ABSTRACT
While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.
Subject(s)
Medulloblastoma/blood supply , Medulloblastoma/pathology , Meningeal Neoplasms/blood supply , Meningeal Neoplasms/secondary , Allografts , Animals , Cell Line, Tumor , Chemokine CCL2/metabolism , Chromosomes, Human, Pair 10/genetics , Female , Humans , Male , Medulloblastoma/genetics , Mice, SCID , Neoplastic Cells, Circulating , ParabiosisABSTRACT
A recent study by Petralia et al. of 218 pediatric brain tumors across seven different entities applied an integrated approach incorporating proteomics, phosphoproteomics, whole-genome sequencing, and RNA sequencing. This elegant study unveiled new signaling pathways, the composition of tumor microenvironments, and functional effects of copy number variants and somatic mutations.
Subject(s)
Brain Neoplasms/genetics , Neoplasm Proteins/genetics , Pediatrics , Proteomics , Brain Neoplasms/pathology , Child , DNA Copy Number Variations/genetics , Humans , Mutation/genetics , Sequence Analysis, RNA , Signal Transduction/genetics , Tumor Microenvironment/genetics , Whole Genome SequencingABSTRACT
Medulloblastoma, neuroblastoma, and pediatric glioma account for almost 30% of all cases of pediatric cancers. Recent evidence indicates that pediatric nervous system tumors originate from stem or progenitor cells and present a subpopulation of cells with highly tumorigenic and stem cell-like features. These cancer stem cells play a role in initiation, progression, and resistance to treatment of pediatric nervous system tumors. Histone modification, DNA methylation, chromatin remodeling, and microRNA regulation display a range of regulatory activities involved in cancer origin and progression, and cellular identity, especially those associated with stem cell features, such as self-renewal and pluripotent differentiation potential. Here, we review the contribution of different epigenetic mechanisms in pediatric nervous system tumor cancer stem cells. The choice between a differentiated and undifferentiated state can be modulated by alterations in the epigenome through the regulation of stemness genes such as CD133, SOX2, and BMI1 and the activation neuronal of differentiation markers, RBFOX3, GFAP, and S100B. Additionally, we highlighted the stage of development of epigenetic drugs and the clinical benefits and efficacy of epigenetic modulators in pediatric nervous system tumors.
Subject(s)
Brain Neoplasms , Glioma , Nervous System Neoplasms , Humans , Child , Epigenome , Glioma/genetics , Glioma/pathology , Brain Neoplasms/pathology , Neoplastic Stem Cells/pathology , Nervous System Neoplasms/genetics , Nervous System Neoplasms/pathologyABSTRACT
The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
Subject(s)
Cerebellar Neoplasms/therapy , Clone Cells/drug effects , Clone Cells/metabolism , Medulloblastoma/therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Selection, Genetic/drug effects , Animals , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/pathology , Cerebellar Neoplasms/radiotherapy , Cerebellar Neoplasms/surgery , Clone Cells/pathology , Craniospinal Irradiation , DNA Mutational Analysis , Disease Models, Animal , Drosophila melanogaster/cytology , Drosophila melanogaster/genetics , Female , Genome, Human/genetics , Humans , Male , Medulloblastoma/genetics , Medulloblastoma/pathology , Medulloblastoma/radiotherapy , Medulloblastoma/surgery , Mice , Molecular Targeted Therapy/methods , Neoplasm Recurrence, Local/therapy , Radiotherapy, Image-Guided , Signal Transduction , Xenograft Model Antitumor AssaysABSTRACT
The aim of the present study was to evaluate the effects of photobiomodulation (PBM) on cytokine levels and angiogenesis during oral wound healing. Ulcers were made on the dorsum of the tongue in 48 Wistar rats. Irradiation with an indium-gallium-aluminum-phosphide (InGaAlP) laser (660 nm; output power, 40 mW; spot size, 0.04 cm(2)) was performed once a day on two points of the ulcer for 14 days. Two different energy densities were used: 4 J/cm(2) (energy per point 0.16 J, total energy 0.32 J) and 20 J/cm(2) (energy per point 0.8 J, total energy 1.6 J). Tissue levels of interleukin (IL)-1ß and tumor necrosis factor (TNF)-α were investigated by enzyme-linked immunosorbent assay (ELISA). Image analysis of CD31-immunostained sections was used to investigate microvessel density (MVD). PBM increased the tissue levels of IL-1ß at the early stage of oral wound healing (p < 0.01) and increased the tissue levels of TNF-α during all stages of oral wound healing (p < 0.05). PBM at a dose of 4 J/cm(2) produced more significant results regarding cytokine modulation and was associated with higher MVD at day 5. Collectively, these findings indicate that cytokine modulation and increased angiogenesis are among the basic mechanisms whereby PBM improves oral wound repair.
