Page 99 - Read Online

Page 2 of 9 Lai et al. J Cancer Metastasis Treat 2019;5:65 I http://dx.doi.org/10.20517/2394-4722.2019.011

Keywords: Membrane lipid binding molecules, extracellular vesicle, cholera toxin B, shiga toxin B, annexin V,
biomarker

INTRODUCTION
Cancer is the second leading cause of death in the world according to WHO (https://www.who.int/news-
room/fact-sheets/detail/cancer). In 2018, there was an estimated 18.1 million new cancer cases and 9.6
[1]
million cancer deaths worldwide with 70% occurring in low and middle-income countries . This creates
a devastating socioeconomic burden. To reduce this cancer burden, WHO has recommended cancer
prevention through avoidance of risk factors and implementation of existing evidence-based prevention
strategies. In addition, this burden can be reduced through early detection of cancer as many cancers could
be cured if diagnosed early and treated adequately.

The gold standard in cancer diagnosis is tissue biopsy. However as this is an invasive procedure, it is often
done when cancer is suspected and when the cancer is usually at an advanced stage. Also, the suspected
cancer may be in tissues that are hard to access such as the brain and tissue biopsy will be difficult with
significant clinical risks such as bleeding or infection. As such, surrogate methods for detecting the
presence of cancer such as liquid biopsy are being aggressively developed. Liquid biopsy was originally
defined by the US. National Cancer Institute as “a test done on a sample of blood to look for cancer cells
from a tumor that are circulating in the blood or for pieces of DNA from tumor cells that are in the blood”
(https://www.cancer.gov/publications/dictionaries/cancer-terms/def/liquid-biopsy). Although tissue biopsy
remains the gold standard for cancer diagnosis, liquid biopsy is gaining traction as it is less invasive and
could be used to screen for cancer prior to disease manifestation when the cancer is in its early stage.
Biomarkers used in liquid biopsy have also expanded beyond circulating tumor cells or DNA to include
circulating exosomes and miRNAs.

This review will focus primarily on the use of exosomes or more precisely, extracellular vesicles (EVs)
[2]
in liquid biopsy. As recommended by Minimal Information for Studies of EVs (MISEV2014) and the
[3]
recently updated and expanded MISEV2018 , the term “Exosomes” is presently used to describe small
(50-200 nm) extracellular vesicle that has an endosomal biogenesis while the term “EV” is a more generic
term to describe membrane vesicles secreted by cells. Since the EV types and biogenesis of most EVs
in bodily fluids are presently not known, the term EV is, therefore, more appropriate when referring to
secreted membrane vesicles in liquid biopsy.

EVS AS SOURCES OF BIOMARKERS
MISEV2018 defines EVs as “particles naturally released from the cell that are delimited by a lipid bilayer
[3]
and cannot replicate, i.e., do not contain a functional nucleus” . They are produced by nearly all cell types
from bacteria to yeast, plants and animals. EVs are known to carry a complex cargo of proteins, lipids,
RNA, DNA and other metabolites. As the cargo is derived from the secreting cell, the cargo reflects the
type and biology of the cells and could potentially inform on the state of health in the cells. Furthermore,
as EVs are generally thought to mediate intercellular communication through the conveyance of biological
materials from one cell to another, EVs could potentially propagate disease or modulate host response.
Hence the cargo of EVs could also predict the progress or resolution of the disease. Together, these EV
features provide a strong rationale for the use of EVs in bodily fluids such as blood, urine, saliva, tears or
[4-8]
sweat in liquid biopsy assays. The reader is referred to several recent comprehensive reviews in this area .