RESUMO
Synovial sarcoma (SS) is a rare soft-tissue tumor characterized by a monomorphic blue spindle cell histology and variable epithelial differentiation. Morphologically, SSs may be confused with other sarcomas. Systemic treatment is more effective for patients with high-risk SSs, patients with advanced disease, and younger patients. However, further studies are required to find new prognostic biomarkers. Herein, we describe the morphological, molecular, and clinical findings, using a wide immunohistochemical panel, of a series of SS cases. We studied 52 cases confirmed as SSs by morphological diagnosis and/or molecular studies. Clinical data (gender, age, tumor size, tumor location, resection margins, adjuvant treatment, recurrences, metastasis, and survival) were also retrieved for each patient. All the available H&E slides were examined by four pathologists. Three tissue microarrays (TMAs) were constructed for each of the tumors, and a wide immunohistochemical panel was performed. For time-to-event variables, survival analysis was performed using Kaplan-Meier curves and log-rank testing, or Cox regression. Statistical significance was considered at p < 0.05. The mean age of our patients was 40.33, and the median was 40.5 years. We found a predominance of males versus females (1.7:1). The most frequent morphological subtype was monophasic. TRPS1, SS18-SSX, and SSX-C-terminus were positive in 96% of cases. GLI1 expression was strong in six and focal (cytoplasmic) in twenty patients. Moreover, BCOR was expressed in more than half of SSs. Positive expression of both proteins, BCOR and GLI1, was correlated with a worse prognosis. Multivariate analysis was also performed, but only BCOR expression appeared to be significant. The combination of GLI1 and BCOR antibodies can be used to group SSs into three risk groups (low, intermediate, and high risk). We hypothesize that these findings could identify which patients would benefit from receiving adjuvant treatment and which would not. Moreover, these markers could represent therapeutic targets in advanced stages. However, further, larger series of SSs and molecular studies are necessary to corroborate our present findings.
Assuntos
Biomarcadores Tumorais , Imuno-Histoquímica , Proteínas Proto-Oncogênicas , Proteínas Repressoras , Sarcoma Sinovial , Proteína GLI1 em Dedos de Zinco , Humanos , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patologia , Sarcoma Sinovial/genética , Masculino , Feminino , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Adulto , Pessoa de Meia-Idade , Prognóstico , Biomarcadores Tumorais/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Idoso , Adulto Jovem , Adolescente , Estimativa de Kaplan-MeierRESUMO
Synovial sarcoma (SS) is an aggressive soft tissue sarcoma with poor prognosis due to late recurrence and metastasis. Metastasis is an important prognostic factor of SS. This study aimed to identify the core genes and mechanisms associated with SS metastasis. Microarray data for GSE40021 and GSE40018 were obtained from the Gene Expression Omnibus database. 186 differentially expressed genes (DEGs) were identified. The biological functions and signalling pathways closely associated with SS metastasis included extracellular matrix (ECM) organization and ECM-receptor interaction. Gene set enrichment analysis showed that the terms cell cycle, DNA replication, homologous recombination and mismatch repair were significantly enriched in the metastasis group. Weighted gene co-expression network analysis identified the most relevant module and 133 hub genes, and 31 crossover genes were identified by combining DEGs. Subsequently, four characteristic genes, EXO1, NCAPG, POLQ and UHRF1, were identified as potential biomarkers associated with SS metastasis using the least absolute shrinkage and selection operator algorithm and validation dataset verification analysis. Immunohistochemistry results from our cohort of 49 patients revealed visible differences in the expression of characteristic genes between the non-metastatic and metastatic groups. Survival analysis indicated that high expression of characteristic genes predicted poor prognosis. Our data revealed that primary SS samples from patients who developed metastasis showed activated homologous recombination and mismatch repair compared to samples from patients without metastasis. Furthermore, EXO1, NCAPG, POLQ and UHRF1 were identified as potential candidate metastasis-associated genes. This study provides further research insights and helps explore the mechanisms of SS metastasis.
