07 Jul 2011

Liver cancer has a high recurrence rate and is refractory to chemotherapy, and these lead to ultimate death in most patients. The University of Hong Kong Li Ka Shing Faculty of Medicine has conducted a study on liver cancer that identified for the first time a subset of Cancer Stem Cells (CSCs) is responsible for chemoresistance, metastasis and tumour recurrence in liver cancer. Clinical data of this study shows that liver cancer patients whose tumours had high CD24+ expression had a significantly high risk of tumour recurrence and metastasis, and the survival rate of these patients is much lower. The study also finds that CD24+ maintains self-renewal of CSCs and forms tumours through activating STAT3 signals, as such, the researchers believe that through inhibiting STAT3 could improve treatment efficacy for liver cancer. The novel finding provides important breakthrough for understanding tumour progression and treatment of cancer patients in the future. The research is just published in "Cell Stem Cell", the top journal in the field of stem cell research.

Professor Irene Ng Oi-lin, Loke Yew Professor in Pathology of the Department of Pathology, The University of Hong Kong Li Ka Shing Faculty of Medicine and Director of State Key Laboratory for Liver Research (HKU) who led the study says, "Identification and characterization of this subpopulation of tumour-initiating cells enables us to develop new treatment modalities and hopefully damp down recurrence." Another leading researcher of the study, Dr Terence Lee Kin-wah, Research Assistant Professor of the Department of Pathology, The University of Hong Kong Li Ka Shing Faculty of Medicine remarks, "In the long term, the study should facilitate the development of a safe, effective and targeted treatment that can be used in combination with chemotherapy to completely eradicate this deadly disease."

Conventional treatment for liver cancer and its deficiency
Surgical resection and liver transplantation are the mainstay of curative treatments for liver cancer. Nevertheless, the majority of liver cancer patients are not treated with these methods because of advanced disease or poor liver function reserve. Even after surgical resection, the long-term prognosis of liver cancer remains unsatisfactory due to high recurrence rates. For liver cancer patients in advanced stages, chemotherapy via transarterial chemoembolization is the second-line treatment. Unfortunately, the overall response rate is unsatisfactory due to the highly chemoresistant nature of tumours. Therefore, understanding the mechanism of tumour recurrence and chemoresistance will improve the survival of liver cancer patients.

HKU study on cancer stem cells
Recent evidence indicates that there are small population of cells called cancer stem cells (CSCs) that are responsible for tumour initiation and maintenance; they are more refractory to conventional chemotherapeutic treatments than the more mature cancer cells within the tumour, making it difficult to completely eradicate the cancer with current therapeutic regimens.

Because CSCs are more refractory to the chemotherapy, researchers in HKU have successfully enriched liver CSCs by the establishment of chemoresistant liver cancer mouse model. In this model, mice implanted with primary liver cancer were treated by chemotherapy drug currently used for the cancer which led to initial tumour shrinkage. The remaining residual tumour cells that was refractory to the chemotherapeutic drug developed recurrence subsequently in another mouse recipient, which indicates enhanced capability in tumour initiation and self-renewal. To determine what markers can specifically label these subpopulations of chemoresistant liver CSCs, an expression array was employed to compare the gene expressions between untreated and chemoresistant tumour.

Study results
The HKU researchers identified a specific marker, CD24+, which marks a subset of chemoresistant CSCs with tumour forming and metastatic capacity.

CD24 expression is a novel predictor for poor prognosis of liver cancer patients. Liver cancer patients whose tumours had high CD24+ expression had a significantly high risk of tumour recurrence in the first year after surgery when compared to patients whose tumours had low CD24+ expression (67% vs 21%). Moreover, patients whose tumour had high CD24+ expression also had a higher chance of tumour metastasis (80% vs 32%). Most importantly, patients with high CD24 expression had shorter disease-free survival.

Furthermore, the mechanism on how CD24+ CSCs initiate tumour development and self-renewal is also revealed in this study. CD24+ CSCs were found to activate STAT3 signals to maintain self-renewal and form tumours. These data highlight the importance of STAT3 as key molecule in CD24+ signaling cascade in liver CSCs. HKU researchers believe that through inhibiting STAT3 could control the growth of tumour and achieve better clinical outcomes for liver cancer patients.

Further studies
The HKU research team is conducting a further study to evaluate the therapeutic efficacy of STAT3 phosphorylation inhibitors alone in the suppression of liver cancer recurrence and its combined effect with conventional chemotherapy, with the aim of developing molecular targeted drugs to effectively eradicate this deadly disease.

About liver cancer
Primary liver cancer is the fifth-ranking cancer in the world, with an annual incidence of over 500,000 new patients. More than half (55%) of the new cases occur in China. The incidence of primary liver cancer is particularly high in Hong Kong because of the high prevalence (10%) of hepatitis B virus infection in the population. In Hong Kong, liver cancer is the fourth most common cancer and there are more than 1,700 new cases per year.

About the HKU research team
This study was performed at State Key Laboratory for Liver Research (HKU) and was led by Professor Irene Ng Oi-lin, Dr Terence Lee Kin-wah and Ms Antonia Castilho of the Department of Pathology, The University of Hong Kong Li Ka Shing Faculty of Medicine. Other researchers include Dr Stephanie Ma Kwai-yee and two other postgraduate students (Vincent Cheung Chi-ho, and Tang Kwan-ho).

About Cell Stem Cell
Cell Stem Cell is a monthly journal from Cell Press launched in June 2007, which is affiliated with the International Society for Stem Cell Research (ISSCR). It publishes research articles and review materials with a focus on stem cells. The journal was named "Best New Journal" of 2007 by the Professional and Scholarly Division of the Association of American Publishers, achieving an impact factor of 25.9 in 3 years since its launch; ranking first in stem cell research and top ten in medical sciences.

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