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Polish Journal of Pathology : Official... 2018The last 25 years have brought significant progress in the treatment of sarcomas in children, especially rhabdomyosarcoma (RMS). Nevertheless, treatment failure in some... (Review)
Review
The last 25 years have brought significant progress in the treatment of sarcomas in children, especially rhabdomyosarcoma (RMS). Nevertheless, treatment failure in some patients results from considerable biological heterogeneity noted in these tumours. RMS, the most common malignant soft tissue neoplasm in children, includes two main subtypes: embryonal (ERMS) and alveolar (ARMS). Due to greater aggressiveness and worse prognosis of ARMS in comparison to ERMS, discrimination between different rhabdomyosarcoma subtypes is of crucial clinical importance. This paper presents the current histological classification of RMS, up-to-date immunohistochemical and biological research regarding RMS, and its associated clinical and prognostic significance.
Topics: Age of Onset; Biomarkers, Tumor; Biopsy; Child; Diagnosis, Differential; Humans; Immunohistochemistry; Molecular Diagnostic Techniques; Neoplasm Staging; Predictive Value of Tests; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal; Terminology as Topic
PubMed: 29895123
DOI: 10.5114/pjp.2018.75333 -
Head and Neck Pathology Mar 2020Skeletal muscle tumors are classified into rhabdomyoma and embryonal, alveolar, spindle cell/sclerosing and pleomorphic rhabdomyosarcoma according to WHO classifications... (Review)
Review
Skeletal muscle tumors are classified into rhabdomyoma and embryonal, alveolar, spindle cell/sclerosing and pleomorphic rhabdomyosarcoma according to WHO classifications of tumors. These tumors arise mostly in the head and neck and, in childhood, represent the largest subset of soft tissue tumors. Although these skeletal muscle tumors show common immunoexpression of two myogenic regulatory factors, MyoD1 and myogenin, their molecular biological backgrounds are quite different. Therefore, treatment regimens vary a great deal depending on the histological subtype. Histopathologically, rhabdomyoma is characterized by well-demarcated lesions with no invasion of the surrounding tissue. Embryonal rhabdomyosarcoma is composed of primitive mesenchymal cells in various stages of myogenesis and shows heterogeneous nuclear staining for myogenin. Alveolar rhabdomyosarcoma, on the other hand, shows a proliferation of uniform primitive round cells arranged in alveolar patterns. The tumor cells at the periphery of alveolar structures adhere in a single layer to the fibrous septa. Diffuse and strong nuclear immunoexpression for myogenin is observed. In genetic backgrounds, almost all alveolar rhabdomyosarcomas contain a characteristic fusion gene such as PAX3/7-FOXO1. Spindle cell/sclerosing rhabdomyosarcoma is characterized by fascicularly arranged spindle-shaped cells or dense hyalinized collagenous matrix. NCOR2- or VGLL2-related gene fusions or MYOD1 (p.L122R) mutation is commonly recognized. Epithelioid rhabdomyosarcoma is a rare variant of rhabdomyosarcoma that shows a proliferation of epithelioid tumor cells having large vesicular nuclei, prominent nucleoli, and amphophilic to eosinophilic cytoplasm arranged in sheets. As these characteristic histological and molecular features are present in each subtype, it is possible to diagnose skeletal muscle tumors accurately.
Topics: Humans; Neoplasms, Muscle Tissue; Soft Tissue Neoplasms
PubMed: 31950473
DOI: 10.1007/s12105-019-01113-2 -
Molecular Therapy : the Journal of the... Sep 2023Rhabdomyosarcoma is the most common pediatric soft tissue tumor, comprising two major subtypes: the PAX3/7-FOXO1 fusion-negative embryonal and the PAX3/7-FOXO1...
