Manara Maria Cristina, Terracciano Mario, Mancarella Caterina, Sciandra Marika, Guerzoni Clara, Pasello Michela, Grilli Andrea, Zini Nicoletta, Picci Piero, Colombo Mario P, Morrione Andrea, Scotlandi Katia
CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna 40136, Italy.
Department of Urology and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Oncotarget. 2016 Nov 29;7(48):79925-79942. doi: 10.18632/oncotarget.13160.
CD99 is a cell surface molecule that has emerged as a novel target for Ewing sarcoma (EWS), an aggressive pediatric bone cancer. This report provides the first evidence of methuosis in EWS, a non-apoptotic form of cell death induced by an antibody directed against the CD99 molecule. Upon mAb triggering, CD99 induces an IGF-1R/RAS/Rac1 complex, which is internalized into RAB5-positive endocytic vacuoles. This complex is then dissociated, with the IGF-1R recycling to the cell membrane while CD99 and RAS/Rac1 are sorted into immature LAMP-1-positive vacuoles, whose excessive accumulation provokes methuosis. This process, which is not detected in CD99-expressing normal mesenchymal cells, is inhibited by disruption of the IGF-1R signaling, whereas enhanced by IGF-1 stimulation. Induction of IGF-1R/RAS/Rac1 was also observed in the EWS xenografts that respond to anti-CD99 mAb, further supporting the role of the IGF/RAS/Rac1 axis in the hyperstimulation of macropinocytosis and selective death of EWS cells. Thus, we describe a vulnerability of EWS cells, including those resistant to standard chemotherapy, to a treatment with anti-CD99 mAb, which requires IGF-1R/RAS signaling but bypasses the need for their direct targeting. Overall, we propose CD99 targeting as new opportunity to treat EWS patients resistant to canonical apoptosis-inducing agents.
CD99是一种细胞表面分子，已成为尤因肉瘤（EWS）这一侵袭性儿童骨癌的新靶点。本报告首次提供了EWS中发生类凋亡的证据，类凋亡是一种由针对CD99分子的抗体诱导的非凋亡性细胞死亡形式。在单克隆抗体触发后，CD99诱导形成IGF-1R/RAS/Rac1复合物，该复合物被内化到RAB5阳性的内吞泡中。然后该复合物解离，IGF-1R循环回到细胞膜，而CD99和RAS/Rac1被分选到未成熟的LAMP-1阳性泡中，其过度积累引发类凋亡。在表达CD99的正常间充质细胞中未检测到这一过程，IGF-1R信号的破坏可抑制该过程，而IGF-1刺激则可增强该过程。在对抗CD99单克隆抗体有反应的EWS异种移植瘤中也观察到了IGF-1R/RAS/Rac1的诱导，进一步支持了IGF/RAS/Rac1轴在巨吞饮过度刺激和EWS细胞选择性死亡中的作用。因此，我们描述了EWS细胞，包括那些对标准化疗耐药的细胞，对抗CD99单克隆抗体治疗的易感性，这种治疗需要IGF-1R/RAS信号传导，但无需直接靶向它们。总体而言，我们提出靶向CD99是治疗对经典凋亡诱导剂耐药的EWS患者的新机会。
