Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37240, USA.
Neoplasia. 2018 Oct;20(10):1008-1022. doi: 10.1016/j.neo.2018.08.005. Epub 2018 Sep 3.
Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that is characterized by resistance to chemotherapy and a poor clinical outcome. The overexpression of the receptor tyrosine kinase AXL is frequently associated with unfavorable prognosis in EAC. Although it is well documented that AXL mediates cancer cell invasion as a downstream effector of epithelial-to-mesenchymal transition, the precise molecular mechanism underlying this process is not completely understood. Herein, we demonstrate for the first time that AXL mediates cell invasion through the regulation of lysosomes peripheral distribution and cathepsin B secretion in EAC cell lines. Furthermore, we show that AXL-dependent peripheral distribution of lysosomes and cell invasion are mediated by extracellular acidification, which is potentiated by AXL-induced secretion of lactate through AKT-NF-κB-dependent MCT-1 regulation. Our novel mechanistic findings support future clinical studies to evaluate the therapeutic potential of the AXL inhibitor R428 (BGB324) in highly invasive EAC.
食管腺癌（EAC）是一种高度侵袭性恶性肿瘤，其特征是对化疗具有耐药性和不良的临床结局。受体酪氨酸激酶 AXL 的过表达与 EAC 的不良预后常相关。尽管已有文献证明 AXL 通过上皮间质转化的下游效应子介导癌细胞侵袭，但这一过程的确切分子机制尚不完全清楚。在此，我们首次证明 AXL 通过调节 EAC 细胞系中的溶酶体周围分布和组织蛋白酶 B 的分泌来介导细胞侵袭。此外，我们表明 AXL 依赖性溶酶体的周围分布和细胞侵袭是由细胞外酸化介导的，而 AXL 通过 AKT-NF-κB 依赖性 MCT-1 调节诱导的乳酸盐分泌增强了这种酸化作用。我们的新发现支持未来的临床研究，以评估 AXL 抑制剂 R428（BGB324）在高度侵袭性 EAC 中的治疗潜力。