Subject(s)
Cytokines/metabolism , Lasers, Semiconductor/therapeutic use , Low-Level Light Therapy , Oral Ulcer/radiotherapy , Wound Healing/radiation effects , Animals , Male , Microvessels/physiopathology , Microvessels/radiation effects , Neovascularization, Physiologic/radiation effects , Oral Ulcer/metabolism , Rats , Rats, Wistar , Tongue/blood supply , Tongue/pathology , Tongue/radiation effectsABSTRACT
Head and neck squamous cell carcinomas (HNSCC) contain a small subpopulation of stem cells endowed with unique capacity to generate tumors. These cancer stem cells (CSC) are localized in perivascular niches and rely on crosstalk with endothelial cells for survival and self-renewal, but the mechanisms involved are unknown. Here, we report that stromal interleukin (IL)-6 defines the tumorigenic capacity of CSC sorted from primary human HNSCC and transplanted into mice. In search for the cellular source of Interleukin-6 (IL-6), we observed a direct correlation between IL-6 levels in tumor-associated endothelial cells and the tumorigenicity of CSC. In vitro, endothelial cell-IL-6 enhanced orosphere formation, p-STAT3 activation, survival, and self-renewal of human CSC. Notably, a humanized anti-IL-6R antibody (tocilizumab) inhibited primary human CSC-mediated tumor initiation. Collectively, these data demonstrate that endothelial cell-secreted IL-6 defines the tumorigenic potential of CSC, and suggest that HNSCC patients might benefit from therapeutic inhibition of IL-6/IL-6R signaling.
Subject(s)
Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Endothelial Cells/metabolism , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/pathology , Interleukin-6/metabolism , Neoplastic Stem Cells/cytology , Animals , Humans , Mice , STAT3 Transcription Factor/metabolism , Signal Transduction/physiology , Squamous Cell Carcinoma of Head and NeckABSTRACT
Effective and less toxic therapies for medulloblastoma have proved to be highly elusive. In this issue of Cancer Cell, Yang et al. show that thyroid hormone treatment leads to the activation of neurogenic differentiation factor 1 (NeuroD1) and differentiation of medulloblastoma cells through reversing EZH2-mediated transcriptional repression of NeuroD1.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors , Cell Differentiation , Cerebellar Neoplasms , Enhancer of Zeste Homolog 2 Protein , Medulloblastoma , Medulloblastoma/pathology , Medulloblastoma/genetics , Medulloblastoma/metabolism , Humans , Enhancer of Zeste Homolog 2 Protein/metabolism , Enhancer of Zeste Homolog 2 Protein/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/genetics , Cerebellar Neoplasms/pathology , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/metabolism , Polycomb Repressive Complex 2/metabolism , Polycomb Repressive Complex 2/genetics , Thyroid Hormones/metabolism , Animals , Gene Expression Regulation, Neoplastic/drug effectsABSTRACT
PURPOSE: Medulloblastoma is the most common malignant childhood brain tumor for which the development of new molecularly targeted therapies is needed. Novel therapeutic targets under investigation include growth factor receptors. Here, we show that the combined inhibition of the epidermal growth factor receptor (EGFR) and neuromedin B receptor (NMBR, BB1) results in increased cell death in human medulloblastoma cell lines. METHODS: DAOY and D283 human medulloblastoma cells were treated with human recombinant neuromedin B (NMB, an NMBR agonist), the NMBR antagonist BIM-23127, the anti-EGFR monoclonal antibody cetuximab, or BIM-23127 combined with cetuximab. Cell death was examined with trypan blue cell counting. RESULTS: Both cell lines expressed mRNA for EGFR, NMB, and NMBR detected by reverse transcriptase polymerase chain reaction. Cetuximab at 10 µg/ml significantly reduced the number of DAOY cells, but did not affect D283 cells. NMB and BIM-23127 did not change cell number when used alone. However, cetuximab, at a dose that did not have an effect by itself, was able to reduce the number of DAOY cells when combined with BIM-23127. CONCLUSION: These results provide preliminary evidence that NMBR blockade can potentiate the antitumor effect of anti-EGFR therapy in medulloblastoma.