Taro Yamashita¹, Junfang Ji¹, Anuradha Budhu¹, Marshonna Forgues¹, Huliang Jia², Qinghai Ye², Lun-Xiu Qin², Elaine Wauthier³, Lola M. Reid³, Hiroshi Minato⁴, Masao Honda⁴, Shuichi Kaneko⁴, Wen Yang⁵, Hongyang Wang⁵, Zhao-You Tang², Xin Wei Wang¹

¹ Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4258, USA, ² Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China, ³ Department of Cell and Molecular Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA, ⁴ Liver Disease Center and Kanazawa University Hospital, Kanazawa University, Kanazawa, 920-8641, Japan, ⁵ Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China

Cancer progression/metastases and embryonic development share many properties including cellular plasticity, dynamic cell motility, and integral interaction with the microenvironment. Here, using global gene expression profiling, we identified a subtype of hepatocellular carcinoma (HCC) that resembled hepatic stem cell features. This subtype expressed alpha-fetoprotein (AFP) and a cell surface hepatic stem cell marker, EpCAM. A subset of EpCAM⁺ AFP⁺ HCC cells was identified by fluorescence-activated cell sorting as hepatic cancer stem cells with features for self-renewal and differentiation, and was highly invasive and could initiate metastatic HCC in NOD/SCID mice. Activation of Wnt/b-catenin signaling augmented the population of EpCAM⁺ AFP⁺ cells, while EpCAM blockage, a target of Wnt/b-catenin signaling, by RNA interference attenuated the activities of these cells. These EpCAM⁺ AFP⁺ HCC stem cell features are currently under investigation using clinical HCC specimens. Taken together, our results suggest that metastatic HCC growth and invasiveness is dictated by a subset of EpCAM⁺ AFP⁺ cells, which opens a new avenue for eradicating HCC cancer stem cells by targeting the Wnt/b-catenin signaling pathway including EpCAM.

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