title: Self-renewal and circulating capacities of metastatic hepatocarcinoma cells required for collaboration between TM4SF5 and CD44.
abstract: Tumor metastasis involves circulating and tumor-initiating capacities of metastatic cancer cells. Hepatic TM4SF5 promotes EMT for malignant growth and migration. Hepatocellular carcinoma (HCC) biomarkers remain unexplored for metastatic potential throughout metastasis. Here, novel TM4SF5/CD44 interaction-mediated self-renewal and circulating tumor cell (CTC) capacities were mechanistically explored. TM4SF5-dependent sphere growth was correlated with CD133+, CD24-, ALDH activity, and a physical association between CD44 and TM4SF5. The TM4SF5/CD44 interaction activated c-Src/STAT3/Twist1/B mi1 signaling for spheroid formation, while disturbing the interaction, expression, or activity of any component in this signaling pathway inhibited spheroid formation. In serial xenografts of less than 5,000 cells/injection, TM4SF5-positive tumors exhibited locally-increased CD44 expression, suggesting tumor cell differentiation. TM4SF5-positive cells were identified circulating in blood 4 to 6 weeks after orthotopic liver- injection. Anti-TM4SF reagents blocked their metastasis to distal intestinal organs. Altogether, our results provide evidence that TM4SF5 promotes self-renewal and CTC properties supported by CD133+/TM4SF5+/CD44+(TM4SF5-bound)/ALDH+/CD24-markers during HCC metastasis.
authors.affiliation: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Doohyung
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000502:physiology*; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; C111029:TM4SF5 protein, human