Assuntos
Biomarcadores Tumorais , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Sarcoma Sinovial , Sarcoma Sinovial/genética , Sarcoma Sinovial/patologia , Sarcoma Sinovial/metabolismo , Humanos , Prognóstico , Biomarcadores Tumorais/genética , Redes Reguladoras de Genes , Feminino , Masculino , Bases de Dados Genéticas , Biologia Computacional/métodos , Pessoa de Meia-IdadeRESUMO
Synovial sarcomas are soft tissue tumours of uncertain origin, most commonly found in the upper or lower extremities. They are characterised by distinctive chromosomal rearrangements involving the gene SS18. Synovial sarcomas can occasionally arise also in visceral sites, but retroperitoneal SSs are very unusual. Among them, a few primary renal synovial sarcomas have been described in the scientific literature. Primary renal synovial sarcomas tend to be monophasic and often show cystic changes. Histologically, they can closely resemble other primary kidney tumours, mainly paediatric tumours such as nephroblastoma and clear cell sarcoma of the kidney. In the current work, a primary synovial sarcoma of the kidney with unusual morphological features (extensively myxoid stroma and immunohistochemical positivity for BCOR) is described. Molecular analysis, through targeted RNA sequencing, was of invaluable help in reaching the correct diagnosis. Despite locally advanced disease at presentation, the patient showed an unexpectedly brilliant response to chemotherapy.
Assuntos
Biomarcadores Tumorais , Neoplasias Renais , Sarcoma Sinovial , Humanos , Sarcoma Sinovial/genética , Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patologia , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Masculino , Diagnóstico Diferencial , Diferenciação Celular , Feminino , Proteínas Proto-Oncogênicas , Proteínas RepressorasRESUMO
BACKGROUND/AIM: Synovial sarcoma (SS) is a rare malignant tumor with a poor survival rate. We previously reported that a combination of auranofin (AUR), a thioredoxin reductase inhibitor, and celecoxib (CE), an anti-inflammatory drug, significantly impedes the local progression of osteosarcoma (OS). However, the role of redox regulation in SS remains to be elucidated. This study aimed to investigate the efficacy of combined treatment of AUR and CE on the local progression of SS in vivo. MATERIALS AND METHODS: Nu/nu mice were implanted with the human SS cell line, Aska-SS, and treated with vehicle control, AUR, or a combination of AUR and CE (AUR-CE). Primary tumor size and weight were evaluated for the study duration and upon resection, respectively. Hematoxylin and eosin (H&E) and Ki-67 staining were performed to assess the local progression of SS. RESULTS: A statistically significant reduction in tumor size and weight was observed in the AUR- and AUR-CE-treated groups upon excision compared to that in the vehicle-treated group. The AUR-CE-treated group showed synergistic inhibition of local tumor growth. H&E staining of local SS tumors revealed decreased cell density and nuclear deformation in the AUR- and AUR-CE-treated groups compared to those in the vehicle-treated group. Immunohistochemical staining revealed a statistically significant decrease in Ki-67-positive cells in the AUR-CE-treated group compared to the vehicle-treated group. CONCLUSION: The combination of AUR and CE showed significant potential for delaying the local progression of SS. These findings support the repurposing of AUR and CE as early treatment options for SS.
Assuntos
Auranofina , Celecoxib , Progressão da Doença , Sarcoma Sinovial , Ensaios Antitumorais Modelo de Xenoenxerto , Celecoxib/farmacologia , Celecoxib/administração & dosagem , Animais , Sarcoma Sinovial/tratamento farmacológico , Sarcoma Sinovial/patologia , Sarcoma Sinovial/metabolismo , Auranofina/farmacologia , Auranofina/uso terapêutico , Humanos , Camundongos , Linhagem Celular Tumoral , Camundongos Nus , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proliferação de Células/efeitos dos fármacosRESUMO
NUT carcinoma is a rare, aggressive malignancy defined as a carcinoma with a chromosomal rearrangement affecting the nuclear protein in testis (NUTM1) gene. This small round blue cell tumor classically exhibits focal abrupt keratinization and immunohistochemical positivity for keratin and squamous markers. However, keratinization is not always present and reports of positivity for other markers that may obscure the diagnosis are increasing. It is also noteworthy that gene fusions involving NUTM1 are not restricted to NUT carcinoma. Herein, we report a NUT carcinoma arising in the mediastinum of a male patient in his 40â s with morphological and immunohistochemical overlap with Ewing family sarcoma and poorly differentiated synovial sarcoma given a round cell morphology, diffuse strong immunoreactivity for CD99, and patchy strong immunoreactivity for TLE1. Squamous differentiation by morphology and p40 expression were notably absent in this case. Classification as NUT carcinoma was ultimately possible when the morphological and immunohistochemical findings were considered in the context of a BRD4::NUTM1 gene fusion identified by next-generation sequencing. While the patient initially responded to palliative radiotherapy, he died approximately one month later. To our knowledge, this is the first report of TLE1 immunoreactivity in NUT carcinoma. This case highlights a potential diagnostic pitfall and emphasizes the need for molecular confirmation in equivocal situations.
