Dormant glioblastoma cells acquire stem cell characteristics and are differentially affected by Temozolomide and AT101 treatment

Cellular dormancy is defined as a state in which cells enter quiescence driven by intrinsic or extrinsic factors, and striking parallels exist between the concept of cellular dormancy in malignancies and the cancer stem cell theory. We showed now that the proven dormancy markers insulin-like growth factor-binding protein 5, ephrin receptor A5 and histone cluster 1 H2B family member K were expressed in human glioblastomas in situ, were located in single tumor cells, and could be co-stained with each other and with the stem cell markers krüppel-like factor 4, octamer binding transcription factor 4 and sex determining region Y-box 2. Human non-stem glioblastoma cell lines and primary cultures were characterized by expression of individual, cell-type specific dormancy- and stemness-associated markers, which were (up)regulated and could be co-stained in a cell-type specific manner upon Temozolomide-induced dormancy in vitro. The induction patterns of dormancy- and stemness-associated markers were reflected by cell-type specific responses to Temozolomide-induced and combined Temozolomide/AT101-mediated cytotoxicity in different glioblastoma cell lines and primary cultures in vitro, and accompanied by higher self-renewal capacity and lower TMZ-sensitivity of Temozolomide-pretreated cells. We postulate that a better understanding of the dormant state of tumor cells is essential to further improve efficiency of treatment.