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

Haiyang Zhang, Ting Deng, Rui Liu, Ming Bai, Likun Zhou, Xia Wang, Shuang Li, et al.

Nat Commun. 2017 Apr 10; 8: 15016

Abstract:

It is well known that particular tumors are prone to metastasize to a specific organ which is also known as the ‘seed and soil’ hypothesis.¹ However, the mechanisms involved in the metastatic organotropism are still not fully understood. It is well understood that cytomembrane epidermal growth factor receptor (EGFR) plays a significant role in tumorigenesis and cancer development.² Some previous studies showed that EGFR can be secreted from cells via a kind of cell-derived vesicles called ‘exosomes’, which sizes are range from 30 to 200 nm. The role of secreted EGFR in exosomes is not clear. Here, the authors used both in vitro and in vivo experiments to clarify the relationship between cancer-derived EGFR-containing exosomes and the development of liver metastasis. They found that the exosomes secreted from gastric cancer (GC) cells can be transported to the livers where the EGFR-containing exosomes could integrate into the plasma membranes of liver stromal cells, such as Kupffer cells and stellate cells. The team further showed that the translocated EGFR was able to upregulate the expression of hepatocyte growth factor (HGF). By using bioinformatics analysis, the authors found that suppressing the expression of miR-26a and miR-26b by EGFR increased the translation of HGF and leaded to upregulation of HGF protein. The upregulated HGF acted as a paracrine to bind the c-MET, the receptor of HGF on the cancer cells, which promotes the invasion and proliferation of GC cells to metastasize to the livers. In addition to the in vitro studies above, the authors also built up an orthotropic mouse tumor model to evaluate the role of liver HGF in GC liver metastasis. They revealed that these tumor-secreted exosomes activated liver HGF pathway via suppressing the expression of miR-26a/b; furthermore, the secretion of liver HGF is associated with the liver metastasis of GC in the mouse tumor model. Therefore, the authors suggested that these GC cell-derived EGFR-containing exosomes plays a role in regulation of liver microenvironment to promote GC metastasis.

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2.          Al-Nedawi, K., Meehan, B., Kerbel, R. S., Allison, A. C. & Rak, J. Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc. Natl Acad. Sci. USA 106, 3794-3799 (2009).