A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2α

Abstract

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.

Oct-4+/Tenascin C+ neuroblastoma cells serve as progenitors of tumor-derived endothelial cells

“…This latter finding may be explained by the fact that BM aspiration does not allow to recover the Oct-4 + tumor cells attached to the stroma. Oct-4 + cells from primary tumors and metastatic BM aspirates carried amplification of the MYCN oncogene or expressed the NB84 neuroblastic marker, respectively, and were located predominantly in perivascular areas and at a lower extent in perinecrotic areas, similarly to that reported recently for primary glioma [59].…”

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

“…Currently, a promising way to reactivate hypoxia-inhibited HIPK2 by zinc has provided great opportunities for developing novel therapeutic strategies for human cancer with inactive wt p53 and/or HIPK2. A recent report established the existence of a hypoxic niche that regulates glioblastoma stem cells (Seidel et al, 2010) that contribute to glioma radioresistance and tumor repopulation (Bao et al, 2006). Assuming that hypoxia inhibits HIPK2, it would be interesting to evaluate whether zinc can target glioma stem cells and restore HIPK2/p53 function in response to therapies.…”

Les tumeurs gliales diffuses de l’adulte

“…À l'intérieur même d'une sous-population tumorale, les cellules présentent de façon hétérogène des altérations moléculaires, telles que l'amplification de l'EGFR (points oranges), de la MET (points jaunes), du PDGFR (points verts) ou la méthylation du promoteur de MGMT (points bleus). B. Les différentes sous-populations tumorales expriment des gènes différents en faveur d'un comportement biologique différent [19][20][21][22][23][24][25][26][27][28][29] (voir Glossaire pour définition des abréviations).…”

“…GFAP et pERK [20] Nestine et pAKT [20] ASPHD2, NFE2L2, LAMC1, CD133 [24] ET-1, IL-8 [26] CD133 [19] IGFBP2 et vimentine [21] Autotaxine, éphrine B3, Bcl-w, PTK 2 [21] Hif1, IL-8 [25] E-sélectine [27] Nestine [28] Stéphine B [22] Cathepsines S et L [22] Gènes de la voie Notch [29] …”