Researchers at Okayama University have identified the conditions under which normal liver stem cells develop into cancer stem cells (CSCs) and have demonstrated conversion under environmental conditions without genetic manipulation.
Cancer stem cells are similar to normal stem cells, which are used to regenerate tissues. In the case of cancer, CSCs drive the growth of tumors and cause new cancerous cells to form and proliferate. If a patient undergoes chemotherapy or has a tumor surgically removed, any CSCs that remain and are not killed would cause the tumor to grow back.
There has been extensive research into cancer stem cells over the past decade. While it has been proposed that normal stem cells in the body can be converted into CSCs under certain environmental conditions or due to genetic factors, the triggers have not been confirmed in the case of liver cancer.
Liver cancer is one of the deadliest forms of cancer. Patients are not typically diagnosed with liver cancer until the disease has progressed to the point where treatments are unlikely to be effective as liver cancer does not typically cause symptoms until the latter stages of the disease. While there has been extensive research into liver cancer, in particular the most common form of liver cancer, hepatocellular carcinoma (HCC), little is known about liver cancer CSCs and how they are formed.
The Okayama University researchers led by Professor Masaharu Seno and Said Mohamed Abdelsabour Afify, identified environmental conditions under which normal stem cells change into CSCs in the liver. The researchers used normal induced pluripotent stem cells (IPSCs) obtained from mice and placed them in HCC cell lines of liver-cancer derived Huh cells. The researchers showed that compounds secreted by the cancer cells triggered inflammation of liver tissue, which caused the IPSCs to convert to liver CSCs.
The researchers injected the CSCs into immunodeficient mice to determine whether they would trigger the formation of tumors in vivo. They report that within 28 days after injection, the mice developed malignant tumors with high nuclear-to-cytoplasmic ratios, high proliferation rates, and the cells expressed markers associated with liver cancer such as alpha fetoprotein, glypican 3 and carcinoembryonic antigen. In the control group, mice injected with standard IPSCs also formed tumors, but only benign teratoma-like tumors.
The researchers therefore demonstrated that liver inflammation triggered by HCC cells transformed healthy stem cells into CSCs and confirmed that liver CSCs drive the formation of tumors. The research also suggests how liver cancer cells could be metastasizing.
“This is the world’s first successful establishment of a liver CSC model from normal iPSCs without genetic manipulation,” explained Professor Masaharu Seno. The model developed by the researchers could be used to test compounds that target liver cancer stem cells. The researchers will now investigate whether liver cancer stem cells can be formed from human IPSCs.
You can read more about the study in the paper – A novel model of liver cancer stem cells developed from induced pluripotent stem cells –which was recently published in the British Journal of Cancer. DOI: 10.1038/s41416-020-0792-z.