UMR1048-I2MC, Université de Toulouse, Inserm, UT3, Toulouse, France.
Department of Gynecology Surgery, University Hospital Centre-Toulouse, IUCT-Oncopole, Toulouse, France.
Cell Death Dis. 2019 Dec 20;10(12):956. doi: 10.1038/s41419-019-2181-1.
Cytotoxic therapy for breast cancer inhibits the growth of primary tumors, but promotes metastasis to the sentinel lymph nodes through the lymphatic system. However, the effect of first-line chemotherapy on the lymphatic endothelium has been poorly investigated. In this study, we determined that paclitaxel, the anti-cancer drug approved for the treatment of metastatic or locally advanced breast cancer, induces lymphatic endothelial cell (LEC) autophagy to increase metastases. While paclitaxel treatment was largely efficacious in inhibiting LEC adhesion, it had no effect on cell survival. Paclitaxel inhibited LEC migration and branch point formation by inducing an autophagy mechanism independent of Akt phosphorylation. In vivo, paclitaxel mediated a higher permeability of lymphatic endothelium to tumor cells and this effect was reversed by chloroquine, an autophagy-lysosome inhibitor. Despite a strong effect on reducing tumor size, paclitaxel significantly increased metastasis to the sentinel lymph nodes. This effect was restricted to a lymphatic dissemination, as chemotherapy did not affect the blood endothelium. Taken together, our findings suggest that the lymphatic system resists to chemotherapy through an autophagy mechanism to promote malignant progression and metastatic lesions. This study paves the way for new combinative therapies aimed at reducing the number of metastases.
乳腺癌的细胞毒性疗法抑制原发性肿瘤的生长，但通过淋巴系统促进转移至前哨淋巴结。然而，一线化疗对淋巴管内皮的影响尚未得到充分研究。在这项研究中，我们确定了紫杉醇，一种批准用于治疗转移性或局部晚期乳腺癌的抗癌药物，可诱导淋巴管内皮细胞（LEC）自噬以增加转移。虽然紫杉醇治疗在很大程度上有效抑制 LEC 黏附，但对细胞存活没有影响。紫杉醇通过诱导独立于 Akt 磷酸化的自噬机制抑制 LEC 迁移和分支点形成。在体内，紫杉醇介导了淋巴管内皮对肿瘤细胞更高的通透性，而氯喹，一种自噬溶酶体抑制剂，可逆转这种作用。尽管紫杉醇对缩小肿瘤大小有很强的作用，但它显著增加了前哨淋巴结的转移。这种作用仅限于淋巴管扩散，因为化疗不会影响血液内皮。总之，我们的研究结果表明，淋巴系统通过自噬机制抵抗化疗，以促进恶性进展和转移病变。这项研究为旨在减少转移数量的新联合治疗铺平了道路。
