title: 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.
authors.affiliation: 1 Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University , Yokohama, Japan .
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Zheng
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tsuchida
authors.forename: Taiki
authors.initials: T
authors.lastname: Shimao
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Takanori
authors.initials: T
authors.lastname: Takebe
authors.forename: Ran-Ran
authors.initials: RR
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Ueno
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sekine
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishibashi
authors.forename: Makiko
authors.initials: M
authors.lastname: Imajima
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hideki
authors.initials: H
authors.lastname: Taniguchi
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002469:Cell Separation; D005982:Glutathione Transferase / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D058990:Molecular Targeted Therapy; D010455:Peptides / Q000378:metabolism*; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D011916:Rats, Inbred F344
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D010455:Peptides; C000606025:Prom1 protein, rat; D005982:Glutathione Transferase