Neurotrophin Signaling in Medulloblastoma.

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.

Expression and pharmacological inhibition of TrkB and EGFR in glioblastoma.

A member of the Trk family of neurotrophin receptors, tropomyosin receptor kinase B (TrkB, encoded by the NTRK2 gene) is an increasingly important target in various cancer types, including glioblastoma (GBM). EGFR is among the most frequently altered oncogenes in GBM, and EGFR inhibition has been tested as an experimental therapy. Functional interactions between EGFR and TrkB have been demonstrated. In the present study, we investigated the role of TrkB and EGFR, and their interactions, in GBM. Analyses of NTRK2 and EGFR gene expression from The Cancer Genome Atlas (TCGA) datasets showed an increase in NTRK2 expression in the proneural subtype of GBM, and a strong correlation between NTRK2 and EGFR expression in glioma CpG island methylator phenotype (G-CIMP+) samples. We showed that when TrkB and EGFR inhibitors were combined, the inhibitory effect on A172 human GBM cells was more pronounced than when either inhibitor was given alone. When U87MG GBM cells were xenografted into the flank of nude mice, tumor growth was delayed by treatment with TrkB and EGFR inhibitors, given alone or combined, only at specific time points. Intracranial GBM growth in mice was not significantly affected by drug treatments. Our findings indicate that correlations between NTRK2 and EGFR expression occur in specific GBM subgroups. Also, our results using cultured cells suggest for the first time the potential of combining TrkB and EGFR inhibition for the treatment of GBM.

Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma.

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.

Combined Inhibition of HDAC and EGFR Reduces Viability and Proliferation and Enhances STAT3 mRNA Expression in Glioblastoma Cells.

Changes in expression of histone deacetylases (HDACs), which epigenetically regulate chromatin structure, and mutations and amplifications of the EGFR gene, which codes for the epidermal growth factor receptor (EGFR), have been reported in glioblastoma (GBM), the most common and malignant type of brain tumor. There are likely interplays between HDACs and EGFR in promoting GBM progression, and HDAC inhibition can cooperate with EGFR blockade in reducing the growth of lung cancer cells. Here, we found that either HDAC or EGFR inhibitors dose-dependently reduced the viability of U87 and A-172 human GBM cells. In U87 cells, the combined inhibition of HDACs and EGFR was more effective than inhibiting either target alone in reducing viability and long-term proliferation. In addition, HDAC or EGFR inhibition, alone or combined, led to G0/G1 cell cycle arrest. The EGFR inhibitor alone or combined with HDAC inhibition increased mRNA expression of the signal transducer and activator of transcription 3 (STAT3), which can act either as an oncogene or a tumor suppressor in GBM. These data provide early evidence that combining HDAC and EGFR inhibition may be an effective strategy to reduce GBM growth, through a mechanism possibly involving STAT3.

A experiência de mundo de uma surda ao aprender LIBRAS: uma abordagem fenomenológico-existencial / The world experience of a deaf learning LIBRAS: An existential-phenomenological approach / La experiencia en el mundo de una sorda a aprender LIBRAS: Un enfoque fenomenológico-existencial

Frequentemente os diferentes discursos sobre a experiência da surdez partem da perspectiva dos ouvintes, tornando opaca essa vivência tão particular. Esse trabalho pretendeu se aproximar da experiência de se viver no mundo cultural sem a apropriação de uma língua sistematizada. Para tanto, foi realizado um estudo de caso sobre uma surda que aprendeu a Língua Brasileira de Sinais (LIBRAS) já adulta. A coleta de dados deu-se por meio de uma entrevista aberta, mediada por um intérprete voluntário de LIBRAS. A análise da entrevista foi orientada pelo método fenomenológico de investigação de Giorgi e os dados interpretados a partir da perspectiva de Merleau-Ponty. Os resultados foram divididos em dois grupos temáticos: O mundo sem sentido: vazio e solidão e O despertar aos sentidos: "uma nova vida". As vivências anteriores ao domínio de uma língua sistematizada foram descritas como incompreensíveis e vazias, permeadas por dissociações e experiências esparsas. Ao aprender LIBRAS, a entrevistada relata uma mudança brusca na forma como se relacionava com o mundo, começando a perceber sentidos e gestos compartilhados culturalmente. Sugere-se estudos mais aprofundados que investiguem o sensível e a corporeidade na experiência das pessoas surdas. Destaca-se a importância da apropriação da língua sistematizada. (AU)

Different discourses on the experience of deafness frequently start from the perspective of the listeners, which implies an opacity of this very particular experience. This work aims to approximate the experience of living in the cultural world without the appropriation of a systematic language. Thus, was conducted a case study of a deaf who learned the Brazilian Sign Language (LIBRAS) as an adult. Data collection took place through an open interview, mediated by a LIBRAS´s volunteer interpreter. The interview analysis was guided by Giorgi´s phenomenological method of research and the data interpreted from the perspective of Merleau-Ponty. The results were divided into two thematic groups: The meaningless world: emptiness and loneliness and Awakening the senses, "a new life". The experiences lived before mastering a systematic language were described as incomprehensible and empty, permeated by dissociation and sparse experiences. The interviewed reported a sudden change in how she was connected to the world after she had learned LIBRAS, when she begun to realize culture´s shared meanings and gestures. It is suggested further studies that investigate the sensible and corporeal experience of deaf people. It highlights the importance of apprenticeship of a systematic language. (AU)

A menudo, los diferentes discursos sobre la experiencia de la sordera emergen desde la perspectiva de oyentes, tornando opaca esa experiencia tan particular. Este trabajo tiene como objetivo aproximarse de la experiencia de vivir en el mundo cultural sin la apropiación de un lenguaje sistemática. Por lo tanto, se realizó un estudio de caso de una sorda que aprendió la Lengua Brasileña de Señales (LIBRAS) cuando adulta. La recolección de datos se llevó a cabo a través de una entrevista abierta, mediada por un intérprete voluntario. El análisis de las entrevistas fue guiado por el método fenomenológico de Giorgi y los datos interpretados desde la perspectiva de Merleau-Ponty. Los resultados se dividieron en dos grupos temáticos: El mundo sin sentido: vacío y soledad y El despertar de los sentidos, "una nueva vida". Las experiencias anteriores al dominio de un lenguaje sistemática fueran descritas como incomprensibles y vacías, permeadas por disociación y por experiencias dispersas. La entrevistada informó que después del aprendizaje, experimentó un cambio repentino en su relación con el mundo, empezando a darse cuenta de sentidos y gestos compartidos culturalmente. Se sugiere nuevos estudios para investigar la experiencia sensible y corporal de los sordos. Se destaca la importancia de la apropiación del lenguaje sistemática. (AU)

BDNF/TrkB Signaling as a Potential Novel Target in Pediatric Brain Tumors: Anticancer Activity of Selective TrkB Inhibition in Medulloblastoma Cells.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Deregulation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling has been associated with increased proliferative capabilities, invasiveness, and chemoresistance in several types of cancer. However, the relevance of this pathway in MB remains unknown. Here, we show that the selective TrkB inhibitor N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide (ANA-12) markedly reduced the viability and survival of human cell lines representative of different MB molecular subgroups. These findings provide the first evidence supporting further investigation of TrkB inhibition as a potential novel strategy for MB treatment.