732P - Cytokeratin 19, a cancer stem cell marker in hepatocellular carcinoma

Date 29 September 2014
Event ESMO 2014
Session Poster Display session
Topics Hepatobiliary Cancers
Pathology/Molecular Biology
Translational Research
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Presenter Takayuki Kawai
Citation Annals of Oncology (2014) 25 (suppl_4): iv210-iv253. 10.1093/annonc/mdu334
Authors T. Kawai1, K. Yasuchika1, T. Ishii2, H. Katayama1, E.Y. Yoshitoshi1, S. Ogiso1, S. Kita1, K. Yasuda1, K. Fukumitsu1, M. Mizumoto1, E. Hatano1, S. Uemoto1
  • 1Department Of Surgery, Graduate School of Medicine, Kyoto University, 6068507 - Kyoto/JP
  • 2Department Of Surgery, Nishikobe Medical Center, Kobe/JP

Abstract

Aim

Cancer stem cells (CSCs) are receiving considerable attention as targets for cancer therapy. Although cytokeratin 19 (CK19) is known to involve in various malignant properties of hepatocellular carcinoma (HCC), the relationship between CK19 and CSCs is unclear. Here, we aimed to determine if CK19, a hepatic progenitor cell marker, can use as a new CSC marker in HCC.

Methods

We examined CK19 expression of 166 consecutive human HCC specimens using immunohistochemistry, and analyzed the gene expression pattern of CK19+/CK19 patients. We transfected the CK19 promoter-driven enhanced green fluorescence protein gene into HCC cell lines, and investigated fluorescence-activated cell sorting (FACS)-isolated CK19+/CK19 cells.

Results

CK19+ HCC patients had significantly poorer recurrence-free survival and larger tumor. They also showed the gene expression profile correlated with epithelial mesenchymal transition (EMT) and epithelial cell adhesion molecule (EpCAM). FACS-isolated single CK19+ cells showed the ability to self-renew and differentiate into CK19 cells, while single CK19 cells never produced CK19+ cells. CK19+ cells displayed greater proliferation capacity and stronger 5-fluorouracil resistance based on higher expression of multidrug-resistant protein 5 in vitro. Xenotransplantation into immunodeficiency mice revealed that CK19+ cells could reproduce themselves, differentiate into CK19 cells, and generate larger tumors at a higher frequency in vivo. CK19+ cells showed greater motility and higher expression of EMT-related genes than CK19 cells, and these properties were suppressed by transforming growth factor beta receptor 1 inhibitor LY2157299. CK19+ cells also expressed EpCAM at higher levels. Additionally, CK19+ cells had the advantage of greater proliferation potency over EpCAM.

Conclusions

CK19+ cells are HCC-CSCs correlated with rapid tumor growth and EMT. CK19 should be a good therapeutic target.

Disclosure

All authors have declared no conflicts of interest.