CD24 + Liver Tumor-Initiating Cells Drive Self-Renewal and Tumor Initiation through STAT3-Mediated NANOG Regulation

• Published in: Cell stem cell Vol. 9; no. 1; pp. 50 - 63
• Main Authors: Lee, Terence Kin Wah, Castilho, Antonia, Cheung, Vincent Chi Ho, Tang, Kwan Ho, Ma, Stephanie, Ng, Irene Oi Lin
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 08.07.2011; Cell Press
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Biological and medical sciences; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; CD24 Antigen - metabolism; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell Line, Tumor; Cell physiology; Cell Proliferation; cisplatin; drug therapy; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; hepatoma; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; liver; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; metastasis; Mice; Middle Aged; Molecular and cellular biology; Nanog Homeobox Protein; neoplasm cells; Neoplasm Metastasis; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; patients; Phosphorylation; STAT3 Transcription Factor - metabolism; Tumors; Up-Regulation - genetics; Xenograft Model Antitumor Assays; Digestive diseases; Hepatic disease; Regulation(control); Liver tumor; Initiation; Tumor cell
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2011.06.005

Tumor-initiating cells (T-ICs) are a subpopulation of chemoresistant tumor cells that have been shown to cause tumor recurrence upon chemotherapy. Identification of T-ICs and their related pathways are therefore priorities for the development of new therapeutic paradigms. We established chemoresistant hepatocellular carcinoma (HCC) xenograft tumors in immunocompromised mice in which an enriched T-IC population was capable of tumor initiation and self-renewal. With this model, we found CD24 to be upregulated in residual chemoresistant tumors when compared with bulk tumor upon cisplatin treatment. CD24 + HCC cells were found to be critical for the maintenance, self-renewal, differentiation, and metastasis of tumors and to significantly impact patients' clinical outcome. With a lentiviral-based knockdown approach, CD24 was found to be a functional liver T-IC marker that drives T-IC genesis through STAT3-mediated NANOG regulation. Our findings point to a CD24 cascade in liver T-ICs that may provide an attractive therapeutic target for HCC patients. ► Enrichment of CD24 + population in chemoresistant HCC xenograft model ► CD24 + cells are able to initiate tumor, self-renew, differentiate, and metastasize ► Targeting CD24 attenuates characteristics of stem/progenitor in HCC cells ► CD24 drives T-IC genesis through Stat3-mediated Nanog regulation