Cancer is a complex disease influenced by numerous factors including genetic make-up, lifestyle, and the environment. Over the years, the growing field of epigenetics has greatly contributed to our understanding of cancer and tumor progression. It has also led to the development of novel drug therapies. Yet, despite the fact that epigenetic regulators have become attractive anticancer targets, many scientists believe that extra caution should be taken when assessing their overall effects.
In a new study, one potential epigenetic therapy in particular that originally showed promise as a cancer treatment ended up exhibiting an opposite effect for lung cancer. Instead of diminishing cancer stem cells, the treatment actually increased the prevalence of tumors in mice. However, during the study, the scientists also discovered a way to reduce these stem cells, thereby reducing lung cancer. Their findings were published in Nature Communications.
Cancer stem cells have only been found in some blood cancers and different solid tumors. They are notoriously difficult to detect due to their fractional amount in tumors, yet regarded as a root cause of cancer origin as well as recurrence. It is hoped that therapies targeted at these stem cells might help improve patient survival rate and quality of life.
Scientists at the Stem Cell Research program at Boston Children’s Hospital have previously demonstrated the importance of cancer stem cells in adenocarcinoma, the most common type of non-small cell lung cancer. They have shown how simply transplanting cancer stem cells from a diseased to a healthy subject can quickly lead to the development of lung cancer.
The focus here, though, was on an epigenetic therapy that inhibits the enzyme G9a – a histone methyltransferase previously considered a cancer promoter. Prior research had shown that inhibiting this enzyme could be effective for treating certain cancers like adenocarcinoma. Colleagues Samuel Rowbotham, PhD, and Carla Kim, PhD, who work on the study questioned this premise.
Rowbotham said, “People had looked at cell lines from lung tumors and found that they are sensitive to drugs inhibiting G9a. In general tumor cell populations, these drugs would slow down growth or even kill the cells. But we found that these drugs were also making the surviving tumor cells more stem-like. We predicted that this would advance disease progression, and this is what we saw.”
The team’s observation of the adenocarcinoma cell lines indicated that the G9a-treated cells behaved more like cancer stem cells. When the stem cells were then transplanted into live mice and the G9a gene knocked down, the cancerous tumors actually grew bigger and spread out across the lung much farther.
According to Kim, “Earlier studies couldn’t see that cancer stem cells were still around, and there’s more of them when you treat with these drugs,” she says. “Because they’re such a small fraction of the tumor, anything that affects them can easily be missed.”
Fortunately, the team was able to determine that histone demethylases are better enzymes to target. This is because their actions are chemically opposite that of G9a. Instead of adding a methyl group to a histone, they remove one. When Dr. Rowbotham gave a demethylase inhibitor to mice already inflicted with lung tumors, the cancer progression slowed and the mice survived longer than the untreated mice.
Cancer stem cells have yet to be found in human adenocarcinoma, although the findings from this mouse study could help identify clinically important targets that this cancer is sensitive to. The scientists foresee adenocarcinoma being tackled in two phases: first targeting the tumor cells to shrink them, then separately treating the cancer stem cells to ensure no further growth.
While more studies are needed to determine the potential therapeutic effects of demethylase inhibitors, the authors noted that because these enzymes have very broad effects, it will be important to also examine how they affect other genes downstream.
“We propose that analyzing the effects of new therapeutics on different tumor populations, especially the most tumorigenic stem-like cells, would be greatly beneficial,” the study stated. “This may increase the success rate of clinical trials and thus reduce the cost and time taken to bring new cancer therapeutics to the patient.”
Source: Rowbotham, S. P. et. al. (2018) H3K9 methyltransferases and demethylases control lung tumor-propagating cells and lung cancer progression. Int J Cancer.
Reference: Boston Children’s Hospital. “Proposed cancer treatment may boost lung cancer stem cells, study warns” November 2018.