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

Abstract

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.

Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma

“…CSCs, also called tumor-initiating cells or cancer stem-like cells, possess stem cell features in their self-renewal and differentiation capacity, and contribute to the formation of heterogeneous tumor cell populations. In HCC, several stem cell markers, including CD133, CD90, CD13, epithelial cell adhesion molecule (EpCAM), and CD24, have been reported to enrich side populations of CSCs [13][14][15]. We recently reported that the stem cell markers EpCAM and alpha-fetoprotein (AFP) can be used to classify HCC subtypes with distinct gene expression profiles and patient prognoses [11].…”

Cyclin G1 Expands Liver Tumor-Initiating Cells by Sox2 Induction via Akt/mTOR Signaling

“…These cells are able to self-renew and differentiate into the bulk tumor population (10). Being a built-in population of tumor, these T-ICs can survive chemotherapy and repopulate the tumor (11). Accumulating evidence has showed that T-ICs exist in various tumors, including leukemia (12), glioma (13), breast (14), and colon cancer (15).…”

“…Accumulating evidence has showed that T-ICs exist in various tumors, including leukemia (12), glioma (13), breast (14), and colon cancer (15). Liver T-ICs have also been identified by several cell surface antigens such as CD133 (16), CD90 (17), CD24 (11), and epithelial cell adhesion molecule (18). Existence of T-ICs in hepatocellular carcinoma is likely to be one of the most principle reasons why current oncologic therapies exhibit poor effectiveness (10,19,20).…”

Tunicamycin Potentiates Cisplatin Anticancer Efficacy through the DPAGT1/Akt/ABCG2 Pathway in Mouse Xenograft Models of Human Hepatocellular Carcinoma

“…Common chemotherapies have been shown to enrich the CSC subpopulations in some studies (4,34). CD133 þ hepatocellular carcinoma CSCs may confer chemoresistance by preferentially expressing the Akt/Bcl-2 or PTEN/Akt/ABCG2 pathway (13,30).…”

“…CSCs appear to be protected from routine chemotherapeutic drugs through various mechanisms, such as high expression levels of ATP-binding cassette (ABC) drug transporters (3). Drug-resistant CSCs have been shown to survive treatment with several widely used chemotherapeutic agents (4,5).…”