Assuntos
Biomarcadores Tumorais , Proteínas Correpressoras , Proteínas Nucleares , Proteínas de Fusão Oncogênica , Humanos , Masculino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Adulto , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Diagnóstico Diferencial , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Carcinoma/diagnóstico , Carcinoma/patologia , Carcinoma/genética , Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/patologia , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Evolução Fatal , Imuno-Histoquímica , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismoRESUMO
The cancer-specific fusion oncoprotein SS18-SSX1 disturbs chromatin accessibility by hijacking the BAF complex from the promoters and enhancers to the Polycomb-repressed chromatin regions. This process relies on the selective recognition of H2AK119Ub nucleosomes by synovial sarcoma X breakpoint 1 (SSX1). However, the mechanism underlying the selective recognition of H2AK119Ub nucleosomes by SSX1 in the absence of ubiquitin (Ub)-binding capacity remains unknown. Here we report the cryo-EM structure of SSX1 bound to H2AK119Ub nucleosomes at 3.1-Å resolution. Combined in vitro biochemical and cellular assays revealed that the Ub recognition by SSX1 is unique and depends on a cryptic basic groove formed by H3 and the Ub motif on the H2AK119 site. Moreover, this unorthodox binding mode of SSX1 induces DNA unwrapping at the entry/exit sites. Together, our results describe a unique mode of site-specific ubiquitinated nucleosome recognition that underlies the specific hijacking of the BAF complex to Polycomb regions by SS18-SSX1 in synovial sarcoma.
Assuntos
Nucleossomos , Sarcoma Sinovial , Humanos , Sarcoma Sinovial/metabolismo , Cromatina , Membrana Celular/metabolismo , Proteínas de Fusão Oncogênica/genéticaRESUMO
The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of the mSWI/SNF (BAF) complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the ability of SS18-SSX to occupy H2AK119ub1-rich regions is an intrinsic property of its SSX C terminus, which can be exploited by fusion to transcriptional regulators beyond SS18. Accordingly, SS18-SSX recruitment occurs in a manner that is independent of the core components and catalytic activity of BAF. Alternative SSX fusions are also recruited to H2AK119ub1-rich chromatin and reproduce the expression signatures of SS18-SSX by engaging with transcriptional activators. Variant Polycomb repressive complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C terminus not only depends on H2AK119ub1 for localization, but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results uncover a critical role for SSX-C in mediating gene deregulation in synovial sarcoma by providing specificity to chromatin and further enabling oncofusion binding by enhancing PRC1.1 stability and H2AK119ub1 deposition.
