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We read with great interest the recent study by Karaulic et al [...]

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.

The gastrin-releasing peptide receptor (GRPR) is expressed across multiple human cancer types, including head and neck tumors, and has also been detected in the oral mucosa of patients bearing head and neck neoplasms. This study aimed to evaluate GRPR expression in tumor samples obtained from patients with histopathologically confirmed squamous cell carcinomas of the head and neck and esophagus. GRPR protein expression was analyzed by immunohistochemistry in 80 tumor specimens and 10 cancer-free tissue samples. GRPR positivity was observed in 72.5% of tumors, whereas all healthy control samples were negative. Additionally, an expression threshold of 10% was sufficient to distinguish between positive and negative tumors ( P  < 0.0001). Overall survival for the cohort was 64.7%. GRPR expression tends to influence patient outcomes, with an expression level exceeding 50% correlating with worse survival ( p  = 0.031). GRPR is overexpressed in head and neck and esophageal squamous cell carcinoma, and higher expression was associated with worse survival, suggesting a promising role of GRPR as a new biomarker for early diagnosis and prognosis.

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.

Medulloblastoma (MB) is a heterogeneous group of malignant pediatric brain tumors, divided into molecular groups with distinct biological features and prognoses. Currently available therapy often results in poor long-term quality of life for patients, which will be afflicted by neurological, neuropsychiatric, and emotional sequelae. Identifying novel therapeutic agents capable of targeting the tumors without jeopardizing patients' quality of life is imperative. Rosmarinic acid (RA) is a plant-derived compound whose action against a series of diseases including cancer has been investigated, with no side effects reported so far. Previous studies have not examined whether RA has effects in MB. Here, we show RA is cytotoxic against human Daoy (IC50 = 168 μM) and D283 (IC50 = 334 μM) MB cells. Exposure to RA for 48 h reduced histone deacetylase 1 (HDAC1) expression while increasing H3K9 hyperacetylation, reduced epidermal growth factor (EGFR) expression, and inhibited EGFR downstream targets extracellular-regulated kinase (ERK)1/2 and AKT in Daoy cells. These modifications were accompanied by increased expression of CDKN1A/p21, reduced expression of SOX2, and a decrease in proliferative rate. Treatment with RA also reduced cancer stem cell markers expression and neurosphere size. Taken together, our findings indicate that RA can reduce cell proliferation and stemness and induce cell cycle arrest in MB cells. Mechanisms mediating these effects may include targeting HDAC1, EGFR, and ERK signaling, and promoting p21 expression, possibly through an increase in H3K9ac and AKT deactivation. RA should be further investigated as a potential anticancer agent in experimental MB.

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.

Background: Neurotrophins (NTs) are pivotal growth factors in cellular development and survival. Their precise implications in Acute Lymphoblastic Leukemia (ALL) remain unclear. Methods: Pediatric ALL samples (2011–2021) were analyzed from a Southern Brazil cohort. Neurotrophin levels were quantified via ELISA, with survival analysis using Kaplan–Meier curves. Gene expression data were sourced from public genomic repositories and analyzed with R software version 4.0.5. Results: At diagnosis, pro-BDNF, BDNF, and NGF levels were significantly lower than in healthy controls. Reduced pro-BDNF correlated with unfavorable outcomes. NGF and sortilin were highly expressed in healthy samples, while BDNF and p75NTR were predominant in T-ALL and B-ALL, respectively. Conclusions: Neurotrophins show significant alterations in the tumor microenvironment of pediatric ALL. Further studies are needed to elucidate their precise role and prognostic potential.

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.

Changes in epigenetic processes such as histone acetylation are proposed as key events influencing cancer cell function and the initiation and progression of pediatric brain tumors. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (HDACs) and could be repurposed as an epigenetic anticancer therapy. Here, we show that VPA reduced medulloblastoma (MB) cell viability and led to cell cycle arrest. These effects were accompanied by enhanced H3K9 histone acetylation (H3K9ac) and decreased expression of the MYC oncogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers and reduced MYC while increasing TP53 expression in these neurospheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and the increased expression of differentiation marker genes TUBB3 and ENO2. The expression of stemness genes SOX2, NES, and PRTG was differentially affected by VPA in MB cells with different TP53 status. VPA increased H3K9 occupancy of the promoter region of TP53. Among the genes regulated by VPA, the stemness regulators MYC and NES showed an association with patient survival in specific MB subgroups. Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in the modulation of stemness, neuronal differentiation, and the expression of genes associated with patient prognosis in specific molecular subgroups. Importantly, the actions of VPA in MB cells and neurospheres include a reduction in the expression of MYC and an increase in TP53.

Over two-thirds of women with breast cancer have positive tumors for hormone receptors, and these patients undergo treatment with endocrine therapy, tamoxifen being the most widely used agent. Despite being very effective in breast cancer treatment, tamoxifen is associated with side effects that include cognitive impairments. However, the specific aspects and mechanisms underlying these impairments remain to be characterized. Here, we have investigated the effects of tamoxifen and interaction with estrogen receptors on formation of memory for inhibitory avoidance conditioning in female rats. In the first experiment, Wistar female rats received a single oral dose of tamoxifen (1, 3, or 10 mg/kg) or saline by gavage immediately after training and were tested for memory consolidation 24 h after training. In the second experiment, rats received a single dose of 1 mg/kg tamoxifen or saline by gavage 3 h after training and were tested 24 h after training for memory consolidation. In the third experiment, rats received a subcutaneous injection with estrogen receptor α agonist or estrogen receptor beta agonist 30 min before the training. After training, rats received a single oral dose of tamoxifen 1 mg/kg or saline and were tested 24 h after training. In the fourth experiment, rats were trained and tested 24 h later. Immediately after test, rats received a single dose of tamoxifen (1 mg/kg) or saline by gavage and were given four additional daily test trials followed by a re-instatement. Tamoxifen at 1 mg/kg impaired memory consolidation when given immediately after training and the estrogen receptor alpha agonist improved the tamoxifen-related memory impairment. Moreover, tamoxifen impairs memory consolidation of the test. These findings indicate that estrogen receptors regulate the early phase of memory consolidation and the effects of tamoxifen on memory consolidation.