Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis

Abstract

The metastatic organotropism has been one of the cancer's greatest mysteries since the ‘seed and soil' hypothesis. Although the role of EGFR in cancer cells is well studied, the effects of secreted EGFR transported by exosomes are less understood. Here we show that EGFR in exosomes secreted from gastric cancer cells can be delivered into the liver and is integrated on the plasma membrane of liver stromal cells. The translocated EGFR is proved to effectively activate hepatocyte growth factor (HGF) by suppressing miR-26a/b expression. Moreover, the upregulated paracrine HGF, which binds the c-MET receptor on the migrated cancer cells, provides fertile ‘soil' for the ‘seed', facilitating the landing and proliferation of metastatic cancer cells. Thus, we propose that EGFR-containing exosomes derived from cancer cells could favour the development of a liver-like microenvironment promoting liver-specific metastasis.

Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers

“…ANXA1 might be responsible for the recruitment of phospho-EGFR into exosomes, and this might be mediated by an (transient) interaction of ANXA1 and phospho-EGFR which has already been reported [33]. Exosomal EGFR has been linked to organ-specific metastasis by influencing premetastatic niche formation and to tumour immunity by inducing tolerance in recipient dendritic cells and as a consequence tumour antigen-specific regulatory T cells [36,37]. In summary, ANXA1 seems to be located at the interface of inflammation and cancer.…”

“…ANXA1 protein levels affect exosome production and the release of exosomal phospho-EGFR Recent findings have demonstrated an important role of exosomal EGFR in metastasis formation. As ILVs can be precursors of exosomes, we speculated that ANXA1 may regulate exosomal EGFR release [35,36]. Extracellular vesicles of HN5 Ctrl and ANXA1 knockdown cells were isolated by ultracentrifugation and characterised by nanoparticle tracking analysis.…”

“…Interestingly, in addition to its intracellular function, lately, a role of extracellular exosomal EGFR in metastasis formation and tumour immunity has been described [36,37]. In this study, we have investigated the involvement of ANXA1 in HNSCC with the aim of exploiting its potential as a prognostic/predictive biomarker and/or therapeutic target in the cancers of head and neck.…”

Exosome‑mediated peritoneal dissemination in gastric cancer and its clinical applications (Review)

“…TEX induce angiogenesis via transportation of paracrine signaling factors and pro-angiogenic molecules including epidermal growth factor receptor (EGFR) mRNA (42). Zhang et al (43) recently verified that gastric cancer-derived exosomes served an important role in liver metastasis; EGFR levels were enriched in exosomes isolated from the serum of gastric cancer patients but not in healthy subject serum exosomes, and the number of serum exosomes increased with the staging of gastric cancer. In a mouse experiment, it was identified that exosomes of the SGC7901 gastric carcinoma cell line could transport EGFR into the liver and ultimately to the membrane of stromal liver cells.…”

“…In a mouse experiment, it was identified that exosomes of the SGC7901 gastric carcinoma cell line could transport EGFR into the liver and ultimately to the membrane of stromal liver cells. As a consequence, SGC-exosome-derived EGFR activated liver hepatocyte growth factor (HGF) by suppressing expression of the microRNA (miRNA/miR) miR-26a/b, establishing the liver as an ideal site for tumor cell metastasis (43). The EGFR positivity rate of metastatic tumors in patients with peritoneal metastasis is reportedly significantly higher (70.1%) than that of metastatic tumors in patients with liver metastasis (37.5%) (44), which indicates that EGFR expression is associated with peritoneal metastasis.…”