Assuntos
Sarcoma Sinovial , Humanos , Animais , Camundongos , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Complexo Repressor Polycomb 1/genética , Ativação Transcricional , Núcleo Celular/metabolismo , Cromatina/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMO
Cancer stem cells (CSCs) has been a key target to cure cancer patients completely. Although many CSC markers have been identified, they are frequently cancer type-specific and those expressions are occasionally variable, which becomes an obstacle to elucidate the characteristics of the CSCs. Here we scrutinized the relationship between stemness elevation and geometrical features of single cells. The PAMPS hydrogel was utilized to create the CSCs from mouse myoblast C2C12 and its synovial sarcoma model cells. qRT-PCR analysis confirmed the significant increase in expression levels of Sox2, Nanog, and Oct3/4 on the PAMPS gel, which was higher in the synovial sarcoma model cells. Of note, the morphological heterogeneity was appeared on the PAMPS gel, mainly including flat spreading, elongated spindle, and small round cells, and the Sox2 expression was highest in the small round cells. To examine the role of morphological differences in the elevation of stemness, over 6,400 cells were segmented along with the Sox2 intensity, and 12 geometrical features were extracted at single cell level. A nonlinear mapping of the geometrical features by using uniform manifold approximation and projection (UMAP) clearly revealed the existence of relationship between morphological differences and the stemness elevation, especially for C2C12 and its synovial sarcoma model on the PAMPS gel in which the small round cells possess relatively high Sox2 expression on the PAMPS gel, which supports the strong relationship between morphological changes and the stemness elevation. Taken together, these geometrical features can be useful for morphological profiling of CSCs to classify and distinguish them for understanding of their role in disease progression and drug discovery.
Assuntos
Sarcoma Sinovial , Sarcoma , Camundongos , Animais , Sarcoma Sinovial/metabolismo , Hidrogéis , Moléculas com Motivos Associados a Patógenos , Células-Tronco Neoplásicas/metabolismo , Sarcoma/metabolismoRESUMO
Synovial sarcoma is a rare translocation-driven cancer with poor survival outcomes, particularly in the advanced setting. Previous synovial sarcoma preclinical studies have relied on a small panel of cell lines which suffer from the limitation of genomic and phenotypic drift as a result of being grown in culture for decades. Patient-derived xenografts (PDX) are a valuable tool for preclinical research as they retain many histopathological features of their originating human tumour; however, this approach is expensive, slow, and resource intensive, which hinders their utility in large-scale functional genomic and drug screens. To address some of these limitations, in this study, we have established and characterised a novel synovial sarcoma cell line, ICR-SS-1, which is derived from a PDX model and is amenable to high-throughput drug screens. We show that ICR-SS-1 grows readily in culture, retains the pathognomonic SS18::SSX1 fusion gene, and recapitulates the molecular features of human synovial sarcoma tumours as shown by proteomic profiling. Comparative analysis of drug response profiles with two other established synovial sarcoma cell lines (SYO-1 and HS-SY-II) finds that ICR-SS-1 harbours intrinsic resistance to doxorubicin and is sensitive to targeted inhibition of several oncogenic pathways including the PI3K-mTOR pathway. Collectively, our studies show that the ICR-SS-1 cell line model may be a valuable preclinical tool for studying the biology of anthracycline-resistant synovial sarcoma and identifying new salvage therapies following failure of doxorubicin.
Assuntos
Sarcoma Sinovial , Neoplasias de Tecidos Moles , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Xenoenxertos , Humanos , Proteínas de Fusão Oncogênica/metabolismo , Proteômica , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patologiaRESUMO
BACKGROUND: Synovial sarcoma is an uncommon soft tissue tumor of soft tissue, characterized by a specific SS18 rearrangement. It generally manifests as a lesion composed of monomorphic spindle cells and sometimes shows variable epithelial differentiation. Epithelial-type synovial sarcoma is rare, and synovial sarcoma with overwhelming neuroendocrine differentiation has not been reported previously. CASE PRESENTATION: Here, we present a case of a young man with an epithelial-type synovial sarcoma of the right leg that showed an overwhelming neuroendocrine differentiation. The diagnosis was confirmed by the detection of targeted fusion re-arrangement associated with synovial sarcoma. CONCLUSIONS: This study emphasizes the importance of molecular approaches in modern soft tissue pathology. Detecting the expression of neuroendocrine antigens in synovial sarcoma is a pre-requisite to avoid misdiagnosis of metastatic neuroendocrine tumor, malignant peripheral nerve sheath tumor with glandular differentiation, and carcinosarcoma.
