A genetically engineered oncolytic adenovirus decoys and lethally traps quiescent cancer stem-like cells into S/G2/M-phases
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels un adénovirus oncolytique génétiquement modifié fait perdre leurs propriétés de cellules souches à certaines cellules de tumeurs solides
Purpose: Since chemo-radiotherapy selectively targets proliferating cancer cells, quiescent cancer stem-like (CS-like) cells are resistant. Mobilization of cell cycle in quiescent leukemia stem cells sensitizes them to cell death signals. However, it is unclear that mobilization of cell cycle can eliminate quiescent CS-like cells in solid cancers. Thus, we explored the use of a genetically engineered telomerase-specific oncolytic adenovirus, OBP-301 to mobilize the cell cycle and kill quiescent CS-like cells. Experimental design: We established CD133+ CS-like cells from human gastric cancer MKN45 and MKN7 cells. We investigated the efficacy of OBP-301 against quiescent CS-like cells. We visualized the treatment dynamics that OBP-301 killed quiescent CS-like cells in dormant tumor spheres and xenografts using fluorescent ubiquitination cell cycle indicator (FUCCI). Results: CD133+ gastric cancer cells had stemness properties. OBP-301 efficiently killed CD133+ CS-like cells resistant to chemo-radiotherapy. OBP-301 induced cell cycle mobilization from G0/G1 to S/G2/M phase and subsequent cell death in quiescent CD133+ CS-like cells by mobilizing cell-cycle related proteins. FUCCI enabled visualization of quiescent CD133+ CS-like cells and proliferating CD133- non CS-like cells. Three-dimensional visualization of the cell cycle behavior in tumor spheres showed that CD133+ CS-like cells maintained stemness by remaining in G0/G1 phase. We demonstrated that OBP-301 mobilized quiescent CS-like cells in tumor spheres and xenografts into S/G2/M phases where they lost viability and CS-like cell property, and became chemosensitive. Conclusion: Oncolytic adenoviral infection is an effective mechanism of cancer cell killing in solid cancer and can be a new therapeutic paradigm to eliminate quiescent CS-like cells.