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents/administration & dosage , Cerebellar Neoplasms/pathology , ErbB Receptors/antagonists & inhibitors , Medulloblastoma/pathology , Peptides, Cyclic/administration & dosage , Receptors, Bombesin/antagonists & inhibitors , Cell Death/drug effects , Cell Line, Tumor , Cetuximab , Drug Synergism , Humans , Medulloblastoma/metabolism , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Medulloblastoma (MB) is the most common primary malignant pediatric brain cancer. We recently identified novel roles for the MEK/MAPK pathway in regulating human Sonic Hedgehog (SHH) MB tumorigenesis. The MEK inhibitor, selumetinib, decreased SHH MB growth while extending survival in mouse models. However, the treated mice ultimately succumbed to disease progression. Here, we perform RNA sequencing on selumetinib-treated orthotopic xenografts to identify molecular pathways that compensate for MEK inhibition specifically in vivo. Notably, the JAK/STAT3 pathway exhibits increased activation in selumetinib-treated tumors. The combination of selumetinib and the JAK/STAT3 pathway inhibitor, pacritinib, further reduces growth in two xenograft models and also enhances survival. Multiplex spatial profiling of proteins in drug-treated xenografts reveals shifted molecular dependencies and compensatory changes following combination drug treatment. Our study warrants further investigation into MEK and JAK/STAT3 inhibition as a novel combinatory therapeutic strategy for SHH MB.
Subject(s)
Cerebellar Neoplasms , Medulloblastoma , Animals , Cerebellar Neoplasms/drug therapy , Cerebellar Neoplasms/genetics , Child , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Humans , Medulloblastoma/drug therapy , Medulloblastoma/genetics , Medulloblastoma/metabolism , Mice , Mitogen-Activated Protein Kinase Kinases/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolismABSTRACT
We report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere.
Subject(s)
Antineoplastic Agents , Brain Neoplasms , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Blood-Brain Barrier , Brain Neoplasms/drug therapy , Mice , Neoplasm Recurrence, Local , ProteomicsABSTRACT
PURPOSE: Histone deacetylase inhibitors (HDACis) are a promising class of anticancer agents for the treatment of brain tumors. HDACis can increase the expression of brain-derived neurotrophic factor (BDNF) in brain cells. We have previously shown that BDNF reduces the viability of medulloblastoma cells. The aim of the present study was to examine the effect of the HDACi sodium butyrate (NaB) combined with human recombinant BDNF (hrBDNF), on the viability of human medulloblastoma cell lines. METHODS: DAOY and ONS76 medulloblastoma cells were treated with NaB, hrBDNF, or NaB combined with hrBDNF. Cell viability was measured with the MTT assay. RESULTS: NaB combined with hrBDNF significantly reduced the viability of DAOY medulloblastoma cells. In ONS76 cells, NaB alone reduced viability, but the effect was not potentiated by hrBDNF. CONCLUSION: These findings provide early evidence for a rationale supporting further evaluation of HDACis and BDNF as a new combinatorial approach to inhibit the growth of medulloblastoma.
Subject(s)
Brain-Derived Neurotrophic Factor/administration & dosage , Butyrates/administration & dosage , Cerebellar Neoplasms/pathology , Histone Deacetylase Inhibitors/administration & dosage , Medulloblastoma/pathology , Butyrates/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Cerebellar Neoplasms/drug therapy , Dose-Response Relationship, Drug , Drug Therapy, Combination , Histone Deacetylase Inhibitors/chemistry , Humans , Medulloblastoma/drug therapyABSTRACT
Personalized therapies have remained elusive in medulloblastoma, resulting in treatment paradigms that have been largely stagnant for almost four decades. A recent study by Rusert and colleagues applies a novel integrated approach to the identification of new targets in medulloblastoma by combining genomics, transcriptomics, and high-throughput drug screening across a panel of molecularly characterized patient-derived models. Actinomysin D, a common chemotherapeutic agent, was identified as highly active in the most aggressive form of medulloblastoma, highlighting the power of this approach over genomic paradigms alone.See related article by Rusert et al.; Cancer Res 80(23):5393-407.
