The majority of meningiomas are benign tumors associated with favorable outcomes; however, the less common aggressive variants with unfavorable outcomes often recur and may be due to sub-populations of less-differentiated cells residing within the tumor. These sub-populations of tumor cells have tumor-initiating properties and may be isolated from heterogeneous tumors when sorted or cultured in defined medium. We report the isolation and characterization of a population of tumor-initiating cells derived from an atypical meningioma.

We identify a tumor-initiating population from an atypical meningioma, termed meningioma-initiating cells (MICs). These MICs self-renew, differentiate, and can recapitulate the histological characteristics of the parental tumor when transplanted at 1,000 cells into the flank regions of athymic nude mice. Immunohistochemistry reveals stem-like protein expression patterns similar to neural stem and progenitor cells (NSPCs) while genomic profiling verified the isolation of cancer cells (with defined meningioma chromosomal aberrations) from the bulk tumor. Microarray and pathway analysis identifies biochemical processes and gene networks related to aberrant cell cycle progression, particularly the loss of heterozygosity of tumor suppressor genes CDKN2A (p16INK4A), p14ARF, and CDKN2B (p15INK4B). Flow cytometric analysis revealed the expression of CD44 and activated leukocyte adhesion molecule (ALCAM/CD166); these may prove to be markers able to identify this cell type. The isolation and identification of a tumor-initiating cell population capable of forming meningiomas demonstrates a useful model for understanding meningioma development. This meningioma model may be used to study the cell hierarchy of meningioma tumorogenesis and provide increased understanding of malignant progression.

BACKGROUND

Contemporary therapy for medulloblastoma results in adverse neurocognitive effects on young children, particularly those under the age of three. Stratification of patients by risk group may allow toxic treatment to be avoided.

METHODS

76 patients diagnosed with medulloblastoma and enrolled on CCG-9921 underwent central review of pathology, and histologic subtype was designated as desmoplastic or non-desmoplastic. Non-parametric event-free survival (EFS) and survival (OS) curves were computed using the product limit (Kaplan-Meier) estimates and the log-rank test was used to compare survival according to histologic subtype.

RESULTS

Patients with desmoplastic medulloblastoma experienced a favorable EFS of 77 ± 9% and OS of 85 ± 8% compared to EFS of 17 ± 5% and OS of 29 ± 6% for patients with tumors in the non-desmoplastic group (p < 0.0001 for both EFS and OS comparisons). Patients without disease progression did not receive radiation therapy.

CONCLUSIONS

Children less than three with desmoplastic histology of medulloblastoma represent a lower-risk group for whom reduction of therapy, including elimination of radiation therapy, is an appropriate strategy.

Placement of ventricular reservoirs is a common practice to treat various tumors of the central nervous system (CNS). Ventricular catheter-reservoir-associated edema has been noted in the literature, but a thorough review of this literature identified no articles that examine this particular complication in neurooncology patients, specifically. We report two cases of ventricular catheter-reservoir-associated edema in patients receiving treatment for CNS metastasis.

Purpose

Children with high risk medulloblastoma and non-cerebellar PNET’s were treated on a phase II study of pre-radiotherapy chemotherapy (CHT) followed by high dose, hyperfractionated craniospinal radiotherapy (CSRT). The protocol objectives were to verify feasibility and monitor progression-free (PFS) and overall survival (OS).

Methods and Materials

Eligibility criteria included age >3 years at diagnosis, medulloblastoma with either high M stage and/or >1.5 cm2 post-op residual disease and all patients with non-cerebellar PNET. Treatment was initiated with 5 alternating monthly cycles of CHT [A (cisplatin, cyclophosphamide, etoposide and vincristine, B (carboplatin and etoposide), A, B and A] followed by hyperfractionated CSRT (40 Gy) with a boost to the primary tumor (72 Gy) given in twice daily 1 Gy fractions.

Results

The valid study group consisted of 124 patients whose median age at diagnosis was 7.8 years. Eighty-four (68%) patients completed the entire protocol within the study guidelines of 9 months and the median time to complete CSRT was 1.6 months. Major reasons for failure to complete CHT included progressive disease (17%) and toxic death (2.4%). The 5-year PFS and OS were 43 ± 5% and 52 ± 5%. No significant differences were detected in subset analysis related to response to CHT, site of primary tumor, post-op residual disease or M-stage.

Conclusions

The feasibility of this intensive multi-modality protocol was confirmed and response to pre-RT CHT did not impact on survival. Survival data from this protocol can not be compared to other studies, given the protocol design.

Angiogenesis is a critical step required for sustained tumor growth and tumor progression. The stimulation of endothelial cells by cytokines secreted by tumor cells such as vascular endothelial growth factor (VEGF) induces their proliferation and migration. This is a prominent feature of high-grade gliomas. The secretion of VEGF is greatly upregulated under conditions of hypoxia because of the transcription factor hypoxia-inducible factor (HIF)-1α, which controls the expression of many genes, allowing rapid adaptation of cells to their hypoxic microenvironment. Flavopiridol, a novel cyclin-dependent kinase inhibitor, has been attributed with antiangiogenic properties in some cancer cell lines by its ability to inhibit VEGF production. Here, we show that flavopiridol treatment of human U87MG and T98G glioma cell lines decreases hypoxia-mediated HIF-1α expression, VEGF secretion, and tumor cell migration. These in vitro results correlate with reduced vascularity of intracranial syngeneic GL261 gliomas from animals treated with flavopiridol. In addition, we show that flavopiridol downregulates HIF-1α expression in the presence of a proteasome inhibitor, an agent that normally results in the accumulation and overexpression of HIF-1α. The potential to downregulate HIF-1α expression with flavopiridol treatment in combination with a proteasome inhibitor makes this an extremely attractive anticancer treatment strategy for tumors with high angiogenic activity, such as gliomas.