Qin Elizabeth Y, Cooper Dominique D, Abbott Keene L, Lennon James, Nagaraja Surya, Mackay Alan, Jones Chris, Vogel Hannes, Jackson Peter K, Monje Michelle
Department of Neurology, Stanford University, Palo Alto, CA 94305, USA.
Baxter Laboratory, Department of Microbiology & Immunology, Stanford University, Palo Alto, CA 94305, USA.
Cell. 2017 Aug 24;170(5):845-859.e19. doi: 10.1016/j.cell.2017.07.016. Epub 2017 Aug 17.
The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecular mechanisms mediating this are poorly understood. We demonstrate that neural precursor cell (NPC):glioma cell communication underpins this propensity of glioma to colonize the SVZ through secretion of chemoattractant signals toward which glioma cells home. Biochemical, proteomic, and functional analyses of SVZ NPC-secreted factors revealed the neurite outgrowth-promoting factor pleiotrophin, along with required binding partners SPARC/SPARCL1 and HSP90B, as key mediators of this chemoattractant effect. Pleiotrophin expression is strongly enriched in the SVZ, and pleiotrophin knock down starkly reduced glioma invasion of the SVZ in the murine brain. Pleiotrophin, in complex with the binding partners, activated glioma Rho/ROCK signaling, and ROCK inhibition decreased invasion toward SVZ NPC-secreted factors. These findings demonstrate a pathogenic role for NPC:glioma interactions and potential therapeutic targets to limit glioma invasion. PAPERCLIP.
侧脑室室管膜下区（SVZ）是小儿和成人胶质瘤扩散的常见且重要部位，但介导这一过程的细胞和分子机制尚不清楚。我们证明神经前体细胞（NPC）与胶质瘤细胞的通讯是胶质瘤通过分泌趋化信号在SVZ定植倾向的基础，胶质瘤细胞会归巢于这些趋化信号。对SVZ NPC分泌因子的生化、蛋白质组学和功能分析揭示，神经突生长促进因子多效生长因子，以及必需的结合伴侣SPARC/SPARCL1和HSP90B，是这种趋化作用的关键介质。多效生长因子在SVZ中高度富集，敲低多效生长因子可显著减少小鼠脑内胶质瘤对SVZ的侵袭。多效生长因子与结合伴侣形成复合物，激活胶质瘤Rho/ROCK信号通路，抑制ROCK可减少对SVZ NPC分泌因子的侵袭。这些发现证明了NPC与胶质瘤相互作用的致病作用以及限制胶质瘤侵袭的潜在治疗靶点。回形针。
