Researchers shed light on how a synthetic form of vitamin A could help to eradicate liver cancer.
Led by researchers from the RIKEN Center for Integrative Medical Sciences in Japan, the study found that acyclic retinoid blocks the expression of a gene that gives rise to liver cancer tumors.
Study leader Soichi Kojima, of the Micro-Signaling Regulation Technology Unit at the RIKEN Center, and colleagues recently reported their findings in the Proceedings of the National Academy of Sciences.
The most common type of liver cancer is hepatocellular carcinoma (HCC). This cancer may begin as a single liver tumor that gets bigger over time, or it can start as multiple cancer nodules throughout the liver.
The biggest risk factor for liver cancer is infection with hepatitis B or hepatitis C; these viruses can lead to liver cirrhosis, which can cause cell damage that gives rise to cancer.
Previous research has found that acyclic retinoid — which is a synthetic derivative of vitamin A — has the potential to stop the recurrence of HCC in individuals who have undergone surgical removal of primary tumors.
The precise mechanisms underlying this association, however, have been unclear.
To learn more about how acyclic retinoid might prevent HCC, the researchers investigated how the compound affects the transcriptome of cells, or the collection of RNA molecules that regulate gene expression.
The scientists found that, compared with untreated cells, cells exposed to acyclic retinoid showed a reduction in the expression of a gene called MYCN. This gene has been linked to the development of cancers such as neuroblastoma.
The researchers then suppressed MYCN gene expression in cancer cells. This not only halted cell proliferation, slowed cell-cycle progression, and stopped colony formation, but it also triggered cancer cell death.
Next, Kojima and colleagues took their investigation to cancer stem cells. Cancer stem cells are self-renewing cells that can drive the formation of tumors. As the researchers note, cancer stem cells manage to evade cancer treatments, so they are key players in cancer recurrence.
The team found that when MYCN gene expression was heightened in human HCC cell lines, this increased the expression of various markers that are linked to cancer stem cells, suggesting that MYCN gene expression is involved in HCC.
As Kojima explains, “The most interesting part of our finding is when we then looked at different subpopulations of heterogeneous cancer cells. We found one specific group of EpCAM-positive cancer stem cells, where MYCN was elevated.”
This spurred the team to investigate whether the anti-cancer effects of acyclic retinoid might be down to its effects on EpCAM-positive cancer stem cells.
When the researchers exposed HCC cancer stem cells to acyclic retinoid, they discovered that the compound selectively targeted and destroyed cells that were EpCAM-positive — the higher the dose of acyclic retinoid, the greater the effects on EpCAM-positive cancer stem cells.
Kojima and his colleagues then took liver biopsies of 12 people with HCC whose cancer had been eradicated following liver resection or ablation.
Six of these patients had received 600 milligrams of acyclic retinoid per day for eight weeks, while the remaining six received 300 milligrams of the compound each day for eight weeks.
The researchers found that the biopsies taken from patients who took the higher dose of acyclic retinoid showed lower MYCN expression.
Taken together, these findings indicate that acyclic retinoid could prevent HCC recurrence by reducing MYCN expression in EpCAM-positive cancer stem cells.
“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.”
The researchers note that acyclic retinoid is currently being tested in a phase III clinical trial for its ability to stop the recurrence of HCC.
27 April 2018