Rhabdomyosarcoma is the most common pediatric soft tissue tumor, comprising two major subtypes: the PAX3/7-FOXO1 fusion-negative embryonal and the PAX3/7-FOXO1 fusion-positive alveolar subtype. Here, we demonstrate that the expression levels of the transcriptional repressor TRPS1 are specifically enhanced in the embryonal subtype, resulting in impaired terminal myogenic differentiation and tumor growth. During normal myogenesis, expression levels of TRPS1 have to decrease to allow myogenic progression, as demonstrated by overexpression of TRPS1 in myoblasts impairing myotube formation. Consequentially, myogenic differentiation in embryonal rhabdomyosarcoma in vitro as well as in vivo can be achieved by reducing TRPS1 levels. Furthermore, we show that TRPS1 levels in RD cells, the bona fide model cell line for embryonal rhabdomyosarcoma, are regulated by miR-1 and that TRPS1 and MYOD1 share common genomic binding sites. The myogenin (MYOG) promoter is one of the critical targets of TRPS1 and MYOD1; we demonstrate that TRPS1 restricts MYOG expression and thereby inhibits terminal myogenic differentiation. Therefore, reduction of TRPS1 levels in embryonal rhabdomyosarcoma might be a therapeutic approach to drive embryonal rhabdomyosarcoma cells into myogenic differentiation, thereby generating postmitotic myotubes.
Topics: Humans; Child; Rhabdomyosarcoma, Embryonal; Myogenin; Cell Differentiation; MicroRNAs; Muscle Development; Cell Line, Tumor; Repressor Proteins
PubMed: 37452493
DOI: 10.1016/j.ymthe.2023.07.003 -
Molecular Cancer Oct 2022Chimeric fusion transcription factors are oncogenic hallmarks of several devastating cancer entities including pediatric sarcomas, such as Ewing sarcoma (EwS) and...
Chimeric fusion transcription factors are oncogenic hallmarks of several devastating cancer entities including pediatric sarcomas, such as Ewing sarcoma (EwS) and alveolar rhabdomyosarcoma (ARMS). Despite their exquisite specificity, these driver oncogenes have been considered largely undruggable due to their lack of enzymatic activity.Here, we show in the EwS model that - capitalizing on neomorphic DNA-binding preferences - the addiction to the respective fusion transcription factor EWSR1-FLI1 can be leveraged to express therapeutic genes.We genetically engineered a de novo enhancer-based, synthetic and highly potent expression cassette that can elicit EWSR1-FLI1-dependent expression of a therapeutic payload as evidenced by episomal and CRISPR-edited genomic reporter assays. Combining in silico screens and immunohistochemistry, we identified GPR64 as a highly specific cell surface antigen for targeted transduction strategies in EwS. Functional experiments demonstrated that anti-GPR64-pseudotyped lentivirus harboring our expression cassette can specifically transduce EwS cells to promote the expression of viral thymidine kinase sensitizing EwS for treatment to otherwise relatively non-toxic (Val)ganciclovir and leading to strong anti-tumorigenic, but no adverse effects in vivo. Further, we prove that similar vector designs can be applied in PAX3-FOXO1-driven ARMS, and to express immunomodulatory cytokines, such as IL-15 and XCL1, in tumor entities typically considered to be immunologically 'cold'.Collectively, these results generated in pediatric sarcomas indicate that exploiting, rather than suppressing, the neomorphic functions of chimeric transcription factors may open inroads to innovative and personalized therapies, and that our highly versatile approach may be translatable to other cancers addicted to oncogenic transcription factors with unique DNA-binding properties.
Topics: Antigens, Surface; Cell Line, Tumor; Child; DNA; Ganciclovir; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Interleukin-15; Oncogene Proteins, Fusion; Proto-Oncogene Protein c-fli-1; RNA-Binding Protein EWS; Sarcoma; Sarcoma, Ewing; Thymidine Kinase
PubMed: 36229873
DOI: 10.1186/s12943-022-01641-6 -
Journal of the National Cancer Institute Jun 2023Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification....
BACKGROUND
Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with RMS.
METHODS
The study included 920 individuals with newly diagnosed RMS who were enrolled in Children's Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards models, adjusted for clinical covariates. All statistical tests were two sided. We also performed stratified analyses by histological subtype (alveolar and embryonal RMS) and carried out sensitivity analyses of statistically significant SNPs by PAX3/7-FOXO1 fusion status and genetic ancestry group.
RESULTS
We identified that rs17321084 was associated with worse EFS (HR = 2.01, 95% CI = 1.59 to 2.53, P = 5.39 × 10-9) and rs10094840 was associated with worse OS (HR = 1.84, 95% CI = 1.48 to 2.27, P = 2.13 × 10-8). Using publicly available data, we found that rs17321084 lies in a binding region for transcription factors GATA2 and GATA3, and rs10094840 is associated with SPAG1 and RNF19A expression. We also identified that CTNNA3 rs2135732 (HR = 3.75, 95% CI = 2.34 to 5.99, P = 3.54 × 10-8) and MED31 rs74504320 (HR = 3.21, 95% CI = 2.12 to 4.86, P = 3.60 × 10-8) were associated with worse OS among individuals with alveolar RMS.