Subject(s)
Cerebellar Neoplasms , Medulloblastoma , Pharmaceutical Preparations , Cerebellar Neoplasms/drug therapy , Cerebellar Neoplasms/genetics , Genomics , Humans , Medulloblastoma/drug therapy , Medulloblastoma/genetics , Precision MedicineABSTRACT
OBJECTIVE: To evaluate the effect of Brazilian propolis on head and neck cancer stem cells in vitro. METHODS: Head and neck squamous cell carcinoma (HNSCC) cell lines (UM-SCC-17B and UM-SCC-74A), human keratinocytes (HK), and primary human dermal microvascular endothelial cells (HDMEC) were treated with 0.5, 5.0, or 50⯵g/mL green, brown or red Brazilian propolis or vehicle control for 24, 36, and 72â¯h. Cell viability was evaluated by Sulforhodamine B assay. Western blots evaluated expression of cancer stem cell (CSC) markers (i.e. ALDH, CD44, Oct-4, Bmi-1) and flow cytometry was performed to determine the impact of propolis in the fraction of CSC, defined as ALDHhighCD44high cells. RESULTS: propolis significantly reduced cell viability of HNSCC and HDMEC cells, but not HK. Notably, red propolis caused a significant reduction in the percentage of CSC, reduced the number of orospheres, and downregulated the expression of stem cell markers. CONCLUSIONS: Collectively, our data demonstrate an anti-CSC effect of propolis, and suggest that propolis (i.e. red propolis) might be beneficial for patients with head and neck cancer.
Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Propolis , Brazil , Carcinoma, Squamous Cell/drug therapy , Cell Line, Tumor , Endothelial Cells , Head and Neck Neoplasms/drug therapy , Humans , Propolis/pharmacology , Squamous Cell Carcinoma of Head and Neck/drug therapyABSTRACT
Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
Subject(s)
Cerebellar Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Hedgehog Proteins/genetics , Medulloblastoma/genetics , Transcriptome , Adolescent , Adult , Child , Child, Preschool , Female , Gene Regulatory Networks , Genetic Variation , Humans , Infant , Male , Middle Aged , Signal Transduction/genetics , Young AdultABSTRACT
Medulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precursors in the developing cerebellum, is the most common malignant brain tumor of childhood. Recurrent and metastatic disease is the principal cause of death and may be related to resistance within cancer stem cells (CSCs). Chromatin state is involved in maintaining signaling pathways related to stemness, and inhibition of histone deacetylase enzymes (HDAC) has emerged as an experimental therapeutic strategy to target this cell population. Here, we observed antitumor actions and changes in stemness induced by HDAC inhibition in MB. Analyses of tumor samples from patients with MB showed that the stemness markers BMI1 and CD133 are expressed in all molecular subgroups of MB. The HDAC inhibitor (HDACi) NaB reduced cell viability and expression of BMI1 and CD133 and increased acetylation in human MB cells. Enrichment analysis of genes associated with CD133 or BMI1 expression showed mitogen-activated protein kinase (MAPK)/ERK signaling as the most enriched processes in MB tumors. MAPK/ERK inhibition reduced expression of the stemness markers, hindered MB neurosphere formation, and its antiproliferative effect was enhanced by combination with NaB. These results suggest that combining HDAC and MAPK/ERK inhibitors may be a novel and more effective approach in reducing MB proliferation when compared to single-drug treatments, through modulation of the stemness phenotype of MB cells.
