Carcinogenesis Advance Access published online on November 6, 2009
Carcinogenesis, doi:10.1093/carcin/bgp232
The Properties of Tumor-initiating Cells from a Hepatocellular Carcinoma Patient's Primary and Recurrent Tumor
1 National Key Laboratory of Protein Engineering and Plant Gene Engineering, Institute of Life Science, Peking University, Beijing, China
2 Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital & Institute, Peking University School of Oncology, Beijing, China
3 Department of Biology, Hong Kong University of Science and Technology, Hong Kong, China
* Correspondence to: Zhiqian Zhang, Ph.D., Peking University School of Oncology, 52 Fucheng Rd., Beijing 100142, P. R. China. Telephone: 86-10-88196792. Fax: 86-10-88122437, E-mail: zlzqzhang{at}bjmu.edu.cn. OR Yu Wang, Ph.D., Immunotherapy laboratory, ImmunoTech Beijing Limited, 89 Zhongguancun East Rd., Hengxing Mansion 9H, Beijing, 100080, P. R. China. Email: yuwang97{at}163.com; Tel: 86-10-88400321 Fax: 86-10-88400152
Hepatocellular carcinoma (HCC) is associated with a high morbidity and mortality due to its high rate of recurrence. However, little is known about the biological characteristics of recurrent HCC cells. A single patient's primary and recurrent HCC derived cell lines, Hep-11 and Hep-12 respectively, were established by primary culture. These two cell lines have the same HBV integration site and share many common amplifications and deletions, which suggest that they have the same clonal origin. While Hep-11 cells were non-tumorigenic at 16 weeks following injection of up to 10,000 cells, injection of only 100 Hep-12 cells was sufficient to initiate tumor growth, and all single Hep-12 clones were tumorigenic in immunodeficient mice. Compared with Hep-11, Hep-12 cells expressed the oval cell markers AFP, NCAM/CD56, c-kit/CD117, as well as multiple stem cell markers such as Nanog, OCT4, and SOX2. In addition, greater than 90% of Hep-12 cells were aldehyde dehydrogenase positive. They were also less resistant to paclitaxel, but more resistant to doxorubicin, cisplatin and hydroxycamptothecin (HCPT) which had been administrated to the patient. Furthermore, Hep-12 expressed higher levels of poly (ADP-ribose) polymerase-1 (PARP-1) than Hep-11, and PARP-1 inhibition potentiated the sensitivity to HCPT in Hep-12 but not in Hep-11 cells. These results indicate that a large population of the recurrent HCC-derived Hep-12 cells were tumor-initiating cells, and that elevated expression of PARP-1 was related to their resistance to HCPT.
Key Words: Hepatocellular carcinoma • recurrence • cancer stem cells • drug resistance • poly (ADP-ribose) polymerase • superarray
Received February 22, 2009; revised August 31, 2009; accepted September 19, 2009.