Self-renewal and circulating capacities of metastatic hepatocarcinoma cells required for collaboration between TM4SF5 and CD44
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Tumor metastasis involves circulating and tumor-initiating capacitiesof metastatic cancer cells. Hepatic TM4SF5 promotesEMT for malignant growth and migration. Hepatocellular carcinoma(HCC) biomarkers remain unexplored for metastatic potentialthroughout metastasis. Here, novel TM4SF5/CD44 interaction-mediated self-renewal and circulating tumor cell (CTC)capacities were mechanistically explored. TM4SF5-dependentsphere 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/ Bmi1 signaling for spheroid formation, while disturbing the interaction,expression, or activity of any component in this signalingpathway inhibited spheroid formation. In serial xenograftsof less than 5,000 cells/injection, TM4SF5-positive tumors exhibitedlocally-increased CD44 expression, suggesting tumorcell differentiation. TM4SF5-positive cells were identified circulatingin blood 4 to 6 weeks after orthotopic liver-injection. Anti-TM4SF reagents blocked their metastasis to distal intestinalorgans. Altogether, our results provide evidence that TM4SF5promotes self-renewal and CTC properties supported byCD133+/TM4SF5+/CD44+(TM4SF5-bound)/ALDH+/ CD24- markersduring HCC metastasis.
Abstract
Tumor metastasis involves circulating and tumor-initiating capacitiesof metastatic cancer cells. Hepatic TM4SF5 promotesEMT for malignant growth and migration. Hepatocellular carcinoma(HCC) biomarkers remain unexplored for metastatic potentialthroughout metastasis. Here, novel TM4SF5/CD44 interaction-mediated self-renewal and circulating tumor cell (CTC)capacities were mechanistically explored. TM4SF5-dependentsphere 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/ Bmi1 signaling for spheroid formation, while disturbing the interaction,expression, or activity of any component in this signalingpathway inhibited spheroid formation. In serial xenograftsof less than 5,000 cells/injection, TM4SF5-positive tumors exhibitedlocally-increased CD44 expression, suggesting tumorcell differentiation. TM4SF5-positive cells were identified circulatingin blood 4 to 6 weeks after orthotopic liver-injection. Anti-TM4SF reagents blocked their metastasis to distal intestinalorgans. Altogether, our results provide evidence that TM4SF5promotes self-renewal and CTC properties supported byCD133+/TM4SF5+/CD44+(TM4SF5-bound)/ALDH+/ CD24- markersduring HCC metastasis.