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Discovery of Healthy Stomach Stem Cells Reveals Cancer Origins

Landmark finding of genetic marker Aquaporin-5 (AQP5) provided researchers a way to isolate human stomach stem cells and uncover insights to gastric cancer progression.

Gastric cancer is the fifth most common cancer worldwide and the third deadliest. Its high incidence rate in Asia makes it a cause for concern and highlights the need to comprehend the molecular role of stem cells in tissue maintenance and cancer progression in the stomach.

In a study published in Nature on 5 February 2020 identified and isolated for the first time human stomach stem cells which are responsible for renewal of stomach tissue. A novel genetic marker AQP5 was a key finding which will provide potential discovery of opportunities for therapy and development of regenerative medicine for gastric cancer treatment.

The study was a nine-year long research by an international team of researchers led by the Agency for Science, Technology and Research’s (A*STAR) Institute of Medical Biology, together with Genome Institute of Singapore (GIS), National University of Singapore (NUS), National University Health System (NUHS), Cancer Research Institute of Kanazawa University, Japan, and Maastricht University, Netherlands.

The current study builds on previous findings from IMB of Lgr5-expressing stem cells at the gland base of the mouse stomach. Despite evidence of Lgr5-marked adult stem cells to be responsible for the continuous regeneration and replacement of tissues in many organs, research were unable to identify an equivalent in human tissues. This was due to the lack of surface markers for isolation and validation. Organ-specificity was also an issue because Lgr5 is expressed across different organs making it challenging for researchers to target cancer-causing mutations specific to stomach stem cells.

With the Lgr5 marker, the team found AQP5, a new surface marker that allowed the isolation of human stomach stem cells using antibodies, proving that they were stem cells. Introducing selective mutations in stomach stem cells of mice highlighted the role of AQP5 in early formation of Wnt-driven gastric cancer. The researchers then found stomach tumours contained populations of AQP5-expressing cells that behaved as cancer stem cells – driving cancer growth.

Professor Nick Barker, Research Director at A*STAR IMB said, “Our work facilitates for the first time, the isolation of mouse and human stomach stem cells using antibodies, identifies dysregulation of the Wnt pathway as a frequent event in human cancer, and reveals stomach stem cells as important sources of gastric cancer. Our ability to identify and purify tumour-resident stem cells in gastric cancer using the new AQP5 marker will allow us to directly evaluate their role in human cancer formation, characterise them in depth and potentially develop drug-screening tests to identify ways to selectively kill these cells.”

“It takes time and resources to bring well-grounded basic research to fruition and translate them into benefits for society. Findings from our study should help to clarify the identity and role of stomach cells in cancer and we hope that they can be translated to positive clinical outcomes in the future.” [APBN]