Glioblastoma multiforme (GBM) are highly proliferative tumors currently treated by surgical removal, followed by radiotherapy and chemotherapy, which are counteracted by intratumoral hypoxia. Here we exploited image guided surgery to sample multiple intratumoral areas to define potential cellular heterogeneity in correlation to the oxygen tension gradient within the GBM mass. Our results indicate that more immature cells are localized in the inner core and in the intermediate layer of the tumor mass, whereas more committed cells, expressing glial fibrillary acidic protein and b-III-tubulin, are distributed along the peripheral and neo-vascularized area, where Smad1/5/8 and Stat3 result to be activated. Moreover, GBM stem cells, identified with the stem cell marker CD133, express high level of DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT) known to be involved in chemotherapy resistance and highly expressed in the inner core of the tumor mass. Importantly, these cells and, particularly, CD133 1 cells result to be resistant to temozolomide (TMZ), the most used oral alkylating agent for the treatment of GBM, which specifically causes apoptosis only in GBM cells derived from the peripheral layer of the tumor mass. These results indicate a correlation between the intratumoral hypoxic gradient, the tumor cell phenotype, and the tumor resistance to chemotherapy leading to a novel concentric model of tumor stem cell niche, which may be useful to define the real localization of the chemoresistant GBM tumor cells in order to design more effective treatment strategies. STEM CELLS 2010; 28:851-862Disclosure of potential conflicts of interest is found at the end of this article.
Hypoxia commonly occurs in solid tumors of the central nervous system (CNS) and often interferes with therapies designed to stop their growth. We found that pediatric high-grade glioma (HGG)-derived precursors showed greater expansion under lower oxygen tension, typical of solid tumors, than normal CNS precursors. Hypoxia inhibited p53 activation and subsequent astroglial differentiation of HGG precursors. Surprisingly, although HGG precursors generated endogenous bone morphogenetic protein (BMP) signaling that promoted mitotic arrest under high oxygen tension, this signaling was actively repressed by hypoxia. An acute increase in oxygen tension led to Smad activation within 30 minutes, even in the absence of exogenous BMP treatment. Treatment with BMPs further promoted astroglial differentiation or death of HGG precursors under high oxygen tension, but this effect was inhibited under hypoxic conditions. Silencing of hypoxia-inducible factor 1␣ (HIF1␣) led to Smad activation even under hypoxic conditions, indicating that HIF1␣ is required for BMP repression. Conversely, BMP activation at high oxygen tension led to reciprocal degradation of HIF1␣; this BMP-induced degradation was inhibited in low oxygen. These results show a novel, mutually antagonistic interaction of hypoxia-response and neural differentiation signals in HGG proliferation, and suggest differences between normal and HGG precursors that may be exploited for pediatric brain cancer therapy.
Medulloblastoma (MDB) is the most common brain malignancyof childhood. It is currently thought that MDB arises from aberrantly functioning stem cells in the cerebellum that fail to maintain proper control of self-renewal. Additionally, it has been reported that MDB cells display higher endogenous Notch signaling activation, known to promote the survival and proliferation of neoplastic neural stem cells and to inhibit their differentiation. While interaction between Hypoxia Inducible Factor-1α (HIF-1α) and Notch signalling is required to maintain normal neural precursors in an undifferentiated state, an interaction has not been identified in MDB. Here we investigate whether hypoxia, through HIF-1α stabilization, modulates Notch1 signaling in primary MDB-derived cells. Our results indicate that MDB-derived precursor cells require hypoxic conditions for in vitro expansion, whereas acute exposure to 20% oxygen induces tumor cell differentiation and death through inhibition of Notch signaling. Importantly, stimulating Notch1 activation with its ligand Dll4 under hypoxic conditions leads to expansion of MDB-derived CD133+ and nestin+ precursors, suggesting a regulatory effect on stem cells. In contrast, MDB cells undergo neuronal differentiation when treated with γ-secretase inhibitor, which prevents Notch activation. These results suggest that hypoxia, by maintaining Notch1 in its active form, preserves MDB stem cell viability and expansion.
The peculiar radiological and pathological findings of four pediatric cases admitted to the University Hospital of Padua between 1990 and 2007 are described. In all cases, the contrast-enhanced head and spine magnetic resonance images revealed thickened and abnormally enhancing subarachnoid spaces particularly at the level of basal cisterns and interhemispheric fissure. Furthermore, small cystic lesions scattered throughout the brain and mainly in the cerebellum were also visible. All patients were missing a well-defined intraparenchymal mass, although during the follow-up a small intramedullary lesion appeared within the cervical spine in two and subsequently in the frontal horn of the left lateral ventricle in one of those. All patients presented an indolent long-term follow-up. Histologically, the tumors were composed by a monotonous population of cells arranged in straight lines or in small lobules. The cells were characterized by round to oval nuclei with finely granular dispersed chromatin, inconspicuous nucleoli with oligodendrocyte-like features. The morphological and immunohistochemical findings suggested in all cases a "glioneuronal commitment" of the tumors. Because of the unique similar clinical and neuroradiological characteristics, we propose this small series of tumors as a new possible distinct pathological and clinical entity.
To characterize some of the short-term and long-term functional consequences of subarachnoid hemorrhage (SAH) in rats, we employed a battery of well-characterized tests for assessment of acute and chronic behavioral and neurologic performances. Three groups of 10 rats (blood injected, mock CSF injected and sham-operated controls) were studied. During the acute stage, simple nonpostural somatomotor reflexes (pinna and corneal reflexes), simple postural responses (paw flexion, tail flexion, and head support), startle response, and postural functions (righting reflex) did not differ significantly between the experimental groups. Assessments of body weight, beam walking ability, and beam balancing revealed significant disturbances in blood-injected rats. This work demonstrates that this single-hemorrhage rodent model of SAH is associated with the induction of enduring neurologic and behavioral deficits. Because of the significant interspecies difference, a direct extrapolation of our results to humans may not be appropriate. However, we suggest that the observed behavioral and neurologic changes may parallel those seen in humans after SAH. Results reported here further confirm the rat model of SAH as a viable laboratory instrument for the study of the pathophysiology of SAH and provide normative values for the evaluation of new treatment modalities.
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