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BioRxiv : the Preprint Server For... Jan 2024Neuroblastoma remains a formidable challenge in pediatric oncology, representing 15% of cancer-related mortalities in children. Despite advancements in combinatorial and...
Neuroblastoma remains a formidable challenge in pediatric oncology, representing 15% of cancer-related mortalities in children. Despite advancements in combinatorial and targeted treatments improving survival rates, nearly 50% of patients with high-risk neuroblastoma will ultimately succumb to their disease. Dysregulation of the epithelial-mesenchymal transition (EMT) is a key mechanism of tumor cell dissemination, resulting in metastasis and poor outcomes in many cancers. Our prior work identified PRMT5 as a key regulator of EMT via methylation of AKT at arginine 15, enhancing the expression of EMT-driving transcription factors and facilitating metastasis. Here, we identify that PRMT5 directly regulates the transcription of the epidermal growth factor receptor (EGFR). PRMT5, through independent modulation of the EGFR and AKT pathways, orchestrates the activation of NFκB, resulting in the upregulation of the pro-EMT transcription factors ZEB1, SNAIL, and TWIST1. Notably, EGFR and AKT form a compensatory feedback loop, reinforcing the expression of these EMT transcription factors. Small molecule inhibition of PRMT5 methyltransferase activity disrupts EGFR/AKT signaling, suppresses EMT transcription factor expression and ablates tumor growth . Our findings underscore the pivotal role of PRMT5 in the control of the EMT program in high-risk neuroblastoma.
PubMed: 38260418
DOI: 10.1101/2024.01.03.574104 -
Cellular and Molecular Life Sciences :... Oct 2022The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis....
The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.
Topics: ADAM Proteins; Humans; Integrin alpha Chains; Integrins; Neoplasm Metastasis; Neuroblastoma; Rhabdomyosarcoma
PubMed: 36221013
DOI: 10.1007/s00018-022-04557-y -
Pediatric and Developmental Pathology :... 2022Neuroblastoma (NB) is among the most common cancers in children. A highly aggressive form of cancer, NB relies on cells in the microenvironment for dissemination...
BACKGROUND
Neuroblastoma (NB) is among the most common cancers in children. A highly aggressive form of cancer, NB relies on cells in the microenvironment for dissemination particularly cancer associated fibroblast (CAFs). CAFs synthesise the extracellular matrix to create a scaffold for tumor growth thus enabling the carcinogenesis of NB, Collagen, an abundant scaffold protein produced by CAFs, has been implicated in the creation of an optimal tumor microenvironment, however, the expression profile of collagen within NB is not yet known.
METHODS
We characterised collagen expression within the tumor-stroma boundary by microarray and confirmed by qRT-PCR and immunohistochemistry.
RESULTS
The collagen marker, COL11A1, was also upregulated in NB CD45+ cells and SMA+ CAFs. Furthermore, SMA+ CAFs led to neuroblastoma cell invasion in an in vitro co-culture system which was subsequently attenuated by gene silencing COL11A1. Immunohistochemical staining of clinical tumor samples revealed that high COL11A1 expression in the stroma adjacent to tumour site, significantly associated with advanced cancer stages, age ≥18 months, undifferentiated tumor status, relapse and poor overall survival.
CONCLUSION
Collectively, these results suggest that a COL11A1 signature in the NB microenvironment could represent a novel target for therapeutic intervention.
Topics: Cancer-Associated Fibroblasts; Child; Collagen; Collagen Type XI; Humans; Infant; Neoplasm Recurrence, Local; Neuroblastoma; Tumor Microenvironment
PubMed: 34460335
DOI: 10.1177/10935266211039200 -
International Journal of Environmental... Feb 2021Neuroblastoma is the most common extra-cranial solid tumor in infants and young children, and accounts for approximately 8-10% of all childhood cancers. The...
Neuroblastoma is the most common extra-cranial solid tumor in infants and young children, and accounts for approximately 8-10% of all childhood cancers. The International Neuroblastoma Staging System (The International Neuroblastoma Risk Group Staging System (INRGSS)) is based on the age of patient and preoperative imaging, with attention paid to whether the primary tumor is affected by one or more of specific Image-Defined Risk Factors (IDRFs). Patients are classified into the following groups: locoregional L1 and L2 (absent or present IDRFs respectively), M stage (a disseminated form of neuroblastoma) and Ms (the stage present in children younger than 18 months of age with the disease spread to the bone marrow and/or liver, and/or skin). This publication is aimed to present an unexpected complication associated with an accidental ligation of the celiac trunk during resection of a neuroblastoma tumor in a 2.5-year-old boy after initial chemotherapy, initially with vascular IDRFs, stage L2. The consequences of this complication were pancreatic and spleen ischemia and necrosis, and ischemia and perforation of the common bile duct, gallbladder, stomach, and duodenum. Despite detailed diagnostic imaging (computed tomography, magnetic resonance), the presence of vascular IDRFs may result in an unexpected complication in the surgical treatment of neuroblastoma in children.
