Undifferentiated malignant glioma cells in a cross-section of human
brain tissue from the temporal lobe.
By uncovering a secret of tumor stem cell survival, scientists make
progress against a devastating cancer
Malignant glioma is generally a
death sentence for patients. These tumors, which arise from non-neuronal cells
within the brain, grow quickly and aggressively, and contain a core population
of glioma stem cells (GSCs) that are largely invulnerable to the weapons
typically brought to bear against other cancers. “GSCs display resistance to
radiation due to increased activation of DNA damage repair pathways, and also
possess intrinsic resistance mechanisms against chemotherapy-induced cell
death,” explains Prabha Sampath of the A*STAR Institute of Medical Biology.
New work from Sampath and her
co-workers has revealed a potential vulnerability in GSCs that might give
glioma patients a fighting chance1. Her team studies microRNAs, tiny RNA
molecules that do not encode protein; instead, they govern the production of
proteins encoded by other genes. This research has a direct bearing on glioma
progression. “MicroRNA-mediated translational control is known to be a major
factor in brain tumor pathology,” explains Sampath.
She and her colleagues obtained
GSCs from five patients with malignant glioma, and examined how their
expression levels of known microRNAs differed relative to normal neural stem
cells (NSCs). This revealed that GSCs produce markedly higher levels of the
microRNA miR-138; importantly, miR-138 levels dropped when the researchers
chemically forced the GSCs to ‘mature’ into differentiated brain cells,
supporting a role for this RNA in uncontrolled tumor growth.
Treatment with ‘antimiR-138’, a
molecule that selectively blocks the function of miR-138, killed cultured GSCs
but had no effect on normal NSCs. Closer examination revealed that the
inactivation of this microRNA prevented GSCs from undergoing cell division, and
instead caused these cells to undergo a cellular ‘self-destruct’ program.
Subsequent transplantation
experiments indicated that this approach might also yield therapeutic fruit:
mice that received implants of human GSCs promptly developed aggressive
gliomas, but inactivation of miR-138 was sufficient to prevent tumorigenesis.
Finally, the researchers demonstrated that elevated miR-138 expression may be
predictive of disease recurrence in patients with glioblastoma multiforme
(GBM), a typical malignant glioma.
Having established this
previously unrecognized role for miR-138 in ensuring GSC survival, Sampath is
interested in examining whether this microRNA also contributes to progression
and post-therapeutic recurrence of other brain cancers. Even if its influence
is limited to a handful of cancers, the clinical impact of these findings could
prove very significant. “We are currently performing tumor regression
experiments and developing specific vectors for delivery of antimiR-138, with a
vision to exploit this further as a novel therapy for treating malignant
gliomas,” she says.
The A*STAR-affiliated researchers
contributing to this research are from the Institute of Medical Biology
References
- Chan, X. H. D., Nama, S., Gopal, F., Rizk, P.,
Ramasamy, S. et al. Targeting glioma stem cells by functional
inhibition of a prosurvival oncomiR-138 in malignant gliomas. Cell
Reports 2, 591–602 (2012). | article
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