A research group led by Soichi Kojima of
the RIKEN Center for Integrative Medical Science has found that acyclic
retinoid prevents the recurrence of hepatocellular carcinoma (the most common
form of liver cancer) by targeting a particular cancer stem cell class, thereby
stopping the formation of new tumors.
- Acyclic retinoid, a
vitamin A derivative prevents the recurrence of hepatocellular carcinoma
(HCC) by targeting a certain category of cancer stem cells
- HCC is a lethal
liver cancer that has a high rate of recurrence
- The vitamin A derivative suppresses
the expression of an oncogene, known as MYCN
gene that is expressed in high levels in the cancer stem cells - this
discovery provides important hints for decreasing cancer recurrence and
truly curing patients.
retinoid is an artificial compound derived from vitamin A.
This study has been
published in the Proceedings of the National Academy of
‘Recurrence of hepatocellular carcinoma can be prevented by acyclic retinoid, an artificial compound derived from vitamin A, by specifically killing certain stem cells.’
HCC is the second deadliest cancer
after non-small cell lung cancer
It is responsible for approximately 600,000 deaths each year around the world. One reason for its high lethality is its
high rate of recurrence
; although surgery and other treatments are
initially effective, cancer relapses very often. Recently, researchers
discovered that acyclic retinoid was effective in stopping recurrence of
tumors. However, scientists were not sure of the mechanism involved.
Working on HCC cell cultures, the scientists at RIKEN
found that the transcriptome of the cells exposed to acyclic retinoid had low
expression of MYCN
gene compared to control untreated cells.
What is the MYCN gene?
function of the MYCN
gene is to provide
instructions for making a protein (MYCN
protein or N-myc) required in
the formation and normal development of tissues and organs of the limbs, heart,
kidneys, nervous system, digestive system, and lungs during embryonic
development. The protein is also a transcription factor, the definition of
which is one that regulates the activity of other genes by attaching to
specific regions of DNA.
MYCN gene belongs to a class of genes known as
. These genes are involved in regulating
cell growth and division (proliferation) and the self-destruction of cells
. When oncogenes get mutated, they can cause normal cells to
become cancerous. Hence the MYCN
often expressed in tumors.
- When the scientists
deliberately repressed the expression of the MYCN gene in cancer
cells, the reduction in MYCN expression led functionally to slower
cell-cycle progression, proliferation, and colony formation, and to
greater cell death. This implied that acyclic
retinoid was actually slowing cancer growth by suppressing the MYCN
- Through another experiment, the
scientists discovered one specific group called the EpCAM-positive cancer stem cells (among several subpopulations
of heterogeneous cancer cells) where
MYCN gene expression level was elevated.
- They wanted to test if perhaps the
key to acyclic retinoid's effect was its ability to target these hepatic
cancer stem cells. And indeed it was - the EpCAM-positive cells were selectively depleted when exposed to
acyclic retinoid, in a dose dependent manner.
- Does this study have clinical
significance? It does - cancer patients were given two concentrations of
acyclic retinoid following liver
cancer surgery and their liver biopsies were studied. Four of
the six patients who received the higher dosage of 600 mg/d had decreased
levels of MYCN expression compared to those who received 300 mg/d.
This suggests that the difference
in recurrence seen in trials may be due to MYCN expressions in
response to acyclic retinoid.
- Finally, data from the Cancer Genome
Atlas revealed that elevated
expression of MYCN correlated with dramatically poorer prognosis.
According to Kojima,
"It is remarkable that the acyclic retinoid clearly targets a certain
category of cancer stem cells, and this provides us with important hints for
decreasing cancer recurrence and truly curing patients. We are waiting to see
what clinical data will show us."
A phase 3 clinical
trial of acyclic retinoid is currently underway in three countries (Korea,
Taiwan and Singapore) to test its ability to prevent HCC recurrence.
HCC develops from the hepatocytes
which are the main liver cells and
accounts for most liver cancers.
Individuals who have a damaged liver from cirrhosis are more prone to get HCC.
Cirrhosis in turn is caused by alcohol abuse, hepatitis B or hepatitis C virus
infections, autoimmune diseases and chronic inflammations of the liver. HCC has
a larger incidence in men than in women and in older people.
type of HCC begins as a single tumor that grows larger and spreads to the other
parts of the liver in late stages.
type that is most often seen in people with cirrhosis starts off as many small
cancer nodules throughout the liver.
- Xian-Yang Qin, Harukazu Suzuki, Masao Honda, Hikari Okada, Shuichi Kaneko, Ikuyo Inoue, Etsuko Ebisui, Kosuke Hashimoto, Piero Carninci, Keita Kanki, Hideki Tatsukawa, Naoto Ishibashi, Takahiro Masaki, Tomokazu Matsuura, Hiroyuki Kagechika, Kan Toriguchi, Etsuro Hatano, Yohei Shirakami, Goshi Shiota, Masahito Shimizu, Hisataka Moriwaki, Soichi Kojima, "Prevention of hepatocellular carcinoma by targeting MYCN-positive liver cancer stem cells with acyclic retinoid", Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.1802279115
- MYCN Gene - (https://ghr.nlm.nih.gov/gene/MYCN#)
- Liver Cancer - (http://www.cancerresearchuk.org/about-cancer/liver-cancer/types)