Abstract
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 β-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.
Highlights
Medulloblastomas (MBs) are highly aggressive and heterogeneous brain tumors of the cerebellum that account for about 20% of pediatric brain cancers (Ramaswamy and Taylor, 2017; Northcott et al, 2019)
Given that Brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway is implicated in the pathogenesis and prognosis of a wide variety of malignancies, including neuroblastoma, glioblastoma, head and neck, breast, lung, and pancreas tumors as well as leukemia, being associated with promotion of proliferation, migration, resistance to anoikis and resistance to chemotherapy (Thiele et al, 2009; Roesler et al, 2011; Radin and Patel, 2017; Meng et al, 2019), here we investigated the potential role of TrkB inhibition in experimental MB
These results indicate that TrkB inhibition reduces viability and proliferation in cell lines representative of different molecular subgroups of MB
Summary
Medulloblastomas (MBs) are highly aggressive and heterogeneous brain tumors of the cerebellum that account for about 20% of pediatric brain cancers (Ramaswamy and Taylor, 2017; Northcott et al, 2019). Integrative genomic and epigenomic studies on MB biology classify this disease into four clinically relevant consensus subgroups: wingless (Wnt), Sonic hedgehog (Shh), group 3, and group 4. The 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System recently acknowledged the molecular subgroups in the classification of MBs, providing clinical utility for the improvement of MB diagnosis (Louis et al, 2016). More recent advancements in deep transcriptional and methylation profiling of 763 primary MB samples revealed new subtypes within each of the four subgroups and further classified MB into 12 subtypes: two Wnt, four Shh, three group 3, and three group 4 subgroups (Cavalli et al, 2017). There is a need for new treatments that can be tolerated in the younger population to treat therapy-resistant disease as well as to decrease potential side effects (Sabel et al, 2016; Northcott et al, 2019)
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