Glioma growth and progression depend on a specialized subpopulation
of tumour cells, termed tumour stem cells. Thus, tumour stem cells
represent a critical therapeutic target, but the molecular mechanisms
that regulate them are poorly understood. Hypoxia plays a key role
in tumour progression and in this study we provide evidence that
the hypoxic tumour microenvironment also controls tumour stem cells.
We define a detailed molecular signature of tumour stem cell genes,
which are overexpressed by tumour cells in vascular and perinecrotic/hypoxic
niches. Mechanistically, we show that hypoxia plays a key role in
the regulation of the tumour stem cell phenotype through hypoxia-inducible
factor 2alpha and subsequent induction of specific tumour stem cell
signature genes, including mastermind-like protein 3 (Notch pathway),
nuclear factor of activated T cells 2 (calcineurin pathway) and aspartate
beta-hydroxylase domain-containing protein 2. Notably, a number of
these genes belong to pathways regulating the stem cell phenotype.
Consistently, tumour stem cell signature genes are overexpressed
in newly formed gliomas and are associated with worse clinical prognosis.
We propose that tumour stem cells are maintained within a hypoxic
niche, providing a functional link between the well-established role
of hypoxia in stem cell and tumour biology. The identification of
molecular regulators of tumour stem cells in the hypoxic niche points
to specific signalling mechanisms that may be used to target the
glioblastoma stem cell population.
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