論文 - 詳細
| RRC ID | 67046 |
|---|---|
| 著者 | Uchihara T, Miyake K, Yonemura A, Komohara Y, Itoyama R, Koiwa M, Yasuda T, Arima K, Harada K, Eto K, Hayashi H, Iwatsuki M, Iwagami S, Baba Y, Yoshida N, Yashiro M, Masuda M, Ajani JA, Tan P, Baba H, Ishimoto T. |
| タイトル | Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing β1 Integrin, Enhancing Drug Resistance. |
| ジャーナル | Cancer Res |
| Abstract |
Extracellular vesicles (EV) from cancer-associated fibroblasts (CAF) are composed of diverse payloads. Although CAFs impact the aggressive characteristics of gastric cancer cells, the contribution of CAF-EV to gastric cancer progression has not been elucidated. Here, we investigated the molecular mechanism of the changes in gastric cancer characteristics induced by CAF-EV. CAF abundance in gastric cancer tissues was associated with poor prognosis of patients with gastric cancer receiving chemotherapy. Moreover, CAF-EV induced tubular network formation and drug resistance of gastric cancer cells in the extracellular matrix (ECM). Comprehensive proteomic analysis of CAF-EV identified that Annexin A6 plays a pivotal role in network formation and drug resistance of gastric cancer cells in the ECM via activation of β1 integrin-focal adhesion kinase (FAK)-YAP. A peritoneal metastasis mouse model revealed that CAF-EV induced drug resistance in peritoneal tumors, and inhibition of FAK or YAP efficiently attenuated gastric cancer drug resistance in vitro and in vivo. These findings demonstrate that drug resistance is conferred by Annexin A6 in CAF-EV and provide a potential avenue for overcoming gastric cancer drug resistance through the inhibition of FAK-YAP signaling in combination with conventional chemotherapeutics. SIGNIFICANCE: This study elucidates a novel molecular mechanism through which Annexin A6 in CAF-EV activates FAK-YAP by stabilizing β1 integrin at the cell surface of gastric cancer cells and subsequently induces drug resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/16/3222/F1.large.jpg. |
| 巻・号 | 80(16) |
| ページ | 3222-3235 |
| 公開日 | 2020-8-15 |
| DOI | 10.1158/0008-5472.CAN-19-3803 |
| PII | 0008-5472.CAN-19-3803 |
| PMID | 32605995 |
| MeSH | Adaptor Proteins, Signal Transducing / metabolism* Animals Annexin A6 / metabolism* Base Sequence Cancer-Associated Fibroblasts / metabolism* Cell Line, Tumor Disease Progression Drug Resistance, Neoplasm* Extracellular Matrix / metabolism Extracellular Matrix / pathology Extracellular Vesicles / metabolism* Focal Adhesion Kinase 1 / metabolism* Humans Integrin beta1 / metabolism* Kaplan-Meier Estimate Mice Mice, Inbred BALB C Mice, Nude Prognosis Real-Time Polymerase Chain Reaction Stomach Neoplasms / drug therapy Stomach Neoplasms / metabolism* Stomach Neoplasms / mortality Stomach Neoplasms / pathology Transcription Factors / metabolism* YAP-Signaling Proteins |
| IF | 9.727 |
| リソース情報 | |
| ヒト・動物細胞 | Kato III(RCB2088) MKN45(RCB1001) |