UC San Diego

Percutaneous thermal ablation (PTA) and transarterial embolization (TAE) represent vital alternatives for patients with early or intermediate stage hepatocellular carcinoma (HCC), for whom surgery is not an option. Nonetheless, incomplete ablation or embolization can lead to local recurrence or the development of new foci of disease. Studies suggest that the sublethal heat stress induced by incomplete PTA and hypoxia induced by TAE can enrich the proportion of the cancer stem cells (CSC), a rare subpopulation of self-renewing cells capable of recapitulating the entire HCC tumor. Their quiescence and self-protective mechanisms make CSC resistant to standard cancer therapies aimed at the rapidly-dividing cells that comprise the bulk of the tumor. If surviving HCC CSC give rise to disease recurrence after PTA or TAE, combining PTA or TAE with HCC CSC inhibitors could improve disease response and decrease recurrence. The current study tested this hypothesis in vitro by subjecting HCC cells to conditions simulating incomplete PTA with sublethal heat stress or TAE in a hypoxia chamber with serum starvation, without or with HCC CSC inhibitors. Surviving cells were analyzed by flow cytometry, cell culture assays, immunoblotting and immunofluorescence results. Our results demonstrated conditions simulating PTA and TAE resulted in an enrichment of cells bearing CSC markers and HCC CSC inhibitors decreased this enrichment. In conclusion, incomplete PTA and TAE activates the cancer stem cell populations in HCC and can generate more aggressive disease. The adjuvant treatments with CSC inhibitors can abolish the enrichment and improve the efficacy of treatments.