"The need to minimize metastasis risk is critical because survival times are very low once LMD has occurred. Guided by this principle, pediatric oncologists have designed multimodality treatments, which combine surgery, chemotherapy, and craniospinal radiation [1,2]. These aggressive regimens reduce the risk of metastasis, but they are associated with disabling side effects, including neuropsychiatric challenges, stunted body growth, hormonal imbalance, epilepsy, and stroke in long-term survivors [3-5]. "
[Show abstract][Hide abstract] ABSTRACT: Leptomeningeal dissemination (LMD), the metastatic spread of tumor cells via the cerebrospinal fluid to the brain and spinal cord, is an ominous prognostic sign for patients with the pediatric brain tumor medulloblastoma. The need to reduce the risk of LMD has driven the development of aggressive treatment regimens, which cause disabling neurotoxic side effects in long-term survivors. Transposon-mediated mutagenesis studies in mice have revealed numerous candidate metastasis genes. Understanding how these genes drive LMD will require functional assessment using in vivo and cell culture models of medulloblastoma. We analyzed two genes that were sites of frequent transposon insertion and highly expressed in human medulloblastomas: Arnt (aryl hydrocarbon receptor nuclear translocator) and Gdi2 (GDP dissociation inhibitor 2). Here we show that ectopic expression of Arnt and Gdi2 promoted LMD in mice bearing Sonic hedgehog (Shh)-induced medulloblastomas. We overexpressed Arnt and Gdi2 in a human medulloblastoma cell line (DAOY) and an immortalized, nontransformed cell line derived from mouse granule neuron precursors (SHH-NPD) and quantified migration, invasiveness, and anchorage-independent growth, cell traits that are associated with metastatic competence in carcinomas. In SHH-NPD cells. Arnt and Gdi2 stimulated all three traits. In DAOY cells, Arnt had the same effects, but Gdi2 stimulated invasiveness only. These results support a mechanism whereby Arnt and Gdi2 cause cells to detach from the primary tumor mass by increasing cell motility and invasiveness. By conferring to tumor cells the ability to proliferate without surface attachment, Arnt and Gdi2 favor the formation of stable colonies of cells capable of seeding the leptomeninges.
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The online version of this article (doi:10.1186/s40478-014-0085-y) contains supplementary material, which is available to authorized users.
[Show abstract][Hide abstract] ABSTRACT: The unexpectedly high frequency and universality of alterations to the chromatin machinery is one of the most striking themes emerging from the current deluge of cancer genomics data. Medulloblastoma (MB), a malignant pediatric brain tumor, is no exception to this trend, with a wealth of recent studies indicating multiple alterations at all levels of chromatin processing. MB is typically now regarded as being composed of four major molecular entities (WNT, SHH, Group 3 and Group 4), which vary in their clinical and biological characteristics. Similarities and differences across these subgroups are also reflected in the specific chromatin modifiers that are found to be altered in each group, and each new cancer genome sequence or microarray profile is adding to this important knowledge base. These data are fundamentally changing our understanding of tumor developmental pathways, not just for MB but also for cancer as a whole. They also provide a new class of targets for the development of rational, personalized therapeutic approaches. The mechanisms by which these chromatin remodelers are dysregulated in MB, and the consequences both for future basic research and for translation to the clinic, will be examined here.
[Show abstract][Hide abstract] ABSTRACT: Over time, the systematic evaluation of conventional chemotherapy for the treatment of childhood malignant brain tumors has revealed subtype-specific effectiveness. While having a pivotal role in improving survival for medulloblastoma patients, its activity against other tumors, such as pediatric high-grade glioma, remains disappointing. Today’s clinician faces a dilemma when trying to improve patient outcomes further; escalating traditional treatment is likely to produce only additional morbidity without improving cure, particularly for the very young. The current evolution of genetic and molecular brain tumor research brings with it the hope of establishing novel targeted agents that can either supplement or replace standard chemotherapy to improve patient outcome and minimize toxicity. This article reviews literature from the past year evaluating both conventional chemotherapy and molecular agents for the three most common tumor subgroups; medulloblastoma, glioma (low/high-grade) and ependymoma. Future treatment strategies across North America and Europe are also highlighted.
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