A. Della Puppa

BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1α stability and MGMT expression.

Glioblastoma multiforme (GBM) is the most common brain tumour, characterized by a central and partially necrotic (i.e., hypoxic) core enriched in cancer stem cells (CSCs). We previously showed that the most hypoxic and immature (i.e., CSCs) GBM cells were resistant to Temozolomide (TMZ) in vitro, owing to a particularly high expression of O6-methylguanine-DNA-methyltransferase (MGMT), the most important factor associated to therapy resistance in GBM. Bone morphogenetic proteins (BMPs), and in particular BMP2, are known to promote differentiation and growth inhibition in GBM cells. For this reason, we investigated whether a BMP2-based treatment would increase TMZ response in hypoxic drug-resistant GBM-derived cells. Here we show that BMP2 induced strong differentiation of GBM stem-like cells and subsequent addition of TMZ caused dramatic increase of apoptosis. Importantly, we correlated these effects to a BMP2-induced downregulation of both hypoxia-inducible factor-1α (HIF-1α) and MGMT. We report here a novel mechanism involving the HIF-1α-dependent regulation of MGMT, highlighting the existence of a HIF-1α/MGMT axis supporting GBM resistance to therapy. As confirmed from this evidence, over-stabilization of HIF-1α in TMZ-sensitive GBM cells abolished their responsiveness to it. In conclusion, we describe a HIF-1α-dependent regulation of MGMT and suggest that BMP2, by down-modulating the HIF-1α/MGMT axis, should increase GBM responsiveness to chemotherapy, thus opening the way to the development of future strategies for GBM treatment.

Wnt activation promotes neuronal differentiation of Glioblastoma

One of the biggest challenges in tumour research is the possibility to reprogram cancer cells towards less aggressive phenotypes. In this study, we reprogrammed primary Glioblastoma multiforme (GBM)-derived cells towards a more differentiated and less oncogenic phenotype by activating the Wnt pathway in a hypoxic microenvironment. Hypoxia usually correlates with malignant behaviours in cancer cells, but it has been recently involved, together with Wnt signalling, in the differentiation of embryonic and neural stem cells. Here, we demonstrate that treatment with Wnt ligands, or overexpression of β-catenin, mediate neuronal differentiation and halt proliferation in primary GBM cells. An hypoxic environment cooperates with Wnt-induced differentiation, in line with our finding that hypoxia inducible factor-1α (HIF-1α) is instrumental and required to sustain the expression of β-catenin transcriptional partners TCF-1 and LEF-1. In addition, we also found that Wnt-induced GBM cell differentiation inhibits Notch signalling, and thus gain of Wnt and loss of Notch cooperate in the activation of a pro-neuronal differentiation program. Intriguingly, the GBM sub-population enriched of cancer stem cells (CD133+ fraction) is the primary target of the pro-differentiating effects mediated by the crosstalk between HIF-1α, Wnt, and Notch signalling. By using zebrafish transgenics and mutants as model systems to visualize and manipulate in vivo the Wnt pathway, we confirm that Wnt pathway activation is able to promote neuronal differentiation and inhibit Notch signalling of primary human GBM cells also in this in vivo set-up. In conclusion, these findings shed light on an unsuspected crosstalk between hypoxia, Wnt and Notch signalling in GBM, and suggest the potential to manipulate these microenvironmental signals to blunt GBM malignancy.

Haemorrhagic presentation of low-grade glioma in adults.

SummaryIntracranial bleeding is rare in patients with low-grade gliomas, above all in adult population. We reviewed the literature of such cases and reported another case of a haemorrhagic low-grade glioma in a 54-year-old woman presenting with a left hemiparesis. Computer tomography (CT) images showed a right basal ganglia haemorrhage with no mass effect. Vascular malformations were ruled out by angiography. Eighteen fluoro–fluoro deossiglucosio (18F-FDG) positron emission tomography (PET/CT) showed a large hypometabolic area corresponding to the lesion. We waited for patient’s improvement. Late magnetic resonance images revealed a low-grade glioma at the bleeding site. Tumour was removed and histopathologic examination revealed a WHO grade II mixed glioma.The authors emphazise that this evidence has to be kept in mind since it has important therapeutic implications.