Assuntos
Sarcoma Sinovial , Neoplasias de Tecidos Moles , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Erros de Diagnóstico , Humanos , Masculino , Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/metabolismoRESUMO
Oncoprotein SS18-SSX is a hallmark of synovial sarcomas. However, as a part of the SS18-SSX fusion protein, SS18's function remains unclear. Here, we depict the structures of both human SS18/BRG1 and yeast SNF11/SNF2 subcomplexes. Both subcomplexes assemble into heterodimers that share a similar conformation, suggesting that SNF11 might be a homologue of SS18 in chromatin remodeling complexes. Importantly, our study shows that the self-association of the intrinsically disordered region, QPGY domain, leads to liquid-liquid phase separation (LLPS) of SS18 or SS18-SSX and the subsequent recruitment of BRG1 into phase-separated condensates. Moreover, our results show that the tyrosine residues in the QPGY domain play a decisive role in the LLPS of SS18 or SS18-SSX. Perturbations of either SS18-SSX LLPS or SS18-SSX's binding to BRG1 impair NIH3T3 cell transformation by SS18-SSX. Our data demonstrate that both LLPS and assembling into chromatin remodelers contribute to the oncogenic activity of SS18-SSX in synovial sarcomas.
Assuntos
Proteínas Proto-Oncogênicas , Proteínas Repressoras , Sarcoma Sinovial , Animais , Transformação Celular Neoplásica , Humanos , Camundongos , Células NIH 3T3 , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
PURPOSE: Synovial sarcoma (SySa) is a rare soft tissue tumor characterized by a reciprocal t(X;18) translocation. The chimeric SS18-SSX fusion protein represents the major driver of the disease, acting as aberrant transcriptional dysregulator. Oncogenic mechanisms whereby SS18-SSX mediates sarcomagenesis are incompletely understood, and strategies to selectively target SySa cells remain elusive. Based on results of Phospho-Kinase screening arrays, we here investigate the functional and therapeutic relevance of the transcription factor CREB in SySa tumorigenesis. METHODS: Immunohistochemistry of phosphorylated CREB and its downstream targets (Rb, Cyclin D1, PCNA, Bcl-xL and Bcl-2) was performed in a large cohort of SySa. Functional aspects of CREB activity, including SS18-SSX driven circuits involved in CREB activation, were analyzed in vitro employing five SySa cell lines and a mesenchymal stem cell model. CREB mediated transcriptional activity was modulated by RNAi-mediated knockdown and small molecule inhibitors (666-15, KG-501, NASTRp and Ro 31-8220). Anti-proliferative effects of the CREB inhibitor 666-15 were tested in SySa avian chorioallantoic membrane and murine xenograft models in vivo. RESULTS: We show that CREB is phosphorylated and activated in SySa, accompanied by downstream target expression. Human mesenchymal stem cells engineered to express SS18-SSX promote CREB expression and phosphorylation. Conversely, RNAi-mediated knockdown of SS18-SSX impairs CREB phosphorylation in SySa cells. Inhibition of CREB activity reduces downstream target expression, accompanied by suppression of SySa cell proliferation and induction of apoptosis in vitro and in vivo. CONCLUSION: In conclusion, our data underline an essential role of CREB in SySa tumorigenesis and provides evidence for molecular targeted therapies.
Assuntos
Sarcoma Sinovial , Animais , Apoptose , Carcinogênese , Linhagem Celular Tumoral , Humanos , Camundongos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Sarcoma Sinovial/tratamento farmacológico , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismoRESUMO
Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12-18 months. Frizzled homolog 10 (FZD10) is overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of ß-radioimmunotherapy (RIT) with the 90 Y-labeled anti-FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α-RIT with OTSA101 labeled with the α-emitter 225 Ac. Competitive inhibition and cell binding assays showed that specific binding of 225 Ac-labeled OTSA101 to SYO-1 synovial sarcoma cells was comparable to that of the imaging agent 111 In-labeled OTSA101. Biodistribution studies showed high uptake in SYO-1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of 225 Ac-labeled OTSA101 for tumors was 7.8 Bd higher than that of 90 Y-labeled OTSA101. 90 Y- and 225 Ac-labeled OTSA101 decreased tumor volume and prolonged survival. 225 Ac-labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. 225 Ac-labeled OTSA101 induced a larger amount of necrosis and apoptosis than 90 Y-labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment-related mortality or obvious toxicity, except for temporary body weight loss, was observed. 225 Ac-labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO-1. RIT with 225 Ac-labeled OTSA101 is a promising therapeutic option for synovial sarcoma.
