Extracellular vesicles: how they interact with endothelium, potentially contributing to metastatic cancer cell implants

Abstract

Extracellular vesicles (EV) are blebs of cellular membranes, which entrap small portions of subjacent cytosol. They are released from a variety of cells, circulate in the blood for an unknown length of time and come to rest on endothelial surfaces. They contribute to an array of physiologic pathways, the complexity of which is still being investigated. They contribute to metastatic malignant cell implants and tumor-related angiogenesis, possibly abetted by the tissue factor that they carry. It is thought that the adherence of the EV to endothelium is dependent upon a combination of their P-selectin glycoprotein ligand-1 and exposed phosphatidylserine, the latter of which is normally hidden on the inner bilayer of the intact cellular membrane. This manuscript reviews what is known about EV origins, their clearance from the circulation and how they contribute to malignant cell implants upon endothelium surfaces and subsequent tumor growth.

Keywords: Endothelium; Exosomes; Extracellular vesicles; Hypercoagulation; Metastatic carcinoma; Microparticles; P-selectin; P-selectin glycoprotein ligand 1; Tissue factor.

Fig. 1

The normal cell membrane is an asymmetrical bilayered structure with phosphatidylserine- and phosphatidyl-ethanolamine-enriched cytosolic layers, maintained by flippase, floppase and scramblase. As extracellular vesicles are formed, the flippases is inactivated while floppase and scramblase are activated, leading to reversal of the normal asymmetry, creating an outward facing phosphatidylserine enriched layer

Fig. 2

Extracellular vesicle attachment to endothelial cells is dependent upon their exposed PSGL-1 attaching to the P-selectin expressed from Weibel–Palade bodies and platelet alpha-granules, and upon the tethering of the exposed surface phosphatidylserine to Tim4, lactadherin/MFG-E8 and probably other cell adhesion molecules