Gustafsson Anna, Fritz Helena K M, Dahlbäck Björn
Lund University, Department of Translational Medicine, Section of Clinical Chemistry, University Hospital Malmö, Malmö, Sweden.
Lund University, Department of Translational Medicine, Section of Clinical Chemistry, University Hospital Malmö, Malmö, Sweden.
Exp Cell Res. 2017 Jun 1;355(1):47-56. doi: 10.1016/j.yexcr.2017.03.040. Epub 2017 Mar 19.
Clear Cell Renal Cell Carcinoma (CCRCC) is a lethal cancer with bad prognosis due to development of chemoresistance and recurrence of more aggressive tumors. Investigation of Gas6-mediated Axl signaling in CCRCC and endothelial cells reveals a Sunitinib resistant Gas6-Axl signaling that is sustained and enhanced and specifically triggers downstream AKT and PRAS40 activation in an intensified manner. Gas6-induced Axl signaling in presence of Sunitinib is also diversified displaying onset of Axl-dependent EGFR and METR activation and activation of classical MAPK pathways. Gas6+Sunitinib-adapted CCRCC cells present increased viability and decreased apoptosis and enhanced production of the multi-tumorigenic Osteopontin (OPN) and of one of its activator matrix metalloproteinase-7. Axl activity is necessary for CCRCC cell sphere formation and the ability of the cells to attach after non-adhesive growth. In addition, Gas6+Sunitinib-adapted CCRCC cells displayed enhanced migration and sphere formation, both mechanisms being Axl and OPN dependent. Altogether, this suggests that Sunitinib while targeting endothelial cells and tumor angiogenesis, simultaneously provides protumorigenic effects due to a constitutively, intensified and divergent Gas6-Axl system.
Gas6-mediated Axl signaling, which is enhanced and diversified in the presence of Sunitinib possibly contributes to acquired chemoresistance, recurrence of aggressive disease and metastasis of CCRCC tumors. Therefore, combinatorial Axl-targeted therapy might be beneficial for CCRCC patients intended for Sunitinib treatment.
透明细胞肾细胞癌（CCRCC）是一种致命癌症，由于化疗耐药性的发展和更具侵袭性肿瘤的复发，其预后较差。对CCRCC和内皮细胞中Gas6介导的Axl信号传导的研究揭示了一种对舒尼替尼耐药的Gas6-Axl信号传导，该信号传导持续且增强，并以强化方式特异性触发下游AKT和PRAS40激活。在舒尼替尼存在的情况下，Gas6诱导的Axl信号传导也呈现多样化，表现为Axl依赖性EGFR和METR激活的开始以及经典MAPK途径的激活。适应Gas6+舒尼替尼的CCRCC细胞活力增加、凋亡减少，多肿瘤生成性骨桥蛋白（OPN）及其激活剂之一基质金属蛋白酶-7的产生增加。Axl活性对于CCRCC细胞球形成以及细胞在非粘附生长后附着的能力是必需的。此外，适应Gas6+舒尼替尼的CCRCC细胞表现出增强的迁移和球形成，这两种机制均依赖于Axl和OPN。总之，这表明舒尼替尼在靶向内皮细胞和肿瘤血管生成的同时，由于组成性、强化和多样化的Gas6-Axl系统，同时产生促肿瘤作用。
在舒尼替尼存在的情况下增强和多样化的Gas6介导的Axl信号传导可能导致CCRCC获得性化疗耐药、侵袭性疾病复发和肿瘤转移。因此，联合Axl靶向治疗可能对打算接受舒尼替尼治疗的CCRCC患者有益。
