Vitamin A Derivative Specifically Targets Certain Cancer Stem Cells

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 is an artificial compound derived from vitamin A. This study has been published in the Proceedings of the National Academy of Scientists.

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?

The normal 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 oncogenes. These genes are involved in regulating cell growth and division (proliferation) and the self-destruction of cells (apoptosis). When oncogenes get mutated, they can cause normal cells to become cancerous. Hence the MYCN gene is often expressed in tumors.

Advertisement

Further studies

• 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 gene.
• 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."

Advertisement

Future plans

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.

Advertisement

Hepatocellular carcinoma (HCC)

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.

One type of HCC begins as a single tumor that grows larger and spreads to the other parts of the liver in late stages.

Another type that is most often seen in people with cirrhosis starts off as many small cancer nodules throughout the liver.

References:

1. 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
2. MYCN Gene - (https://ghr.nlm.nih.gov/gene/MYCN#)
3. Liver Cancer - (http://www.cancerresearchuk.org/about-cancer/liver-cancer/types)

Source-Medindia