Stem Cell-Like Properties of Glioma Tumor-Initiating Cells: Microenvironmental Inputs

A superior tumor-initiation capacity of a relatively small sub-population of tumor cells has earned them the name of cancer stem cells (CSCs). CSCs identification and experimental sorting is primarily based on expression of certain surface markers rather than on the basis of unique properties shared by all other stem cells in adult organs. Such a property is their slow cell division rate compared to the rapid amplification of their descendants.

Here we examined brain grafts of glioblastoma multiforme (GBM) cells pre-labeled with a membrane-bound fluorescent dye to follow cell division rates, reasoning that CSCs will be distinguished as label-retaining cells due to their relative quiescence. Label-retaining cells were indeed shown to possess CSC hallmarks such as expression of stem cell surface marker CD133 and higher tumor initiation potential upon implantation into NOD/SCID mice.

To examine the notion that microenvironmental cues, in general, and that proximity to blood vessels, in particular, impact acquisition of CSC properties, we analyzed spatial patterns of CSC distribution and show that label-retaining glioma cells are indeed preferentially distributed in proximity to blood vessels. Further, RNA-seq analysis of tumor cells sorted according to their relative proximity to blood vessels reveals differences in multiple genes related to ‘stemness’ control, cell cycle regulation, metabolic changes and oncogenic signaling.