Identification of Keratin 19-Positive Cancer Stem Cells Associating Human Hepatocellular Carcinoma Using18F-Fluorodeoxyglucose Positron Emission Tomography.
Purpose:The current lack of tools for easy assessment of cancer stem cells (CSC) prevents the development of therapeutic strategies for hepatocellular carcinoma (HCC). We previously reported that keratin 19 (K19) is a novel HCC-CSC marker and that PET with18F-fluorodeoxyglucose (18F-FDG) is an effective method for predicting postoperative outcome in hepatocellular carcinoma. Herein, we examined whether K19+HCC-CSCs can be tracked using18F-FDG-PET.Experimental Design:K19 and glucose transporter-1 (GLUT1) expression was evaluated by IHC in 98 hepatocellular carcinoma patients who underwent18F-FDG-PET scans before primary tumor resection. Standardized uptake values (SUV) for primary tumors and tumor-to-nontumor SUV ratios (TNR) were calculated using FDG accumulation levels, and values were compared among K19+/K19-patients. Using hepatocellular carcinoma cell lines encoding with a K19 promoter-driven enhanced GFP,18F-FDG uptake and GLUT1 expression were examined in FACS-isolated K19+/K19-cells.Results:In hepatocellular carcinoma patients, K19 expression was significantly correlated with GLUT1 expression and FDG accumulation. ROC analyses revealed that among preoperative clinical factors, TNR was the most sensitive indicator of K19 expression in hepatocellular carcinoma tumors. In hepatocellular carcinoma cells, FACS-isolated K19+cells displayed significantly higher18F-FDG uptake than K19-cells. Moreover, gain/loss-of-function experiments confirmed that K19 regulates18F-FDG uptake through TGFβ/Smad signaling, including Sp1 and its downstream target GLUT1.Conclusions:18F-FDG-PET can be used to predict K19 expression in hepatocellular carcinoma and should thereby aid in the development of novel therapeutic strategies targeting K19+HCC-CSCs.Clin Cancer Res; 23(6); 1450-60. ©2016 AACR.
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Hepatobiliary Surgery and Liver Transplantation, Pitié-Salpétrière Hospital, University of Pierre and Marie Curie (UPMC), Paris, France.
Takayuki
T
Kawai
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. kent@kuhp.kyoto-u.ac.jp.
Kentaro
K
Yasuchika
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Satoru
S
Seo
Department of Diagnostic Radiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Tatsuya
T
Higashi
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Takamichi
T
Ishii
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yuya
Y
Miyauchi
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Hidenobu
H
Kojima
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Ryoya
R
Yamaoka
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Hokahiro
H
Katayama
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
Elena Yukie
EY
Yoshitoshi
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Satoshi
S
Ogiso
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Sadahiko
S
Kita
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
Katsutaro
K
Yasuda
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Ken
K
Fukumitsu
Department of Diagnostic Radiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yuji
Y
Nakamoto
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Etsuro
E
Hatano
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Shinji
S
Uemoto
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053539:Keratin-19 / Q000235:genetics* / Q000302:isolation & purification; D008113:Liver Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011379:Prognosis; D014057:Tomography, X-Ray Computed
D053539:Keratin-19; D019788:Fluorodeoxyglucose F18