EGFR‐rich extracellular vesicles derived from highly metastatic nasopharyngeal carcinoma cells accelerate tumour metastasis through PI3K/AKT pathway‐suppressed ROS

Abstract

Nasopharyngeal carcinoma (NPC) is the most common cancer with high metastatic potential that occurs in the epithelial cells of the nasopharynx. Distant metastases are the primary cause for treatment failure and mortality of NPC patients. However, the underlying mechanism responsible for the initiation of tumour cell dissemination and tumour metastasis in NPC is not well understood. Here, we demonstrated that epidermal growth factor receptor (EGFR) was highly expressed in tumour tissues of NPC patients with distant metastases and was associated with a decrease in reactive oxygen species (ROS). We also revealed that extracellular vesicles (EVs) transfer occurred from highly to poorly metastatic NPC cells, mediating cell–cell communication and enhancing the metastatic potential of poorly metastatic NPC cells. Further experiments indicated that EVs derived from highly metastatic NPC cells induced the up‐regulation of EGFR and down‐regulation of ROS in low metastatic NPC cells. Mechanistically, EGFR‐rich EVs‐mediated EGFR overexpression down‐regulated intracellular ROS levels through the PI3K/AKT pathway, thus promoting the metastatic potential of poorly metastatic NPC cells. Strikingly, treatment with EVs secreted from highly metastatic NPC cells was significantly associated with rapid NPC progression and shorter survival in xenografted mice. These findings not only improve our understanding of EVs‐mediated NPC metastatic mechanism but also have important implications for the detection and treatment of NPC patients accompanied by aberrant EGFR‐rich EVs transmission.

Tumor metastasis: Mechanistic insights and therapeutic interventions

“…In nasopharyngeal carcinoma (NPC), EVs migrate from highly metastatic to poorly metastatic NPC cells, mediate intercellular communication, and enhance the metastatic potential of poorly metastatic NPC cells by inducing the up‐regulation of epidermal growth factor receptor (EGFR) and down‐regulation of reactive oxygen species (ROS). 191 Mechanistically, overexpression of EGFR mediated by EGFR‐rich EVs down‐regulates intracellular ROS levels through regulating PI3K/AKT pathway, thereby promoting the metastatic potential of NPC with poorly metastatic ability. 191 …”

“… 191 Mechanistically, overexpression of EGFR mediated by EGFR‐rich EVs down‐regulates intracellular ROS levels through regulating PI3K/AKT pathway, thereby promoting the metastatic potential of NPC with poorly metastatic ability. 191 …”

Nasopharyngeal Carcinoma: The Role of the EGFR in Epstein–Barr Virus Infection

“…Recently, research showed that highly metastatic NPC cells secrete EGFR-rich extracellular vesicles (EVs) that can be absorbed by poorly metastatic NPC cells. Then, EGFR-rich EVs promote EGFR up-regulation and intracellular ROS reduction through the EGFR/PI3K/Akt pathway, thus aggravating the metastasis and progression of NPC [ 81 ]. Undoubtedly, EVs delivering EGFR or EGFR ligands promote angiogenesis, metastasis, and osteoclastogenesis in tumors, modulating the immune system and blocking these EVs’ activities to reduce drug resistance [ 82 , 83 ].…”

Effects and mechanisms of Eps8 on the biological behaviour of malignant tumours (Review)

“…Mechanistically, on one hand, Eps8 increases p53 and decreases Src and AKT in such a way that HeLa and SiHa cells are sensitive to chemotherapeutic drugs ( 14 ). On the other hand, PI3K/AKT is an important cascade reaction of tumour chemotherapy resistance ( 120 ), and EGFR is the key to activating the PI3K/AKT signalling pathway ( 121 ). In general, EGFR TKI resistance is divided into ‘on target’ and ‘off-target’.…”