In a new study, researchers from The University of Hong Kong Li Ka Shing Faculty of Medicine recently found that the culprit of liver cancer recurrence and chemoresistance is a type of cancer stem cell, and that by inhibiting the proteins that deliver messages for this stem cell, the effectiveness of treatment for liver cancer can be enhanced. This new finding represents a major breakthrough in understanding liver tumor formation and future cancer treatment. The findings were published in Cell stem cell, the most prestigious academic journal in the field of stem cell research. The research was conducted primarily at the State Key Laboratory for Liver Research at The University of Hong Kong and led by Professor Irene Ng, Dr. Jianhua Li and Antonia CASTILHO of the Department of Pathology, The University of Hong Kong Li Ka Shing Faculty of Medicine. Other researchers include Dr. Guiyi MA and two graduate students, Zhihao ZHANG and Junhao TANG. Primary liver cancer is one of the five most common cancers in the world, with more than 500,000 new patients worldwide each year. China accounts for more than half (55%) of all new liver cancer cases worldwide. Surgical resection and liver transplantation are the primary treatments for liver cancer, with chemotherapy via hepatic artery embolization as a second line of treatment. However, due to the high recurrence rate and resistance to chemotherapy in liver cancer, the overall treatment outcome is not satisfactory. Therefore *** The mechanisms of tumor recurrence and chemoresistance are of great importance to improve the survival of patients with liver cancer. In recent years, numerous studies have shown that cancer stem cells (CSCs), a subset of cancer cells with stem cell characteristics within cancer tumors, are the source of inducing and maintaining continuous tumor growth. These CSCs are more resistant to conventional chemotherapy than other more mature cancer cells within the tumor, making it difficult to completely cure liver cancer with current chemotherapy regimens. In this article, researchers at the University of Hong Kong have successfully grown cancer stem cells in a mouse model, taking advantage of the chemoresistant nature of cancer stem cells. In this animal model, mice were first implanted with human primary liver cancer cells and then treated with chemotherapy drugs. Initially, the tumors shrank, but when the chemo-resistant tumor cells were inoculated into another mouse, the tumors recurred, as in the clinical setting. This suggests that these chemotherapy-resistant tumor cells are more capable of promoting tumor formation and metastasis than cancer cells in untreated tumors. Using gene expression profiling microarrays, the researchers analyzed gene expression between untreated and chemotherapy-resistant tumors, which led to the identification of CD24+, a surface marker for cancer stem cells. Clinical data showed that patients with liver cancer who had high levels of CD24+ marker cancer stem cells in their tumors had a 3-fold higher recurrence rate one year after surgery than patients who had only low levels of CD24+ cancer stem cells in their tumors. Also, liver cancer patients with high CD24+ cancer stem cells in their tumors had a higher chance of developing metastases. The researchers also confirmed that patients with liver cancer who had high CD24+ expression in their liver tumors had significantly lower survival rates. In a further study, the researchers also broke new ground in dismantling the mechanism by which CD24+-labeled cancer stem cells initiate tumor development and self-renewal. They found that CD24+ marker cancer stem cells contribute to tumor formation by activating STAT3 signaling to sustain hepatocellular carcinoma stem cell self-renewal. The findings suggest that STAT3 phosphorylation plays a critical role in CD24 signaling. The researchers believe that by inhibiting STAT3 phosphorylation, tumor growth can be controlled and the chances of complete ablation of liver cancer can be greatly improved. Professor Irene Ng, the Luk v Foundation Professor in the Department of Pathology and Director of the State Key Laboratory of Liver Research at The University of Hong Kong Li Ka Shing Faculty of Medicine, who led the study, said the study not only provides patients with indicators to predict the recurrence of liver cancer, but will also facilitate the development of targeted drugs for the treatment of liver cancer to reduce the chance of tumor recurrence or metastasis.