CONCLUSIONS
We demonstrated that common germline variants are associated with EFS and OS among individuals with RMS. Additional replication and investigation of these SNP effects may further support their consideration in risk stratification protocols.
Topics: Child; Humans; Genome-Wide Association Study; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar; Proportional Hazards Models; Germ Cells; Ubiquitin-Protein Ligases; Mediator Complex
PubMed: 36951526
DOI: 10.1093/jnci/djad055 -
Molecular Oncology Aug 2021Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma. There are two main subtypes of RMS, alveolar rhabdomyosarcoma (ARMS) and embryonal...
Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma. There are two main subtypes of RMS, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma. ARMS typically encompasses fusion-positive rhabdomyosarcoma, which expresses either PAX3-FOXO1 or PAX7-FOXO1 fusion proteins. There are no targeted therapies for ARMS; however, recent studies have begun to illustrate the cooperation between epigenetic proteins and the PAX3-FOXO1 fusion, indicating that epigenetic proteins may serve as targets in ARMS. Here, we investigate the contribution of BMI1, given the established role of this epigenetic regulator in sustaining aggression in cancer. We determined that BMI1 is expressed across ARMS tumors, patient-derived xenografts, and cell lines. We depleted BMI1 using RNAi and inhibitors (PTC-209 and PTC-028) and found that this leads to a decrease in cell growth/increase in apoptosis in vitro, and delays tumor growth in vivo. Our data suggest that BMI1 inhibition activates the Hippo pathway via phosphorylation of LATS1/2 and subsequent reduction in YAP levels and YAP/TAZ target genes. These results identify BMI1 as a potential therapeutic vulnerability in ARMS and warrant further investigation of BMI1 in ARMS and other sarcomas.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Epigenesis, Genetic; Heterografts; Hippo Signaling Pathway; Humans; Phosphorylation; Polycomb Repressive Complex 1; RNA Interference; Rhabdomyosarcoma
PubMed: 33523558
DOI: 10.1002/1878-0261.12914 -
PloS One 2017Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma affecting children and is often diagnosed with concurrent metastases. Unfortunately, few effective...
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma affecting children and is often diagnosed with concurrent metastases. Unfortunately, few effective therapies have been discovered that improve the long-term survival rate for children with metastatic disease. Here we determined effectiveness of targeting the receptor tyrosine kinase, EphB4, in both alveolar and embryonal RMS either directly through the inhibitory antibody, VasG3, or indirectly by blocking both forward and reverse signaling of EphB4 binding to EphrinB2, cognate ligand of EphB4. Clinically, EphB4 expression in eRMS was correlated with longer survival. Experimentally, inhibition of EphB4 with VasG3 in both aRMS and eRMS orthotopic xenograft and allograft models failed to alter tumor progression. Inhibition of EphB4 forward signaling using soluble EphB4 protein fused with murine serum albumin failed to affect eRMS model tumor progression, but did moderately slow progression in murine aRMS. We conclude that inhibition of EphB4 signaling with these agents is not a viable monotherapy for rhabdomyosarcoma.
Topics: Animals; Cell Line; Ephrin-B2; Humans; Mice; Mice, Transgenic; Prognosis; Receptor, EphB4; Rhabdomyosarcoma; Signal Transduction
PubMed: 28817624
DOI: 10.1371/journal.pone.0183161 -
Proceedings of the National Academy of... Jun 2022Rhabdomyosarcoma (RMS) is one of the most common pediatric soft-tissue cancer. Previously, we discovered a gene fusion, formed by chromosomal inversion in RMS....
