CD44s signals the acquisition of the mesenchymal phenotype required for anchorage-independent cell survival in hepatocellular carcinoma

• Published in: British journal of cancer Vol. 110; no. 4; pp. 958 - 966
• Main Authors: Okabe, H, Ishimoto, T, Mima, K, Nakagawa, S, Hayashi, H, Kuroki, H, Imai, K, Nitta, H, Saito, S, Hashimoto, D, Chikamoto, A, Ishiko, T, Watanabe, M, Nagano, O, Beppu, T, Saya, H, Baba, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.02.2014; Nature Publishing Group
• Subjects: 631/67/1504/1610; 631/67/322; 631/80/84/2176; 631/80/86; Anoikis - genetics; Apoptosis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Movement; Cell Survival; Down-Regulation; Drug Resistance; Epidemiology; Epithelial-Mesenchymal Transition; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Genotype & phenotype; Growth factors; Humans; Hyaluronan Receptors - genetics; Hyaluronan Receptors - metabolism; Liver cancer; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical prognosis; Medical research; Medical sciences; Mesoderm - cytology; Metastasis; Molecular Diagnostics; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplastic Cells, Circulating - pathology; Nuclear Proteins - biosynthesis; Nuclear Proteins - genetics; Oncology; Proto-Oncogene Proteins c-akt - biosynthesis; RNA Interference; RNA, Small Interfering; Stem cells; Thy-1 Antigens - metabolism; Tumors; Twist-Related Protein 1 - biosynthesis; Twist-Related Protein 1 - genetics; Japan; epithelial–mesenchymal transition; anoikis; CD44; Twist1; Transmembrane protein; Cell survival; Cell adhesion molecule; Mesenchyma; Hepatic disease; Hepatocellular carcinoma; Malignant tumor; Mesenchymal cell; Cell transformation; Adhesion; Liver cancer; Signal transduction; Phenotype; Cancerology; Digestive diseases; Anoikis; epithelial-mesenchymal transition; Epithelial mesenchymal transition; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.759

Background: Circulating tumour cells (CTCs) have an important role in metastatic processes, but details of their basic characteristics remain elusive. We hypothesised that CD44-expressing CTCs show a mesenchymal phenotype and high potential for survival in hepatocellular carcinoma (HCC). Methods: Circulating CD44 + CD90 + cells, previously shown to be tumour-initiating cells, were sorted from human blood and their genetic characteristics were compared with those of tumour cells from primary tissues. The mechanism underlying the high survival potential of CD44-expressing cells in the circulatory system was investigated in vitro . Results: CD44 + CD90 + cells in the blood acquired epithelial–mesenchymal transition, and CD44 expression remarkably increased from the tissue to the blood. In Li7 and HLE cells, the CD44 high population showed higher anoikis resistance and sphere-forming ability than did the CD44 low population. This difference was found to be attributed to the upregulation of Twist1 and Akt signal in the CD44 high population. Twist1 knockdown showed remarkable reduction in anoikis resistance, sphere formation, and Akt signal in HLE cells. In addition, mesenchymal markers and CD44s expression were downregulated in the Twist1 knockdown. Conclusions: CD44s symbolises the acquisition of a mesenchymal phenotype regulating anchorage-independent capacity. CD44s-expressing tumour cells in peripheral blood are clinically important therapeutic targets in HCC.