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Comparative Study Reveals Foetal-Like Reprogramming of Liver Cancer Cells
Scientists from A*STAR’s Genome Institute of Singapore (GIS), Singapore Immunology Network (SIgN), National Cancer Centre Singapore (NCCS) and KK Women’s and Children’s Hospital (KKH) uncover interactions involved in foetal-like reprogramming of liver cancer cells.

Liver cancer is a serious cause for concern in Asia, particularly in the Asia-Pacific region. Asia accounts for 80 percent of worldwide cases, and liver cancer is the most common cancer in Laos, Mongolia, Taiwan and Thailand. Among the various types of liver cancer, hepatocellular carcinoma (HCC) is most predominant, and is the third most common cause of cancer-related death in the Asia-Pacific region.

HCC occurs most commonly in men over 40 years of age. Its prevalence in the Asia-Pacific region is often attributed to the high incidence of chronic hepatitis B virus and hepatitis C virus infections, which cause inflammation of the liver, and eventually cirrhosis, which refers to the development of hard scar tissue in the liver. This increases the risk of developing HCC.

Treatment of HCC remains difficult, and there is much more to be understood about the disease before better treatment methods can be developed. In a collaborative study between A*STAR’s Genome Institute of Singapore (GIS), Singapore Immunology Network (SIgN), National Cancer Centre Singapore (NCCS) and KK Women’s and Children’s Hospital (KKH), novel insights were discovered about the tumour ecosystem of HCC in humans, which could provide new avenues for research into potential treatments. The study employed a platform created by the National Medical Research Council (NMRC) Translational and Clinical Research (TCR) Flagship Programme in Liver Cancer in Singapore, and its findings were published in Cell in September 2020.

The tumour ecosystem consists of many cell types, including cancer, immune and tissue cells with molecular and functional heterogeneity and plasticity, in addition to several other components, all of which contribute to the development and progression of cancer. Past research studies have revealed similarities between the tumour ecosystem and embryonic development, specifically the presence of foetal-like antigens in both environments.

In over 80 percent of HCC cases, alpha-fetoprotein (AFP) levels were found to be increased. AFP is an oncofoetal protein, which is also a major plasma protein produced in the liver during foetal development and is the most abundant plasma protein in the human foetus. In the context of HCC, AFP levels were especially high in more aggressive and poorly differentiated cell types, which may be a mechanism employed by cancer cells to avoid rejection by the body. While the tendency of HCC to undergo oncofoetal programming has been well established, details of the interactions between HCC and the tumour microenvironment are not yet fully understood.

By conducting a comparative study that involved mapping 200,000 single human liver cells from foetal development to terminal liver cancer, the researchers discovered two new foetal-associated cell types that were present in the tumour ecosystem of HCC. These were foetal-like endothelial cells that regulate blood supply, and foetal-like macrophages that are important immune cells against pathogens and play a role in tissue homeostasis. The foetal-like reprogramming was found to be mediated by the sequential activation of two cell signalling pathways: the vascular endothelial growth factor (VEGF) pathway in endothelial cells is first activated by a dividing cancer cell, and the Notch signalling pathway is activated as the endothelial cells communicated with macrophages through Notch-Delta interactions. This reprogramming promotes uncontrolled cell growth, while protecting the tumour from the immune system, driving cancer development.

“Our research underscores a fundamental understanding of how early developmental processes can be hijacked by cancers in order to facilitate their own growth, and escape immune surveillance,” says Dr. Ramanuj DasGupta, the Senior Group Leader at GIS and the lead corresponding author of the study. “This study also opens up exciting possibilities for the discovery of biomarkers and novel therapeutic targets associated with non-malignant cells, especially in the context of combinatorial immunotherapy with anti-angiogenic drugs. Most importantly, it highlights the power of like-minded scientists and clinicians coming together to solve big problems.”  

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