Targeting liver cancer stem cells as a novel therapeutic approach for liver cancer

Summary

PhD and Master's candidates are welcome

Supervisor(s)

Dr Liang Qiao, Professor Jacob George

Research Location

Westmead - Westmead Millennium Institute

Program Type

Masters/PHD

Synopsis

Liver cancer is a stem cell disease in that the cancer tissue may have derived from a subset of cells possessing the capacity to self-renew and to tumour formation. This subset of the tumour-forming cells are termed cancer stem cells (CSCs), and have been demonstrated in many solid tumours including liver cancer. However, markers that can unequivocally identify CSCs in all tumours remain elusive and the origin of liver CSCs (LCSCs) is unclear. It is known believed that both liver progenitor cells (LPCs) and LCSCs are responsible for the formation of a proportion of liver cancer. It was estimated that ~55% of pre-malignant small dysplastic foci and 25-50% of HCCs contain stem cells. Thus, LCSCs are responsible for at least a portion of clinical HCC cases. Furthermore, LCSCs may play an important role in cancer treatment failure, metastasis, and relapse. CSCs are generally resistant to chemo- and radiotherapy. In clinical practice, tumour aggressiveness and patient survival are correlated with the proportion of CSCs and the level of CSC gene expression within a tumour. Conventional cancer treatments (e.g., surgery, chemotherapy, radiation, or hormonal manipulation) only remove or kill rapidly-dividing differentiated cancer cells. However, these methods have many limitations. Only ~25% of HCC patients are suitable for curative treatment, and even in its early stage, partial hepatectomy is performed in just 5% of Western patients because of limited liver reserve. Other treatment options for HCC such as chemoembolization (TACE), radiofrequency ablation, or Sorafenib are only effective in a fraction of cases and the latter does not target LCSCs. An adaptive resistance of liver cancer cells to Sorafenib is a critical clinical problem. CSCs have several unique characteristics, such as a strong ability for self-renewal and differentiation into heterogeneous non-tumorigenic cancer cells that make up the bulk of the tumor, and an innate resistance to chemotherapy. Thus, CSCs not only contribute to cancer initiation, but are also mechanistically linked to treatment failure, relapse, and metastasis. Consequently, LCSCs constitute an ideal therapeutic target for liver cancer. Theoretically, a combined approach that targets CSCs together with conventional chemotherapy, should kill differentiated HCC cells and LCSCs, thus leading to tumor eradication. Direct targeting of CSC-specific markers is a powerful approach to eliminate this cell population. Although universal makers for LCSCs are not available, several studies targeting markers such as CD133, CD90, CD44, CD13 and EpCAM, have shown promising results. Specifically targeting LCSCs without harming healthy cells is a great challenge in cancer therapy. Aptamers, also known as chemical antibodies, are short single-stranded DNA or RNA that can fold into complex three-dimensional structures and bind to target molecules with high affinity and specificity. Aptamers have several advantages over conventional antibodies, such as low immunogenicity and toxicity, high stability, cab be chemically synthesized, smaller size for better tissue diffusion, and can be tightly conjugated with other anticancer agents. More recently, aptamers targeting carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) have been shown to inhibit the growth and metastasis of colon and liver cancers respectively.

In the current project, we aim to target LCSCs using RNA aptamers against LCSC marker CD44 (Apt-CD44). In particular, Apt-CD44 will be conjugated with anticancer drug doxorubicin (Dox), and the therapeutic effect of Apt-CD44-Dox against LCSCs will be tested in vitro and in vivo. This project is a collaborative study between the host laboratory and Professor W. Duan in the Deakin University. A wide range of cellular and molecular techniques will be employed in this project.

Additional Information

About the Storr Liver Unit
The Western Clinical School's Storr Liver Unit investigates the pathogenesis of liver disease, and the diverse causes of liver injury, such as drugs and toxins, metabolic factors and viruses. Internationally acclaimed, the Unit has made substantial contributions to defining how the liver responds to injury, and how genes involved in the metabolisms of drugs and toxic products of liver metabolism are regulated.
Liver cancer is Australia's fastest growing cancer, and this is an opportunity to take a role in the research of this emerging health focus. The Unit is well funded and thus there is the opportunity to employed cutting edge techniques and tools to bring each project to fruition. Joining a successful research team with expertise in liver disease and cancer, there will also be opportunity to collaborate with internationally-renowned cancer researchers at the Westmead Millennium Institute. As part of the community of over 400 researchers based on the Westmead campus, there will be the possibility to utilise the Institute's state-of-the-art molecular, translational and cell biological facilities.

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Keywords

Liver cancer, Stem cells, targeting, therapy, Sorafenib, aptamer

Opportunity ID

The opportunity ID for this research opportunity is: 1318

Other opportunities with Dr Liang Qiao

Other opportunities with Professor Jacob George