子：
5.8
作者：
Hostettler KE;Zhong J;Papakonstantinou E;Karakiulakis G;Tamm M;Seidel P;Sun Q;Mandal J;Lardinois D;Lambers C;Roth M
通讯作者：
Roth M
DOI：
10.1186/1755-1536-2-7
发表时间：
2009-12-15
期刊：
Fibrogenesis & tissue repair
影响因子：
--
作者：
Chen CZ;Raghunath M
通讯作者：
Raghunath M
DOI：
10.1146/annurev-bioeng-071813-105259
发表时间：
2014-07-11
影响因子：
9.7
作者：
Jain RK;Martin JD;Stylianopoulos T
通讯作者：
Stylianopoulos T
影响因子：
--
作者：
Lugo R;Gabasa M;Andriani F;Puig M;Facchinetti F;Ramírez J;Gómez-Caro A;Pastorino U;Fuster G;Almendros I;Gascón P;Davalos A;Reguart N;Roz L;Alcaraz J
通讯作者：
Alcaraz J
影响因子：
11.2
作者：
Bertolini, Giulia;D'Amico, Lucia;Roz, Luca
通讯作者：
Roz, Luca