Researcher Studies Mechanistic Characterization of Tumor Initiating Cells That Give Rise To Hepatocellular Carcinoma



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One Year Research Update: 

Debanjan Dhar, PhD at the University of California, San Diego has completed his first year of a two-year Young Investigator award from CureSearch for Children's Cancer to study the role of a specific protein, CD44, in the creation of hepatocellular carcinoma (HCC). In his work, he is investigating the molecular mechanisms it regulates to see how it affects the development of liver tumors. CD44 is a protein primarily seen on the cell surface and is a well-known cancer stem cell marker.

During his first year of research, Dr. Dhar found novel ways to identify, isolate and characterize the HCC progenitor cells (HcPC) "long before" actual tumors were visible. Further, his research found that HcPCs have deregulated microRNA pathways that lead to activation of oncogenic signaling pathways such as IL-6-STAT3. These signaling pathways are critical in the maintenance of HcPC as well as their progression into full-blown HCC. Dr. Dhar found that these pathways were also activated in certain human dysplastic lesions, indicating that these lesions have high probability of advancing into HCC at a later stage. Therefore, the markers and signaling pathways activated in HcPC provide novel biomarkers for early detection as well as therapeutic targets for HCC. The results of this study were published in Cell (2013; 10.155 (2): 384-96).

CD44 is one of the markers that were highly overexpressed in HcPC. When trying to create HCC in mice that don't have CD44, Dr. Dhar found that HCC development is reduced if CD44 is not there, suggesting that CD44 is a key driver in the creation and progression of HCC. Dr. Dhar found that CD44 expression prevents tumor progenitor cells from dying and orchestrates important signals that help the cells to become cancerous.

During the second year of research, Dr. Dhar will examine how CD44 expression is controlled and how exactly they affect the growth of cancer cells.


Liver cancer is rare in children and adolescents. There are two main types of childhood liver cancer: hepatoblastoma, a very rare kind of liver cancer usually found in children under 4; and hepatocellular carcinoma (HCC), the most common type of liver cancer in adolescents, young adults, and adults.

HCC is one of the most aggressive and difficult to treat cancers. Although major progress has been made in understanding HCC risk factors, the molecular mechanisms that cause HCC to begin and progress are poorly understood, particularly in children. Regardless of the cause, cancer stem cells (CSC) are known to play a role in the development, growth, and spread of cancer, as well as in the cancer becoming resistant to treatment or recurring.

Every cancerous tumor is believed to have begun from a single progenitor cell that has developed the ability to survive and grow in what might otherwise be abnormal circumstances. Debanjan Dhar, PhD at the University of California, San Diego is currently conducting a study to isolate and purify HCC stem/progenitor cells long before tumor nodules are visible.

In addition, Dr. Dhar has been awarded a two-year grant from CureSearch for Children's Cancer to study the role of a specific protein, CD44, in the creation of HCC and to investigate the molecular mechanisms that are regulated by CD44 in the development of liver tumors.

 
  • Debanjan Dhar, PhD
  • University of California, San Diego

CD44 is a protein primarily seen on the cell surface and is well-known as a cancer stem cell marker. When trying to create HCC in mice that don't have CD44, Dr. Dhar found that HCC development is reduced if CD44 is not there. This suggests that CD44 is more than just a marker, but that is a key driver in the creation and progression of HCC.

Because normal mature liver cells do not express CD44 and those from HCC tumors overexpress it, it is important to understand how CD44 affects the development of cancer. Dr. Dhar hypothesizes that CD44 expression prevents tumor progenitor cells from dying and orchestrates important signals that tell the cells to become cancerous.

He hopes that understanding the function and regulation of CD44 in HCC will generate new knowledge and help develop novel targets (treatments) for this cancer.


 

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