Authors: Xingwang Hu, Laura Ghisolfi, Andrew C. Keates, Jian Zhang, Shuanglin Xiang, Dong-ki Lee and Chiang J. Li

Xingwang Hu

Key Laboratory of Protein Chemistry and Developmental Biology of Education Ministry of China; College of Life Science; Hunan Normal University; Changsha, Hunan, China; Skip Ackerman Center for Molecular Therapeutics; Division of Gastroenterology; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston MA USA

Laura Ghisolfi

Skip Ackerman Center for Molecular Therapeutics; Division of Gastroenterology; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston MA USA

Andrew C. Keates

Skip Ackerman Center for Molecular Therapeutics; Division of Gastroenterology; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston MA USA

Jian Zhang

Key Laboratory of Protein Chemistry and Developmental Biology of Education Ministry of China; College of Life Science; Hunan Normal University; Changsha, Hunan, China

Shuanglin Xiang

Key Laboratory of Protein Chemistry and Developmental Biology of Education Ministry of China; College of Life Science; Hunan Normal University; Changsha, Hunan, China

Dong-ki Lee

Global Research Laboratory for RNAi Medicine; Department of Chemistry; Sungkyunkwan University; Suwon, Korea

Chiang J. Li

Corresponding author: cli@bidmc.harvard.edu
Skip Ackerman Center for Molecular Therapeutics; Division of Gastroenterology; Beth Israel Deaconess Medical Center; Harvard Medical School; Boston MA USA

Abstract:
Recent studies indicate that cancer stem cells (CSCs) exist in most hematological and solid tumors. CSCs are characterized by their ability to self-renew and their capacity to differentiate into the multitude of cells that comprise the tumor mass. Moreover, these cells have been shown to be intrinsically resistant to conventional anticancer therapies. Despite their fundamental role in cancer pathogenesis, the cellular origin of CSCs remains highly controversial. The aim of this study was to examine whether heterogeneous cancer cells can acquire stem cell-like properties in response to chemotherapy. We demonstrate that carboplatin can induce the self-renewal (spherogenesis) and pluripotency (Sox2 and Oct3/4 expression) of hepatocellular carcinoma (HCC) cells grown under stem cell culture conditions. Moreover, we show that non-CSC cells, obtained by side population flow cytometric sorting using Hoechst 33342, can acquire stem-like properties after exposure to carboplatin. Finally, we show that knockdown of Sox2 and Oct3/4 gene expression in HCC cells can reduce carboplatin-mediated increases in sphere formation and increase cellular sensitivity to chemotherapy. Taken together, our data indicate that bulk cancer cells may be an important source of CSCs during tumor development, and that targeting Sox2 and/or Oct3/4 may be a promising approach for targeting CSCs in clinical cancer treatment.

Received: May 31, 2012; Accepted: June 5, 2012

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