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Achilles’ Heel of Brain Cancer Identified
in Tumor Stem Cells
Few words strike me with more dread than glioblastoma, the name for a very
aggressive, incurable cancer of the brain. Although surgery and chemotherapy
can help hold off or reverse a glioblastoma’s growth for a while, almost
inevitably the tumor comes back along with a terrible prognosis: an average
survival time of 12 to 15 months after diagnosis with a less than 5% survival
rate beyond five years.
MRI scans of glioblastoma in the brain of a 15 year-old boy.
Brain tumor stem cells (BTSCs) are thought to be the culprits behind the
cancer’s reoccurrence because of their stem cell-like ability for limitless selfrenewal. So the idea is that even a tiny number of BTSCs left behind after
treatment will likely to lead to a tumor regrowth and treatment relapse. If
researchers can better understand what makes the BTSCs tick, they could find
ways to eliminate them and cure this dreadful disease.
Brain tumor stem cells (BTSCs)
This week researchers largely from The Ottawa Hospital Research Institute
report on the identification of a key piece of BTSCs’ molecular machinery that
provides a promising target for novel glioblastoma treatments. The study,
published in Nature Neuroscience, focuses on the epidermal growth factor
(EGF) cell signaling pathway. In normal cells, the EGF protein binds to the
EGF receptor (EGFR) on a cell’s surface which triggers a cascade of protein
interactions inside the cell that stimulate cell growth among other things.
EGFRvIII: a cancer stem cell gas pedal stuck to the floorboard
Eventually a given EGF signaling event subsides. But many BTSCs found in
glioblastoma tissue samples have a mutant form of EGFR, called EGFRvIII,
that permanently switches this signaling pathway into the “on position” even in
the absence of EGF. It’s like the gas pedal of a car that gets stuck to the
floorboard, causing the car to dangerously accelerate even though no one is
pressing on the accelerator.
Previous studies had shown this always-on EGFRvIII growth signal causes
abnormally high activation of a messenger protein, STAT3, which in turn hyper
stimulates a network of genes that leads to cancerous growth of the tumor
stem cells. But it wasn’t clear exactly how this protein carries out the
uncontrolled cell division. Through a detailed genetic analysis of BTSCs from
several glioblastoma patient samples, the team zeroed in on the oncostatin M
receptor (OSMR) as a critical player. This analysis revealed that STAT3 was a
natural activator of the OSMR gene and that high levels of both proteins in
patient samples correlated to a poorer prognosis.
No OSMR = no tumors
To investigate further, human BTSCs genetically engineered to lack OSMR
were injected under the skin of mice and showed an 80% reduction in tumor
formation. Injection of similar cells directly into the brains of mice found no
tumor formation when OSMR was absent. In an interview posted by Genetic
Engineering News, senior author Michael Rudnicki recalled his team’s reaction to
this finding:
“Being able to stop tumor formation entirely was a dramatic and stunning result. It
means that this protein is a key piece of the puzzle, and could be a possible target for
future treatments.”
Three proteins form a vicious cycle toward cancerous growth
Additional experiments testing the interactions between EGFRvIII, STAT3 and
OSMR point out where those future treatments should act. Like the screeching
audio feedback you hear when a microphone is held too close to a speaker,
the team showed these three proteins create a self amplifying signal. In the
tumor stem cells, EGFRvIII comes in direct physical contact with OSMR and
together these two proteins act as co-receptors to activate STAT3 which, in
turn, stimulates the production of OSMR which, in turn, stimulates even more
STAT3 production. And so on and so on.
Co-senior author, Azad Bonni, explained how they intend to break up this
vicious cycle while also acknowledging these are very early days for
developing a treatment:
“The next step is to find small molecules or antibodies that can shut down the protein
OSMR or stop it from interacting with EGFR. But any human treatment targeting this
protein is years away.”