Pass Harvey I, Lavilla Carmencita, Canino Claudia, Goparaju Chandra, Preiss Jordan, Noreen Samrah, Blandino Giovanni, Cioce Mario
Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, USA.
New York University Langone Medical Center, New York University, New York, USA.
Oncotarget. 2016 Aug 30;7(35):56408-56421. doi: 10.18632/oncotarget.10895.
In the present work we show that multiple lung cancer cell lines contain cisplatin resistant cell subpopulations expressing the Colony-Stimulating-Factor-Receptor-1 (CSF-1R) and surviving chemotherapy-induced stress. By exploiting siRNA-mediated knock down in vitro and the use of an investigational CSF-1R TKI (JNJ-40346527) in vitro and in vivo, we show that expression and function of the receptor are required for the clonogenicity and chemoresistance of the cell lines. Thus, inhibition of the kinase activity of the receptor reduced the levels of EMT-associated genes, stem cell markers and chemoresistance genes. Additionally, the number of high aldehyde dehydrogenase (ALDH) expressing cells was reduced, consequent to the lack of cisplatin-induced increase of ALDH isoforms. This affected the collective chemoresistance of the treated cultures. Treatment of tumor bearing mice with JNJ-40346527, at pharmacologically relevant doses, produced strong chemo-sensitizing effects in vivo. These anticancer effects correlated with a reduced number of CSF-1Rpos cells, in tumors excised from the treated mice. Depletion of the CD45pos cells within the treated tumors did not, apparently, play a major role in mediating the therapeutic response to the TKI. Thus, lung cancer cells express a functional CSF-1 and CSF-1R duo which mediates pro-tumorigenic effects in vivo and in vitro and can be targeted in a therapeutically relevant way. These observations complement the already known role for the CSF-1R at mediating the pro-tumorigenic properties of tumor-infiltrating immune components.
在本研究中，我们发现多种肺癌细胞系含有表达集落刺激因子受体1（CSF-1R）的顺铂耐药细胞亚群，这些亚群能在化疗诱导的应激中存活。通过在体外利用小干扰RNA介导的基因敲低以及在体外和体内使用一种研究性CSF-1R酪氨酸激酶抑制剂（JNJ-40346527），我们表明该受体的表达和功能是这些细胞系克隆形成能力和化疗耐药性所必需的。因此，抑制该受体的激酶活性可降低上皮-间质转化相关基因、干细胞标志物和化疗耐药基因的水平。此外，由于顺铂诱导的醛脱氢酶（ALDH）亚型增加缺乏，表达高活性ALDH的细胞数量减少。这影响了处理后培养物的总体化疗耐药性。用JNJ-40346527以药理学相关剂量治疗荷瘤小鼠，在体内产生了强烈的化疗增敏作用。这些抗癌作用与从治疗小鼠切除的肿瘤中CSF-1R阳性细胞数量减少相关。在处理的肿瘤内耗竭CD45阳性细胞显然在介导对该酪氨酸激酶抑制剂的治疗反应中不起主要作用。因此，肺癌细胞表达功能性的CSF-1和CSF-1R二者组合，其在体内和体外介导促肿瘤作用，并且可以以治疗相关的方式作为靶点。这些观察结果补充了CSF-1R在介导肿瘤浸润免疫成分的促肿瘤特性方面已为人知的作用。
