Role of cell quiescence in glioblastoma cytotoxic resistance and strategies for therapeutic intervention

Abstract The understanding of how cancer stem cells behave is important in understanding how tumors are initiated and how they recur following initial treatment. More specifically to understand how cancer stem cells behave, the different signaling mechanisms orchestrating their growth, cell cycle dynamics, differentiation, trans-differentiation, and survival following cytotoxic challenges need to be deciphered. Ultimately, this will advance the ability to predict how these cells will behave in individual patients and under different therapeutic conditions. Glioblastoma (GBM) stem cells, which have low proliferative capacity, exhibiting characteristics similar to quiescent stem cells are a likely source of treatment-resistant cells that contribute to tumor recurrence, which occurs in all patients. The molecular mechanisms regulating quiescent tumor cells are not well understood. Investigating the molecular mechanisms that regulate quiescence or slow cell cycling within a cell population requires that specific cells be isolated, examined, and compared to faster cycling cells. Identification of cells with different cycling rates, in vitro, has been made possible by the development of nontoxic vital fluorescent dyes, making it possible to track and select cells with different proliferation rates. In this review, we illustrate the use of vital dyes to select slow-cycling quiescent-like GBM cells to examine key biological mechanisms responsible for drug and radiation resistance.