Extracellular vesicles (EVs) including exosomes, microvesicles, oncosomes, and microparticles have been associated with communicating anti-cancer drug-resistance. The in vitro, pre-clinical in vivo and patients’ data linking EVs to drug-resistance (and the specific drugs involved) in breast cancer, prostate cancer, lung cancer, ovarian cancer, haematological malignancies, colorectal cancer, gastric cancer, pancreatic cancer, glioblastoma, neuroblastoma, melanoma, kidney cancer and osteosarcoma. Details of the mechanisms by which the resistance seems to be occurring (e.g. EVs transferring drug-efflux pumps from drug-resistant cancer cells, EVs binding monoclonal antibodies in the peripheral circulation and so reducing their bioavailability, EVs from tumour microenvironment cells, etc.) are outlined, as are efforts to try to block such resistance. Research to date strongly supports EVs as playing a key role in drug-resistance. Further studies including tailored clinical studies are now warranted to determine how best to prevent this occurring, in the interest of patients and also for economic benefit. Furthermore, efforts to exploit safe (non-cancer origin) EVs as anti-cancer drug delivery vehicles that may achieve efficacy with more limited side-effects than free drug, deserve further investigation.

Introduction

Approximately 30 years ago, exosomes were described as involved in reticulocyte maturation by transporting transferrin receptor out of the cell [35]. Building on this knowledge, over recent years increasing evidence indicates that substantial cargos of information are released from cells via lipid bilayer-enclosed vesicles typically termed exosomes and microvesicles. These vesicles are proposed to be tailor-made specialised mini-maps of their cell of origin; are transported in the bloodstream and other body fluids; and much evidence indicates them to be involved in cell-to-cell communication. Exosomes and microvesicles, collectively termed extracellular vesicles (EVs), are often defined and sub-grouped based on size and cellular origin (exosomes ~30 nm–۱۲۰ nm, endosomal origin; microvesicles/ectosomes > 120- 1000 nm, from the cell membrane). It should be noted that some reports use additional or alternative terms including, but not limited to, ectosomes, microparticles, oncosomes and prostasomes; all of which are EVs, as, indeed, are apoptotic bodies. However, once outside the cell and released into the environment (for example, the bloodstream) we cannot be certain if the EVs originated from the cells’ endosomal region or directly from the cell membrane. Furthermore, EV size distinctions are not absolute i.e. there is no known reason why vesicles budding from the cell membrane cannot be < 120 nm. In diseases such as cancer, regardless of the size and origin of EVs released, arguably the problems that EVs contribute to when released are of much importance to understand. Evidence from pre-clinical and clinical specimens’ studies, by ourselves and others, strongly associate EVs with transmitting anti-cancer drug-resistance from cell-to-cell in multiple cancer types. This phenomenon, known as multi-drug resistance or multiple-drug resistance (MDR) and initially described > 30 years ago [8], is manifest as cancer cells being resistant to anti-cancer drugs that are structurally and mechanistically unrelated. MDR may present as innate/primary or it may be acquired. Innate MDR means that, from the outset, the cancer cells are already equipped to be resistant to the anti-cancer drug being used. Acquired resistance occurs when cancer cells initially respond to treatment, but develop resistance mechanisms overtime. Advancing on early work where the mdr1 gene (which encodes the ABC transporter, ABCB1, also known as P-glycoprotein (P-gp) and now well established as causally involved in MDR) was cloned [72], many research studies and reviews (exemplified by [17,26,28,40,43,45,56–۵۸,۷۳,۷۹,۸۴]; but too many to detail here) have been published on this topic. MDR is a substantial concern in cancer management. Our understanding is that the first study showing transmission of drug-resistance by EVs, was a study performed by our group in prostate cancer [18], Numerous important studies by other research groups have been reported.