A retrospective study analyzing the association between tumor response (TR) according to Mcdonald criteria (MC) on MRI and survival (OS) in patients (PTS) with glioblastoma (GBM) treated with antiangiogenic drugs (AD).

e12514 Background: In high-grade gliomas, MC using two-dimensional measurement is the most widely used method for assessing TR to treatment on MRI. With the recent introduction of AD that affect the permeability of tumor vasculature there are many doubts about the validity of MC mainly due to the probability of having a pseudo-response. We analyzed PTS treated with AD to evaluate the association between TR according to MC and survival (OS) (from antiangiogenic treatment to death). METHODS Retrospectively, we examined 48 consecutive PTS with GBM treated with AD: bevacizumab (20 PTS), sorafenib (27 PTS) and cilengitide (1 PT). All patients underwent MRI assessments according to MC every two months or when clinically indicated. Univariate and multivariate analyses of patient, disease and therapy characteristics were used to identify factors predicting OS. RESULTS 13 (27.1%) and 35 PTS (72.9%) performed an AD as third or second line chemotherapy, respectively. 5 PTS performed a subsequent therapy after progression during antiangiogenic treatment. Median age was 55.1, ECOG performance status (PS) was 0 in 8 PTS, 1 in 19 PTS, 2 in 18 PTS and 3 in 3 PTS. After two months of treatment 25 PTS (52.1%) obtained a disease control (DC): stable disease (22 PTS) or partial response (3 PTS). 23 PTS (47.9%) obtained a progression disease. The median OS for all PTS was 6.2 months (CI 95% 4.9 - 7.6); the median time-to-progression from AD was 2.5 months. According to univariate analysis, good PS and DC were related to a longer OS (p=0.006 and 0.01, respectively). On multivariate analysis the same variables were found to be independent favourable predictors for OS: good PS (p=0.05; HR=0.08, CI 95% 0.01-0.5) and DC (p=0.02; HR=0.4, CI 95% 0.2-0.8). CONCLUSIONS PTS with a good PS and DC on MRI according to MC after two months of antiangiogenic treatment have a better chance of prolonged OS. MC might be a valid method to assess the effectiveness of AD, especially in clinical trials.

Venous stroke can be the unusual clinical presentation of an arising naso-ethmoidal encephalo-meningocele in adulthood.

Trans-ethmoidal encephalo-meningocele is an extremely rare event among the adult population. It mainly affects young people who have previously reported a head injury. Even though early treatment is mandatory to avoid septic complications, the diagnosis is usually late because of the misleading symptomatology. We describe the unusual clinical history of an adult patient with a giant trans-ethmoidal encephalo-meningocele. A 61-year-old woman presented progressively more intense headache and rhinorrhea. No trauma was reported. We learned that she had a history of misunderstood spontaneous rhinorrhea beginning two years before, followed one year later by a lateral sinus thrombosis which worsened the cerebrospinal fluid leakage. Some months after stroke a new cerebral magnetic resonance scan revealed a giant trans-ethmoidal encephalo-meningocele. The brain herniation was surgically removed by a subfrontal intradural approach through a frontal craniotomy. Even rare, giant naso-ethmoidal encephalo-meningocele has to be considered in adult patients presenting with rhinorrhea even without a history of meningitis or neurological defects. Venous stroke can affect patients in whom prolonged CSF leakage occurs because of misunderstood cerebrospinal fistula. These patients must be monitored after stroke for the possible onset of an encephalo-meningocele.

Transverse sinus thrombosis after posterior fossa surgery for cerebellar tumor treated by endovascular thrombectomy. A case report.

Dural sinus thrombosis is a rare complication after posterior fossa surgery, particularly in cerebellar tumour surgery. The authors describe the case of a young male patient who presented a postoperative neurological deterioration due to transverse sinus thrombosis after surgery for cerebellar medulloblastoma. He was treated by mechanical clot thrombectomy using an endovascular catch system technique without anticoagulation therapy. Final angiographic recanalization was obtained. This kind of endoluminal mechanical revascularization is an efficacious method to treat dural sinus thrombosis during perioperative time but speed in diagnosis is crucial for clinical outcome.