Topics: Child; Child, Preschool; Family; Humans; Infant; Magnetic Resonance Imaging; Male; Neoplasm Staging; Neuroblastoma; Risk Factors; Tomography, X-Ray Computed
PubMed: 33672809
DOI: 10.3390/ijerph18041841 -
Journal of Dentistry For Children... Sep 2020Neuroblastoma is a malignant embryonal tumor derived from the neural crest cells of the sympathetic nervous system. Curative therapy is challenging, especially because...
Neuroblastoma is a malignant embryonal tumor derived from the neural crest cells of the sympathetic nervous system. Curative therapy is challenging, especially because early-stage diagnosis in toddlers is difficult. Successful treatment of high-risk neuroblastoma is only achieved in approximately half of the cases and requires an immediate interdisciplinary approach. We present a 34-month-old toddler with swelling of the left side of the face of three days duration and a mandibular mass of unknown duration, which was diagnosed as a metastasis of a neuroblastoma. He also had metastases in the kidney, long bones and skull. Despite the poor prognosis in cases of disseminated skeletal involvement and N-myc amplification, the young patient remained free of recurrence during a follow-up period of 36 months after multidisciplinary treatment. The purpose of this case report is to increase awareness of the clinical features of neuroblastoma among pediatric dentists to support early-stage diagnosis and highlight interdisciplinary management.
Topics: Child, Preschool; Humans; Infant; Male; Neuroblastoma; Prognosis
PubMed: 33349301
DOI: No ID Found -
Biomaterials Science Mar 2021Metastasis is a complex and multifactorial process highly dependent on the interaction between disseminated tumor cells and the pre-metastatic niche. The metastatic...
Metastasis is a complex and multifactorial process highly dependent on the interaction between disseminated tumor cells and the pre-metastatic niche. The metastatic sites detected in the bone of patients affected by neuroblastoma (NB), a malignancy of the developing sympathetic nervous system, are particularly aggressive. To improve our current knowledge of metastatic tumor cell biology and improve treatment success, appropriate in vitro and in vivo models that more closely resemble the native metastatic niche are needed. In this study, the impact of the geometry of synthetic β-tricalcium-phosphate (β-TCP) structures on the interaction of NB tumor cells with the stromal component has been examined. The tumor microenvironment is dynamically shaped by the stroma, which sustains the growth of NB cells inside the metastatic niche. The 3D growth conditions are a determining factor for the cell proliferation rate in β-TCP. With respect to planar counterparts, channeled 3D β-TCP structures stimulate more interleukin-6 and Fibronectin production and define Connexin 43 distribution inside the cells. Together, these results highlight how the biomechanical properties of the 3D microenvironment enable tumor cells to form spheroid-shaped arrangements. This, in turn, facilitates their pro-migratory and pro-invasive patterns and mimics the in vivo situation by translating realistic mechanobiological cues to the metastatic NB.
Topics: Cell Line, Tumor; Cues; Humans; Neuroblastoma; Printing, Three-Dimensional; Tumor Microenvironment
PubMed: 33428699
DOI: 10.1039/d0bm00921k -
Cureus May 2023Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant tumor of neuroectodermal origin that arises from the olfactory epithelium. We...
Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant tumor of neuroectodermal origin that arises from the olfactory epithelium. We present a case of ENB metastasizing through the leptomeningeal route to the spinal dura, which was treated with CyberKnife (CK) stereotactic radiosurgery (SRS), and aim to assess the safety and effectiveness of SRS in such cases. To the best of our knowledge, this is the first case report in the literature that discusses ENB spinal leptomeningeal metastases treated with CK radiosurgery. We retrospectively review the clinical and radiological outcomes in a 70-year-old female with ENB metastasis to the spine. Progression-free survival (PFS), overall survival (OS), and local tumor control (LTC) are investigated. In our patient, ENB had been diagnosed at the age of 58 years and spinal metastases had been first noted at the age of 65 years. A total of six spinal lesions received CK SRS. Lesions were present at the level of C1, C2, C3, C6-C7, T5, and T10-11. The median target volume was 0.72 cc (range: 0.32-2.54). A median marginal dose of 24 Gy was delivered to the tumors with a median of three fractions to a median isodose line of 80% (range: 78-81). LTC at the 24-month follow-up was 100%. PFS and OS were 27 months and 40 months, respectively. No adverse radiation effects were reported. Even though the treated spinal lesions remained stable, the number of new metastatic lesions had increased with progressive osseous and dural metastatic lesions within the cervical, thoracic, and lumbar spine at the last follow-up. SRS provides relatively good LTC for patients with ENB metastasizing to the spine, with no radiation-induced adverse events.
