According to the International Agency for Research on Cancer, hundreds of Singaporeans die from stomach cancer every year, and many more are newly diagnosed. The global picture is not much better: gastric cancer is the fourth deadliest cancer in the world, causing nearly 800,000 deaths in 2020.
In recent years, researchers have developed many mouse models, specially bred laboratory mice, to help identify genetic and other molecular aberrations underlying the disease. However, most of these models capture only the earliest stages of the disease, leaving a glaring gap in our understanding of advanced gastric cancer, which spreads to distant body parts as it progresses.
To address this gap, a research team led by Nick Barker, a Research Director at A*STAR’s Institute of Molecular and Cell Biology (IMCB), used two separate mouse models in parallel to study gastric cancer progression.
The first model involved genetically engineered mice that enabled researchers to induce tumours exclusively in the stomach, giving them a physiologically accurate picture of gastric cancer. “Because these cancers developed only in the stomach, the mice survived long enough for cancer to invade the muscle and spread to distant organs,” Barker explained.
This model provided, for the first time, a highly accurate tool to derive clinically relevant insights into how gastric cancer develops and spreads throughout the body and for evaluating new drugs as more effective cancer treatments. However, the inherent complexity of this model made it challenging to quickly generate sufficient cancer mice for larger-scale analyses and high throughput drug testing.
This is where the second model came in, which involved growing stomach cancer tissues in culture before transplanting them back into the mice. Though not as physiologically faithful, tumours in this model grew and spread much faster, enabling researchers to more quickly analyse the impacts of different gene mutations and drugs.
These experiments revealed that a pool of cancer cells expressing Lgr5, a hallmark of stem cells, was crucial for disease progression. Indeed, using an anti-cancer drug to eliminate the Lgr5 cells strongly suppressed tumour growth and spread in mice. However, prematurely stopping treatment not only allowed gastric cancer to recur, but also made it more aggressive and lethal.
“This seminal finding, which identifies the Lgr5-expressing cells as likely cancer stem cells, underscores the therapeutic value of targeting this cell population as a potential new treatment regimen,” Barker said.
Clinical protocols incorporating these results would likely involve long-term treatment combined with traditional chemotherapy to ensure the best outcomes, Barker added, although future trials are still needed to arrive at definitive regimens. In the meantime, the team will continue to find ways to target Lgr5-expressing tumour stem cells without affecting other healthy stem cell populations.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB), Singapore Immunology Network (SIgN) and Genome Institute of Singapore (GIS).