Assuntos
Actínio/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Receptores Frizzled/antagonistas & inibidores , Sarcoma Sinovial/radioterapia , Actínio/química , Actínio/farmacocinética , Partículas alfa/uso terapêutico , Animais , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacocinética , Linhagem Celular Tumoral , Receptores Frizzled/imunologia , Receptores Frizzled/metabolismo , Humanos , Camundongos , Radioimunoterapia , Dosagem Radioterapêutica , Indução de Remissão , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patologia , Distribuição Tecidual/efeitos da radiação , Carga Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto , Radioisótopos de Ítrio/química , Radioisótopos de Ítrio/farmacocinética , Radioisótopos de Ítrio/uso terapêuticoRESUMO
The recently introduced, highly sensitive and specific SS18-SSX immunohistochemistry (IHC) is an attractive alternative to SS18 fluorescence in situ hybridization (FISH) testing in synovial sarcoma (SS). However, little is known about how SS18-SSX IHC correlates with SS18 FISH. We correlated the SS18 FISH results of SS from 36 patients with SS18-SSX IHC. Twenty-six tumours had a classic break-apart FISH pattern (1 fused, 1 red and 1 green signal) and all stained positive for the IHC. Ten had an atypical (non-classic) FISH pattern of which 5 stained positive for the IHC. Four of these (including two with novel atypical SS18 FISH patterns) were confirmed to harbour the SS18-SSX fusion on targeted RNA sequencing, while one had classic features of a biphasic SS. The remaining 5 tumours stained negative for the IHC. One had a TPM3-NTRK1 fusion, and one had no fusion, while the remaining three had insufficient tissue/RNA for sequencing. The sensitivity of the IHC was 91% (after excluding the 2 cases with confirmed absence of SS18-SSX fusion). Twenty histologic mimics of SS also stained negative for the IHC (100% specificity). Our study shows that the SS18-SSX IHC is more specific than SS18 FISH in diagnosing SS, especially in cases with atypical FISH patterns. It correlates well with RNA sequencing result and has the potential to replace SS18 FISH testing. A positive IHC result supports the diagnosis of SS, while a tumour with atypical FISH pattern and negative IHC result should undergo further molecular testing.
Assuntos
Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Sarcoma Sinovial/genética , Adulto , Biomarcadores Tumorais/genética , Feminino , Humanos , Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente/métodos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/imunologia , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Sarcoma Sinovial/imunologia , Sarcoma Sinovial/metabolismoRESUMO
Synovial sarcoma is an aggressive malignancy with no effective treatments for patients with metastasis. The synovial sarcoma fusion SS18-SSX, which recruits the SWI/SNF-BAF chromatin remodeling and polycomb repressive complexes, results in epigenetic activation of FGF receptor (FGFR) signaling. In genetic FGFR-knockout models, culture, and xenograft synovial sarcoma models treated with the FGFR inhibitor BGJ398, we show that FGFR1, FGFR2, and FGFR3 were crucial for tumor growth. Transcriptome analyses of BGJ398-treated cells and histological and expression analyses of mouse and human synovial sarcoma tumors revealed prevalent expression of two ETS factors and FGFR targets, ETV4 and ETV5. We further demonstrate that ETV4 and ETV5 acted as drivers of synovial sarcoma growth, most likely through control of the cell cycle. Upon ETV4 and ETV5 knockdown, we observed a striking upregulation of DUX4 and its transcriptional targets that activate the zygotic genome and drive the atrophy program in facioscapulohumeral dystrophy patients. In addition to demonstrating the importance of inhibiting all three FGFRs, the current findings reveal potential nodes of attack for the cancer with the discovery of ETV4 and ETV5 as appropriate biomarkers and molecular targets, and activation of the embryonic DUX4 pathway as a promising approach to block synovial sarcoma tumors.
