Cancer Biology and Immunotherapies Group, Sanford Research, 2301 East 60th St north, Sioux Falls, SD, 57104, USA.
Pediatrics and Rare Diseases Group, Sanford Research, 2301 East 60th St north, Sioux Falls, SD, 57104, USA.
Nat Commun. 2018 Oct 16;9(1):4284. doi: 10.1038/s41467-018-06640-0.
Patients with densely innervated tumors suffer with increased metastasis and decreased survival as compared to those with less innervated tumors. We hypothesize that in some tumors, nerves are acquired by a tumor-induced process, called axonogenesis. Here, we use PC12 cells as an in vitro neuronal model, human tumor samples and murine in vivo models to test this hypothesis. When appropriately stimulated, PC12 cells extend processes, called neurites. We show that patient tumors release vesicles, called exosomes, which induce PC12 neurite outgrowth. Using a cancer mouse model, we show that tumors compromised in exosome release are less innervated than controls. Moreover, in vivo pharmacological blockade of exosome release similarly attenuates tumor innervation. We characterize these nerves as sensory in nature and demonstrate that axonogenesis is potentiated by the exosome-packaged axonal guidance molecule, EphrinB1. These findings indicate that tumor released exosomes induce tumor innervation and exosomes containing EphrinB1 potentiate this activity.
与神经分布较少的肿瘤相比，神经密集型肿瘤的患者转移率更高，生存率更低。我们假设在某些肿瘤中，神经是通过一种称为轴突发生的肿瘤诱导过程获得的。在这里，我们使用 PC12 细胞作为体外神经元模型、人类肿瘤样本和小鼠体内模型来验证这一假设。当受到适当刺激时，PC12 细胞会延伸出称为神经突的过程。我们表明，患者肿瘤释放囊泡，称为外泌体，可诱导 PC12 神经突生长。使用癌症小鼠模型，我们表明，外泌体释放受损的肿瘤比对照组的神经支配程度更低。此外，体内外泌体释放的药理学阻断也可类似地减弱肿瘤神经支配。我们将这些神经定性为感觉神经，并证明外泌体包装的轴突导向分子 EphrinB1 增强了这种活性。这些发现表明，肿瘤释放的外泌体诱导肿瘤神经支配，并且包含 EphrinB1 的外泌体增强了这种活性。