Rhabdomyosarcoma (RMS) is one of the most common pediatric soft-tissue cancer. Previously, we discovered a gene fusion, formed by chromosomal inversion in RMS. Suspecting that forming a fusion with a housekeeping gene may be one of the mechanisms to dysregulate an oncogene, we investigated AVIL expression and its role in RMS. We first showed that MARS-AVIL translates into an in-frame fusion protein, which is critical for RMS cell tumorigenesis. Besides forming a gene fusion with the housekeeping gene, , the AVIL locus is often amplified, and its RNA and protein expression are overexpressed in the majority of RMSs. Tumors with AVIL dysregulation exhibit evidence of oncogene addiction: Silencing MARS-AVIL in cells harboring the fusion, or silencing AVIL in cells with AVIL overexpression, nearly eradicated the cells in culture, as well as inhibited in vivo xenograft growth in mice. Conversely, gain-of-function manipulations of AVIL led to increased cell growth and migration, enhanced foci formation in mouse fibroblasts, and most importantly transformed mesenchymal stem cells in vitro and in vivo. Mechanistically, AVIL seems to serve as a converging node functioning upstream of two oncogenic pathways, PAX3-FOXO1 and RAS, thus connecting two types of RMS associated with these pathways. Interestingly, AVIL is overexpressed in other sarcoma cells as well, and its expression correlates with clinical outcomes, with higher levels of AVIL expression being associated with worse prognosis. is a bona fide oncogene in RMS, and RMS cells are addicted to its activity.
Topics: Humans; Animals; Mice; Paired Box Transcription Factors; Cell Line, Tumor; Rhabdomyosarcoma; Oncogenes; Pheniramine; Oncogene Proteins, Fusion; Gene Expression Regulation, Neoplastic; Rhabdomyosarcoma, Alveolar; Microfilament Proteins
PubMed: 37146302
DOI: 10.1073/pnas.2118048119 -
Gene Aug 2018The PAX3 gene encodes a member of the PAX family of transcription factors that is characterized by a highly conserved paired box motif. The PAX3 protein is a... (Review)
Review
The PAX3 gene encodes a member of the PAX family of transcription factors that is characterized by a highly conserved paired box motif. The PAX3 protein is a transcription factor consisting of an N-terminal DNA binding domain (containing a paired box and homeodomain) and a C-terminal transcriptional activation domain. This protein is expressed during development of skeletal muscle, central nervous system and neural crest derivatives, and regulates expression of target genes that impact on proliferation, survival, differentiation and motility in these lineages. Germline mutations of the murine Pax3 and human PAX3 genes cause deficiencies in these developmental lineages and result in the Splotch phenotype and Waardenburg syndrome, respectively. Somatic genetic rearrangements that juxtapose the PAX3 DNA binding domain to the transcriptional activation domain of other transcription factors deregulate PAX3 function and contribute to the pathogenesis of the soft tissue cancers alveolar rhabdomyosarcoma and biphenotypic sinonasal sarcoma. The wild-type PAX3 protein is also expressed in other cancers related to developmental lineages that normally express this protein and exerts phenotypic effects related to its normal developmental role.
Topics: Animals; Gene Expression; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Humans; Mutation; PAX3 Transcription Factor; Sarcoma; Waardenburg Syndrome
PubMed: 29730428
DOI: 10.1016/j.gene.2018.04.087 -
Frontiers in Oncology 2023This review aims to summarize the putative role of histone deacetylases (HDACs) in rhabdomyosarcoma (RMS) and the effects of HDAC inhibitors (HDACi) on RMS by... (Review)
Review
This review aims to summarize the putative role of histone deacetylases (HDACs) in rhabdomyosarcoma (RMS) and the effects of HDAC inhibitors (HDACi) on RMS by elucidating and highlighting known oncogenic pathways, mechanisms of resistance, and the synergistic potential of histone deacetylase inhibitors. We searched two databases (PubMed and Google Scholar) for the keywords "Rhabdomyosarcoma, histone deacetylase, histone deacetylase inhibitors." We excluded three publications that did not permit access to the full text to review and those that focus exclusively on pleiomorphic RMS in adults. Forty-seven papers met the inclusion criteria. This review highlights that HDACi induce cytotoxicity, cell-cycle arrest, and oxidative stress in RMS cells. Ultimately, HDACi have been shown to increase apoptosis and the cessation of embryonal and alveolar RMS proliferation and , both synergistically and on its own. HDACi contain potent therapeutic potential against RMS. This review discusses the significant findings and the biological mechanisms behind the anti-cancer effects of HDACi. Additionally, this review highlights important clinical trials assessing the efficacy of HDACi in sarcomas.
PubMed: 37664028
DOI: 10.3389/fonc.2023.1244035