Laboratoire EA 3842, Homéostasie cellulaire et Pathologies, Faculté de Médecine et de Pharmacie, Université de Limoges, Limoges Cedex, France.
CHU de Limoges, Service de chirurgie digestive générale et endocrinienne, Limoges Cedex, France.
J Cell Mol Med. 2017 Oct;21(10):2610-2622. doi: 10.1111/jcmm.13181. Epub 2017 Jun 9.
Colorectal cancer (CRC) is the most common digestive cancer in the Western world. Despite effective therapies, resistance and/or recurrence frequently occur. The present study investigated the impact of two survival pathways-neurotrophic factors (TrkB/BDNF) and autophagy-on cell fate and tumour evolution. In vitro studies were performed on two CRC cell lines, SW480 (primary tumour) and SW620 (lymph node invasion), which were also used for subcutaneous xenografts on a nude mouse model. In addition, the presence of neurotrophic factors (NTs) and autophagy markers were assessed in tissue samples representative of different stages. On the basis of our previous study (which demonstrated that TrkB overexpression is associated with prosurvival signaling in CRC cells), we pharmacologically inhibited NTs pathways with K252a. As expected, an inactivation of the PI3K/AKT pathway was observed and CRC cells initiated autophagy. Conversely, blocking the autophagic flux with chloroquine or with ATG5-siRNA overactivated TrkB/BDNF signaling. In vitro, dual inhibition improved the effectiveness of single treatment by significantly reducing metabolic activity and enhancing apoptotic cell death. These findings were accentuated in vivo, in which dual inhibition induced a spectacular reduction in tumour volume following long-term treatment (21 days for K252a and 12 days for CQ). Finally, significant amounts of phospho-TrkB and LC3II were found in the patients' tissues, highlighting their relevance in CRC tumour biology. Taken together, our results show that targeting NTs and autophagy pathways potentially constitutes a new therapeutic approach for CRC.
结直肠癌（CRC）是西方世界最常见的消化道癌症。尽管有有效的治疗方法，但耐药性和/或复发仍经常发生。本研究调查了两种生存途径——神经营养因子（TrkB/BDNF）和自噬——对细胞命运和肿瘤进化的影响。在体外研究了两种 CRC 细胞系，SW480（原发肿瘤）和 SW620（淋巴结侵犯），并在裸鼠模型上进行了皮下异种移植。此外，还评估了组织样本中神经营养因子（NTs）和自噬标志物的存在，这些组织样本代表了不同的阶段。基于我们之前的研究（表明 TrkB 过表达与 CRC 细胞中的生存信号有关），我们用 K252a 药理学抑制 NT 途径。正如预期的那样，观察到 PI3K/AKT 途径失活，CRC 细胞开始自噬。相反，用氯喹或 ATG5-siRNA 阻断自噬流会过度激活 TrkB/BDNF 信号。在体外，双重抑制通过显著降低代谢活性和增强凋亡细胞死亡，显著提高了单一治疗的效果。这些发现在体内得到了加强，其中双重抑制在长期治疗（K252a 治疗 21 天，CQ 治疗 12 天）后显著减少了肿瘤体积。最后，在患者的组织中发现了大量的磷酸化-TrkB 和 LC3II，强调了它们在 CRC 肿瘤生物学中的相关性。总之，我们的研究结果表明，靶向 NTs 和自噬途径可能为 CRC 提供一种新的治疗方法。
