Stem-like tumour-initiating cells (TICs) are a subpopulation of cells thought to be responsible for the regenerative and treatment-resistant properties of tumours. Brain tumour-initiating stem cells (BTICs) display resistance to chemotherapy and radiotherapy, contributing to recurrence of brain tumours after therapy and making them a potential therapeutic target. BTICs are driven by both hypoxic and acidic stress, allowing survival in poorly vascularized and necrotic regions of tumours with low glucose levels. Understanding how BTICs react to glucose withdrawal is critical to ellucidate tumour dynamics. A study, led by Jeremy N. Rich, has now shown that glucose restriction can contribute to brain tumour progression by increasing the number of BTICs.

The researchers found that glioblastoma cells isolated from dissociated tumours grown under restricted glucose conditions showed elevated expression of BTIC markers, and flow cytometry confirmed an increase in the percentage of BTIC-derived cells under these conditions. In low glucose conditions, BTICs preferentially survived and surviving non-BTICs showed increased expression of BTIC markers. This has important clinical implications, as Rich explains: “any therapy designed to target TICs will have to take into account that non-TICs can be driven into a TIC-like state by glucose restriction, or potentially other microenvironmental cues.”

The investigators also showed, using an ex vivo glucose uptake assay, that BTICs uptake glucose better than non-BTICs; this was mediated through elevated expression of glucose transporter 3 (GLUT3), a high-affinity isoform of the glucose transporter. Knockdown of GLUT3, using short-hairpin RNAs, decreased growth in BTICs but not in non-BTICs. Rich emphasizes the importance of these findings: “GLUT3 allows the TICs a consistent source of glucose even when environmental levels of glucose fall, so any therapies that attempt to deprive TICs of glucose will probably be unsuccessful if the therapy does not take GLUT3 into account. GLUT3 also correlates strongly with poor survival in patients of many different types of cancer, suggesting that TIC acquisition of GLUT3 is a universal cancer phenomenon that may have great therapeutic potential.”