The cross-talk between tumor cells and activated fibroblasts mediated by lactate/BDNF/TrkB signaling promotes acquired resistance to anlotinib in human gastric cancer

• DOI: 10.1016/j.redox.2021.102076
• Publication Date: 2021-07-20T06:48:06Z
• Authors: Zhijian Jin; Yifan Lu; Xiongyan Wu; Tao Pan; Zhenjia Yu; Junyi Hou; Airong Wu; Jianfang Li; Zhongyin Yang; Chen Li; Min Yan; Chao Yan; Zhenggang Zhu; Bingya Liu; Weihua Qiu; Liping Su
• Keywords: 0301 basic medicine; Medicine (General); Indoles; QH301-705.5; Brain-Derived Neurotrophic Factor; TrkB; ROS; Anlotinib; Fibroblasts; Nrf2; 3. Good health; 03 medical and health sciences; BDNF; R5-920; Stomach Neoplasms; Quinolines; Tumor Microenvironment; Fibroblast; Humans; Lactic Acid; Biology (General); Research Paper

Acquired resistance to tyrosine kinase inhibitors (TKIs) is the major obstacle to improve clinical efficacy in cancer patients. The epithelial-stromal interaction in tumor microenvironment influences cancer drug response to TKIs. Anlotinib is a novel oral multi-targeted TKI, and has recently been proven to be effective and safe for several tumors. However, if and how the epithelial-stromal interaction in tumor microenvironment affects anlotinib response in gastric cancer (GC) is not known. In this study, we found that anlotinib inhibited GC cells growth by inducing GC cells apoptosis and G2/M phase arrest in a dose- and time-dependent manner. Reactive oxygen species (ROS) mediated anlotinib-induced apoptosis in GC cells, while cancer-associated fibroblasts (CAFs) significantly suppressed anlotinib-induced apoptosis and ROS in GC cells. Increased BDNF that was derived from CAFs activated TrkB-Nrf2 signaling in GC cells, and reduced GC cells response to anlotinib. We identified secreted lactate from GC cells as the key molecule instructing CAFs to produce BDNF in a NF-κB-dependent manner. Additionally, functional targeting BDNF-TrkB pathway with neutralizing antibodies against BDNF and TrkB increased the sensitivity of GC cells towards anlotinib in human patient-derived organoid (PDO) model. Taken together, these results characterize a critical role of the epithelial-stroma interaction mediated by the lactate/BDNF/TrkB signaling in GC anlotinib resistance, and provide a novel option to overcome drug resistance.