The CD133⁺CD44⁺ Precancerous Subpopulation of Oval Cells Is a Therapeutic Target for Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a malignant tumor associated with a generally poor prognosis and a high rate of recurrence. HCC usually develops in the context of chronic liver diseases, and long-lasting premalignant conditions precede cancer development. A promising therapeutic approach is to eliminate precancerous cells, which are considered as the precursors of cancer stem cells, to prevent further malignant transformation. In this study, we identified a subpopulation of precancerous cells in a rat liver carcinogenesis model, which were enriched in CD133+ CD44 + CD45 -HIS49 -cells that formed part of the hepatic oval cells fraction. Prospective isolation of the precancerous cells using flow cytometry identified stem cell properties such as the ability to expand clonally and differentiate into bi-lineage cell types. Furthermore, an acyclic retinoid, which was recently shown to improve overall survival after HCC resection, directly inhibited the extensive expansion of the isolated precancerous cells in vitro and decreased the emergence of the precancerous cells and their progeny in vivo. Long-term follow-up after the acyclic retinoid treatment confirmed reduction in precancerous changes, ultimately resulting in suppression of HCC development. These findings, together with data from recent clinical trials showing marked reduction in intrahepatic recurrence, suggest that acyclic retinoid directly prevents de novo HCC by inhibiting the development of precancerous cells. Given recent advances in diagnostic techniques and the establishment of surveillance programs, the targeting of precancerous cells may have a huge impact on preventative cancer therapies.

Clinicopathological significance and prognostic value of the expression of the cancer stem cell marker CD133 in hepatocellular carcinoma: a meta-analysis

“…Ma et al found that CD133 + ALDH + cells were significantly more tumorigenic than CD133 + ALDH − or CD133 − ALDH − cells both in vitro and in vivo [46]. Zhu et al suggested that the CD133 + CD44 + subpopulation might allow a better understanding of HCC initiation and progression and establish a precise target for the development of more effective therapies [47], which was consistent with the conclusion by Zheng et al [48]. Thus, we speculated that the coexpression of markers for the identification of HCC may be more meaningful and efficient for clinicopathological and prognostic estimation.…”

Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice

“…CSCs contribute to liver carcinogenesis (46)(47)(48). The fro/ fro liver tumors contained pockets of proliferating cells (Figs.…”

A Role for Acyclic Retinoid in the Chemoprevention of Hepatocellular Carcinoma: Therapeutic Strategy Targeting Phosphorylated Retinoid X Receptor-α

“…In fact, the inhibitory effects of ACR on the development of secondary HCC lasted for about 3 years after termination of its administration [17]. In addition, Zheng et al [84] recently reported that ACR treatment decreased the emergence of precancerous cells and their progeny in a rat liver carcinogenesis model, consequently leading to suppression of HCC development. This experimental data sufficiently supports the previous clinical reports and the concept of "clonal deletion" [15][16][17].…”