期刊
REDOX BIOLOGY
卷 46, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.redox.2021.102076
关键词
Fibroblast; Anlotinib; BDNF; TrkB; ROS; Nrf2
资金
- National Natural Science Foundation of China [81871902, 82072616]
- Shanghai Municipal Edu-cation Commission-Gaofeng Clinical Medicine Grant Support [20152505]
- China Scholarship Council [201906230139]
- Shanghai Sailing Program [21YF1427600]
In this study, anlotinib inhibited gastric cancer (GC) cell growth by inducing apoptosis and G2/M phase arrest in a dose- and time-dependent manner. The interaction between epithelial and stromal cells in the tumor microenvironment affects the response of GC cells to anlotinib. Secreted lactate from GC cells activates cancer-associated fibroblasts (CAFs) to produce BDNF in a NF-kappa B-dependent manner, reducing the sensitivity of GC cells to anlotinib. Targeting the BDNF-TrkB pathway increased the sensitivity of GC cells to anlotinib in a human patient-derived organoid model.
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-kappa B-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.
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