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Glioblastoma is driven by two distinct subsets of cancer stem cells

A new study published in Nature Medicine demonstrates, for the first time, that glioblastoma (GBM), the most common and most lethal brain tumour, is driven by two distinct subsets of cancer stem cells.

Moreover, each subtype of glioma stem cells is driven by distinct transcriptional programmes for growth and treatment resistance, and these different cell populations correspond to well-known morphological differences within the GBM itself.

More importantly, the researchers found that while chemotherapeutic agents targeting each subtype achieve modest efficacy alone, they are synergistic when combined as demonstrated in a mouse model.

Senior co-author of the study, Andrew Sloan, MD, Medical Director, Brain Tumour and Neuro-Oncology Center at University Hospitals Cleveland Medical Center, observed that GBMs typically have two radiologically distinct regions on MRI: The enhancing mass and the necrotic core.

He noted, "We hypothesised that the different parts of the tumour might respond differently to treatment. Our findings are consistent with this hypothesis."

Even the best surgeons can only remove the entire tumour about 75 percent of the time, according to Dr. Sloan. Therefore, it is essential to learn more about the mechanisms for tumour growth and how the chemo agents can inhibit the pathways for growth.

Dr. Sloan said, "The enhancing edge and the invading tumour are driven by glioma stem cells (GSCs) dependent on the EZH2 pathway. They are driven by stem cells with the proneural pattern of gene expression and depend on rapid cell division and angiogenesis--creation of new blood vessels.

"Conversely, the necrotic part of the tumour is driven by a distinct set of glioma stem cells utilising the BIM1 pathway and are characterised by a mesenchymal, inflammatory cell type dependent on glucose metabolism in the absence of oxygen.

"Inhibition of the EZH2 pathway slows growth of tumours in mouse brain derived from glioma stem cells from the enhancing margin of human tumours. Conversely, BIM1 inhibitors inhibit growth of mouse brain tumours derived from human glioma stem cells derived from the necrotic core of brain tumours in mice

Dr. Sloan said that since a single tumour may contain different pools of glioma stem cells, combined targeting should be considered for the pathways and stem cells.

Source: University Hospitals Cleveland Medical Center



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