Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, 69120 Heidelberg, Germany.
Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Nature. 2015 Dec 3;528(7580):93-8. doi: 10.1038/nature16071. Epub 2015 Nov 4.
Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
星形细胞瘤等神经胶质脑肿瘤是不可治愈的肿瘤，其特征为弥漫浸润性生长。在这里，我们发现星形细胞瘤中的许多肿瘤细胞会延伸超长的膜突，并利用这些独特的肿瘤微管作为大脑侵袭、增殖和远距离连接的途径。由此产生的网络允许通过微管相关的间隙连接进行细胞间通讯。当网络受损时，肿瘤微管会被用于修复。此外，连接的星形细胞瘤细胞，而不是在肿瘤进展过程中始终未连接的细胞，能够免受放疗引起的细胞死亡。神经元生长相关蛋白 43 对于微管的形成和功能很重要，并驱动微管依赖性肿瘤细胞侵袭、增殖、连接和放射抵抗。少突胶质细胞瘤在这种机制上存在缺陷。总之，星形细胞瘤可以形成功能性的多细胞网络结构。通过靶向肿瘤微管使星形细胞瘤细胞脱连接，为降低这种疾病的治疗抵抗提供了新的原则。