PubMed: 37398775
DOI: 10.7759/cureus.39791 -
JCO Clinical Cancer Informatics Jan 2021Prognosis of high-risk neuroblastoma (HRNB) remains poor despite multimodal therapies. Better prediction of survival could help to refine patient stratification and...
Prognosis of high-risk neuroblastoma (HRNB) remains poor despite multimodal therapies. Better prediction of survival could help to refine patient stratification and better tailor treatments. We established a mechanistic model of metastasis in HRNB relying on two processes: growth and dissemination relying on two patient-specific parameters: the dissemination rate μ and the minimal visible lesion size S. This model was calibrated using diagnosis values of primary tumor size, lactate dehydrogenase circulating levels, and the meta-iodobenzylguanidine International Society for Paediatric Oncology European (SIOPEN) score from nuclear imaging, using data from 49 metastatic patients. It was able to describe the data of total tumor mass (lactate dehydrogenase, R > 0.99) and number of visible metastases (SIOPEN, R = 0.96). A prediction model of overall survival (OS) was then developed using Cox regression. Clinical variables alone were not able to generate a model with sufficient OS prognosis ability ( = .507). The parameter μ was found to be independent of the clinical variables and positively associated with OS ( = .0739 in multivariable analysis). Critically, addition of this computational biomarker significantly improved prediction of OS with a concordance index increasing from 0.675 (95% CI, 0.663 to 0.688) to 0.733 (95% CI, 0.722 to 0.744, < .0001), resulting in significant OS prognosis ability ( = .0422).
Topics: Child; Humans; Models, Theoretical; Neuroblastoma; Prognosis
PubMed: 33439729
DOI: 10.1200/CCI.20.00092 -
World Neurosurgery Feb 2020Olfactory neuroblastoma (ON) is a highly aggressive and locally recurrent neoplasm. Distant systemic metastases are not uncommon, but remote leptomeningeal dissemination...
BACKGROUND
Olfactory neuroblastoma (ON) is a highly aggressive and locally recurrent neoplasm. Distant systemic metastases are not uncommon, but remote leptomeningeal dissemination is extremely rare.
CASE DESCRIPTION
We report 2 cases of ON previously treated with endoscopic endonasal radical surgical resection and radiotherapy. After a relatively long period of disease-free survival, multiple leptomeningeal lesions were seen around the sagittal sinus giving a radiologic appearance of parasagittal meningiomas. Both patients underwent surgery and multimodal treatment with radiotherapy and chemotherapy for the disseminated disease. Pathologic examination confirmed the parasagittal lesions as metastatic ON.
CONCLUSIONS
A high suspicion of secondary disease should be maintained in patients with previous history of ON and parasagittal leptomeningeal enhancing lesion, particularly when multiple lesions are detected around the sagittal sinus. Radical resection and multimodal treatment are warranted to improve long-term outcome. Understanding the venous drainage route as a potential pathway for remote seeding from the primary site of disease has therapeutic implications. We postulate that en-bloc tumor resection and proximal sagittal sinus ligation might reduce potential for leptomeningeal metastasis.
Topics: Adult; Diagnosis, Differential; Esthesioneuroblastoma, Olfactory; Humans; Male; Meningeal Carcinomatosis; Meningeal Neoplasms; Meningioma; Middle Aged; Nasal Cavity; Nose Neoplasms; Superior Sagittal Sinus
PubMed: 31734430
DOI: 10.1016/j.wneu.2019.11.042 -
Medical Hypotheses Mar 2020Although frequently disseminated to other anatomical sites, neuroblastoma (NB) is rarely reported as involving the central nervous system (CNS), which may reflect...
Although frequently disseminated to other anatomical sites, neuroblastoma (NB) is rarely reported as involving the central nervous system (CNS), which may reflect insufficient research in poorly controlled systemic disease. Here we demonstrate the involvement of the CNS in patients with NB over 18 months of age at diagnosis of extensive systemic disease. Meningeal metastases were observed even in the presence of complete systemic control. Although no improvement in patient's survival was observed, radiotherapy was effective in preventing CNS recurrence after observation of actual or previous dural disease. In conclusion, this study uncovered the uncommon pathologic involvement of the CNS in children with advanced NB and underscores the meningeal surface as a potential pathway for this to occur.
Topics: Central Nervous System; Child, Preschool; Humans; Infant; Meningeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neuroblastoma; Prospective Studies; Radiotherapy; Skull Neoplasms; Treatment Outcome
PubMed: 31778890
DOI: 10.1016/j.mehy.2019.109479