바로가기  >

[Abstract]

Tumor metastasis involves circulating and tumor-initiating capacities of metastatic cancer cells. Epithelial-mesenchymal transition (EMT) is related to self-renewal capacity and circulating tumor cell (CTC) characteristics for tumor metastasis. Although tumor metastasis is a life-threatening, complicated process that occurs through circulation of tumor cells, mechanistic aspects of self-renewal and circulating capacities have been largely unknown. Hepatic transmembrane 4 L six family member 5 (TM4SF5) promotes EMT for malignant growth and migration, so it was rationalized that TM4SF5, as a hepatocellular carcinoma (HCC) biomarker, might be important for metastatic potential. Here, self-renewal capacity by TM4SF5 was mechanistically explored using hepatocarcinoma cells with or without TM4SF5 expression, and we explored whether they became CTCs using mouse liver-orthotopic model systems. We found that TM4SF5-dependent sphere growth correlated with CD24(-) , aldehyde dehydrogenase (ALDH) activity, as well as a physical association between CD44 and TM4SF5. Interaction between TM4SF5 and CD44 was through their extracellular domains with N-glycosylation modifications. TM4SF5/CD44 interaction activated proto-oncogene tyrosine-protein kinase Src (c-Src)/signal transducer and activator of transcription 3 (STAT3)/Twist-related protein 1 (Twist1)/B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) signaling for spheroid formation, whereas disturbing the interaction, expression, or activity of any component in this signaling pathway inhibited spheroid formation. In serial xenografts using 200∼5,000 cells per injection, TM4SF5-positive tumors exhibited subpopulations with locally increased CD44 expressions, supporting for tumor cell differentiation. TM4SF5-positive, but not TM4SF5- or CD44-knocked-down, cells were identified circulating in blood 4-6 weeks after orthotopic liver injection using in vivo laser scanning endomicroscopy. Anti-TM4SF5 reagent blocked their metastasis to distal intestinal organs.

CONCLUSION: TM4SF5 promotes self-renewal and CTC properties supported by TM4SF5(+) /CD44(+(TM4SF5-bound)) /ALDH(+) /CD24(-) markers during HCC metastasis. (Hepatology 2015;61:1978-1997).

© 2015 by the American Association for the Study of Liver Diseases.

[Author information]

Lee D1, Na J2, Ryu J1, Kim HJ1, Nam SH3, Kang M1,4, Jung JW3, Lee MS1, Song HE1, Choi J3, Lee GH1, Kim TY1, Chung JK2,5, Park KH6, Kim SH7, Kim H7, Seo H8, Kim P8, Youn H2,5, Lee JW1,3.

​1 Department of Pharmacy, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.

2 Department of Nuclear Medicine, Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea.

3 Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Korea.

4 Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.

5 Cancer Imaging Center, Seoul National University Hospital, Seoul, Korea.

6 Division of Applied Life Science, Gyeongsang National University, Jinju, Korea.

7 School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.

8 Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology, Daejeon, Korea.