Stem Cell Phenotype in Cirrhosis and Hepatocellular Carcinoma
Iram Siddiqui, Zia A Khan, Subrata Chakrabarti. London Health Sciences Center, London, ON, Canada; University of Western Ontario, London, ON, Canada
Background: Recent data support the existence of cancer stem cells (CSCs) in some and perhaps, all cancers. While cancers are a heterogeneous mix of cells at various stages of differentiation, undifferentiated tumor-specific stem cells acquire the transforming mutations necessary for tumourigenesis. In the present study, we determined whether stem cells play a significant role in the initiation and/or progression of hepatocellular carcinoma (HCC).
Design: We have investigated the role of CSCs in the genesis of HCC by analyzing CD133, a specific stem cell marker, in cirrhosis and HCC arising in cirrhotic and non-cirrhotic liver with comparison to normal liver. Paraffin-embedded archival material was used to identify stem cells and to examine protein and mRNA expression. Quantitative immunostaining was done for CD133 and Hep-par1. Real time RT-PCR was performed to evaluate CD133, Oct4, and Nanog (all stem cell markers) mRNA expression. All of these analyses were also performed on fibrolamellar carcinoma.
Results: Normal liver demonstrated rare presence of CD133+ cells and low mRNA levels of stem cell markers. In cirrhosis, CD133+ cells and mRNA expression of stem cell markers was significantly (p=0.04) higher. These CD133+ cells were localized primarily to neoplastic hepatocytes. Similarly, in HCC with cirrhosis, CD133+ cells were significantly increased (p=0.001) in the neoplastic hepatocytes and were localized in the periphery of the tumour nodules. Several such cells co-expressed Hep-par1. On the contrary, HCC without cirrhosis did not show significant increase in both stem cell number and mRNA expression of CD133 or other stem cell markers. Fibrolamellar carcinoma showed increase in these cells similar to HCC with cirrhosis. Interestingly, no significant changes in the stem cell number or mRNA levels were observed in HCC without cirrhosis and normal liver. Other stem cell markers such as Nanog and Oct 4 showed similar trend.
Conclusions: Our findings indicate presence of CD133-expressing stem/precursor cells in hepatocellular carcinoma with cirrhosis, fibrolamellar carcinoma and cirrhosis. Based on this data, CD133+ stem cells are significantly increased in cirrhosis with or without HCC, suggesting a role of these stem cells in the regenerative/reparative process. This implies a bystander role of these stem cells. In fibrolamellar carcinoma, likely the presence of fibrosis within the tumour caused increased expression of CD133. The tumourigenic capacity of these CD133+ stem cells in the immunodeficient mice will potentially delineate the underlying pathogenesis.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 119, Monday Morning