Extracellular Vesicle Dissemination of Epidermal Growth Factor Receptor and Ligands and Its Role in Cancer Progression

SIMPLE SUMMARY: Overexpression of the transmembrane protein, epidermal growth factor receptor (EGFR), drives tumour progression in several cancers including breast, lung, glioblastoma and head and neck cancers. In recent years, it has been shown that tumour cells can transfer EGFR to other tumour cells and non-tumour cells using extracellular vesicles (EVs). EVs are nano-sized vesicles secreted by cells and contain protein, RNA and DNA. The function of EVs is to send messages between cells which occurs in both healthy and diseased states. In this review, we will discuss how the transfer of EGFR and EGFR ligands by EVs in cancer can promote metastases, the formation of new tumour blood vessels and decrease the anti-tumour activity of immune cells. We will also discuss how EGFR contained in EVs can be used as a non-invasive diagnostic marker of cancer, and finally, how EVs can be re-engineered to promote targeting to EGFR expressing tumours. ABSTRACT: The epidermal growth factor receptor (EGFR) pathway functions through the autocrine or paracrine activation of cellular EGFR by a number of transmembrane ligands. Amplified or mutant EGFR can lead to tumour formation due to increased cell proliferation, growth, migration and survival signals. These oncogenic effects were thought to be confined to aberrant cells hosting genetic alterations in EGFR. However, in the past decade, numerous studies identified that tumour cells could harness extracellular vesicles (EVs) to disseminate EGFR, mutant EGFR, phosphorylated EGFR and EGFR ligands to local and distant cells. This functions to impart a pro-tumourigenic phenotype in recipient cells. EVs play an essential role in intracellular communication, through receptor signalling or the release of their intra-vesicular content into recipient cells. This review will discuss the role of EVs delivering EGFR or EGFR ligands either to or from tumour cells and how this can promote metastases, pre-metastatic niche formation, osteoclastogenesis, angiogenesis and immune modulation in cancer. We will examine how circulating EVs positive for EGFR may be exploited as diagnostic, prognostic or therapeutic markers in cancers including breast, lung, glioblastoma, ovarian and prostate. Finally, we will explore recent breakthroughs in bio-engineering EVs with EGFR targeting abilities for targeted drug delivery.