Oncostatin m renders epithelial cell adhesion molecule-positive liver cancer stem cells sensitive to 5-Fluorouracil by inducing hepatocytic differentiation.
Recent evidence suggests that a certain type of hepatocellular carcinoma (HCC) is hierarchically organized by a subset of cells with stem cell features (cancer stem cells; CSC). Although normal stem cells and CSCs are considered to share similar self-renewal programs, it remains unclear whether differentiation programs are also maintained in CSCs and effectively used for tumor eradication. In this study, we investigated the effect of oncostatin M (OSM), an interleukin 6-related cytokine known to induce the differentiation of hepatoblasts into hepatocytes, on liver CSCs. OSM receptor expression was detected in the majority of epithelial cell adhesion molecule-positive (EpCAM(+)) HCC with stem/progenitor cell features. OSM treatment resulted in the induction of hepatocytic differentiation of EpCAM(+) HCC cells by inducing signal transducer and activator of transcription 3 activation, as determined by a decrease in stemness-related gene expression, a decrease in EpCAM, alpha-fetoprotein and cytokeratin 19 protein expressions, and an increase in albumin protein expression. OSM-treated EpCAM(+) HCC cells showed enhanced cell proliferation with expansion of the EpCAM-negative non-CSC population. Noticeably, combination of OSM treatment with the chemotherapeutic agent 5-fluorouracil (5-FU), which eradicates EpCAM-negative non-CSCs, dramatically increased the number of apoptotic cells in vitro and suppressed tumor growth in vivo compared with either saline control, OSM, or 5-FU treatment alone. Taken together, our data suggest that OSM could be effectively used for the differentiation and active cell division of dormant EpCAM(+) liver CSCs, and the combination of OSM and conventional chemotherapy with 5-FU efficiently eliminates HCC by targeting both CSCs and non-CSCs.
Yamashita
Taro
T
Center for Liver Diseases, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan.
Honda
Masao
M
Nio
Kouki
K
Nakamoto
Yasunari
Y
Yamashita
Tatsuya
T
Takamura
Hiroyuki
H
Tani
Takashi
T
Zen
Yoh
Y
Kaneko
Shuichi
S
D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000071858:Epithelial Cell Adhesion Molecule; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D053683:Oncostatin M / Q000008:administration & dosage / Q000494:pharmacology*; D053681:Oncostatin M Receptor beta Subunit / Q000096:biosynthesis / Q000378:metabolism
D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C508348:OSMR protein, human; D053681:Oncostatin M Receptor beta Subunit; D053683:Oncostatin M; D005472:Fluorouracil