Subject(s)
Antineoplastic Agents/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Medulloblastoma/metabolism , Neoplastic Stem Cells/drug effects , Protein Kinase Inhibitors/pharmacology , AC133 Antigen/genetics , AC133 Antigen/metabolism , Cell Line, Tumor , Cell Proliferation , Humans , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/physiology , Polycomb Repressive Complex 1/genetics , Polycomb Repressive Complex 1/metabolism , Tumor Cells, CulturedABSTRACT
Neurotrophins are a family of secreted proteins that act by binding to tropomyosin receptor kinase (Trk) or p75NTR receptors to regulate nervous system development and plasticity. Increasing evidence indicates that neurotrophins and their receptors in cancer cells play a role in tumor growth and resistance to treatment. In this review, we summarize evidence indicating that neurotrophin signaling influences medulloblastoma (MB), the most common type of malignant brain cancer afflicting children. We discuss the potential of neurotrophin receptors as new therapeutic targets for the treatment of MB. Overall, activation of TrkA and TrkC types of receptors seem to promote cell death, whereas TrkB might stimulate MB growth, and TrkB inhibition displays antitumor effects. Importantly, we show analyses of the gene expression profile of neurotrophins and their receptors in MB primary tumors, which indicate, among other findings, that higher levels of NTRK1 or NTRK2 are associated with reduced overall survival (OS) of patients with SHH MB tumors.
ABSTRACT
Brain cancers are the leading cause of cancer-related deaths in children. Biological changes in these tumors likely include epigenetic deregulation during embryonal development of the nervous system. Histone acetylation is one of the most widely investigated epigenetic processes, and histone deacetylase inhibitors (HDACis) are increasingly important candidate treatments in many cancer types. Here, we review advances in our understanding of how HDACis display antitumor effects in experimental models of specific pediatric brain tumor types, i.e., medulloblastoma (MB), ependymoma (EPN), pediatric high-grade gliomas (HGGs), and rhabdoid and atypical teratoid/rhabdoid tumors (ATRTs). We also discuss clinical perspectives for the use of HDACis in the treatment of pediatric brain tumors.
ABSTRACT
Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.
Subject(s)
Brain Neoplasms/therapy , Cancer Vaccines/administration & dosage , Cerebrospinal Fluid/drug effects , Ependymoma/therapy , Immunotherapy, Adoptive/methods , Medulloblastoma/therapy , Animals , Brain Neoplasms/cerebrospinal fluid , Brain Neoplasms/immunology , Brain Neoplasms/pathology , Cerebellar Neoplasms/cerebrospinal fluid , Cerebellar Neoplasms/immunology , Cerebellar Neoplasms/pathology , Cerebellar Neoplasms/therapy , Cerebrospinal Fluid/immunology , Child , Child, Preschool , Drug Delivery Systems/methods , Ependymoma/cerebrospinal fluid , Ependymoma/immunology , Ependymoma/pathology , Female , HEK293 Cells , Humans , Infant , Injections, Intraventricular , Male , Medulloblastoma/cerebrospinal fluid , Medulloblastoma/immunology , Medulloblastoma/pathology , Mice , Neoplasm Metastasis , Receptors, Chimeric Antigen/administration & dosage , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/transplantation , Treatment Outcome , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Neurotrophins are critically involved in regulating normal neural development and plasticity. Brain-derived neurotrophic factor (BDNF), a neurotrophin that acts by binding to the tropomyosin receptor kinase B (TrkB) receptor, has also been implicated in the progression of several types of cancer. However, its role in medulloblastoma (MB), the most common type of malignant brain tumor afflicting children, remains unclear. Here we show that selective TrkB inhibition with the small molecule compound ANA-12 impaired proliferation and viability of human UW228 and D283 MB cells, and slowed the growth of MB tumors xenografted into nude mice. These effects were accompanied by increased apoptosis, reduced extracellular-regulated kinase (ERK) activity, increased expression of signal transducer and activator of transcription 3 (STAT3), and differential modulation of p21 expression dependent on the cell line. In addition, MB cells treated with ANA-12 showed morphological alterations consistent with differentiation, increased levels of the neural differentiation marker ß-III Tubulin (TUBB3), and reduced expression of the stemness marker Nestin. These findings are consistent with the possibility that selective TrkB inhibition can display consistent anticancer effects in MB, possibly by modulating intracellular signaling and gene expression related to tumor progression, apoptosis, and differentiation.