Assuntos
Proteínas Proto-Oncogênicas c-ets/metabolismo , Sarcoma Sinovial/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas c-ets/genética , Pirimidinas/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/deficiência , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Sarcoma Sinovial/genética , Sarcoma Sinovial/patologia , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression. METHOD: We performed a phase I clinical trial evaluating the safety of NY-ESO-1-specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15. RESULTS: Four patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1-specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor-based products at other centers. CONCLUSIONS: ETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1-specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.
Assuntos
Antígenos de Neoplasias/imunologia , Proliferação de Células/efeitos dos fármacos , Imunoterapia Adotiva , Interleucina-15/farmacologia , Lipossarcoma Mixoide/terapia , Ativação Linfocitária/efeitos dos fármacos , Proteínas de Membrana/imunologia , Células T de Memória/efeitos dos fármacos , Células T de Memória/transplante , Sarcoma Sinovial/terapia , Adulto , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Ciclofosfamida/uso terapêutico , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Memória Imunológica , Imunoterapia Adotiva/efeitos adversos , Lipossarcoma Mixoide/imunologia , Lipossarcoma Mixoide/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Células T de Memória/imunologia , Células T de Memória/metabolismo , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Projetos Piloto , Sarcoma Sinovial/imunologia , Sarcoma Sinovial/metabolismo , Fatores de Tempo , Condicionamento Pré-Transplante , Resultado do Tratamento , Microambiente TumoralRESUMO
Synovial sarcoma is a rare but aggressive soft-tissue sarcoma associated with translocation t(X;18). Metastasis occurs in approximately 50% of all patients, and curative outcomes are difficult to achieve in this group. Since the efficacies of current therapeutic approaches for metastatic synovial sarcoma remain limited, new therapeutic agents are urgently needed. Tilapia piscidin 4 (TP4), a marine antimicrobial peptide, is known to exhibit multiple biological functions, including anti-bacterial, wound-healing, immunomodulatory, and anticancer activities. In the present study, we assessed the anticancer activity of TP4 in human synovial sarcoma cells and determined the underlying mechanisms. We first demonstrated that TP4 can induce necrotic cell death in human synovial sarcoma AsKa-SS and SW982 cells lines. In addition, we saw that TP4 initiates reactive oxygen species (ROS) production and downregulates antioxidant proteins, such as uncoupling protein-2, superoxide dismutase (SOD)-1, and SOD-2. Moreover, TP4-induced mitochondrial hyperpolarization is followed by elevation of mitochondrial ROS. Calcium overload is also triggered by TP4, and cell death can be attenuated by a necrosis inhibitor, ROS scavenger or calcium chelator. In our experiments, TP4 displayed strong anticancer activity in human synovial sarcoma cells by disrupting oxidative status, promoting mitochondrial hyperpolarization and causing calcium overload.
Assuntos
Antineoplásicos/farmacologia , Cálcio/metabolismo , Proteínas de Peixes/farmacologia , Mitocôndrias/efeitos dos fármacos , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sarcoma Sinovial/tratamento farmacológico , Tilápia/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Mitocôndrias/fisiologia , Sarcoma Sinovial/metabolismoRESUMO
TLE 1 is the human homologue belonging to a family of four genes and is located on chromosome 9q21. It consists of 19 exons. Although it does not bind directly to DNA, it acts as a repressor of several signalling pathways via transcription factors. TLE1 protein has several physiological roles in embryogenesis, haematopoiesis, general differentiation, and both neuronal and eye development. Much attention was focused on its expression in the tumour cell nuclei of synovial sarcoma (SS). However, several other soft tissue tumours that do and do not share morphological similarity with SS also display nuclear immunoreactivity for TLE1; hence, caution in interpretation is advocated.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas Correpressoras/genética , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Neoplasias de Tecidos Moles/metabolismo , Núcleo Celular/patologia , Proteínas Correpressoras/metabolismo , Humanos , Imuno-Histoquímica , Oncogenes/genética , Neoplasias de Tecidos Moles/patologiaRESUMO
Synovial sarcoma accounts for 5% to 10% of soft tissue sarcoma and it typically presents as a deep soft tissue mass. Primary cutaneous presentation is exceptionally rare, with only isolated case reports. We report a case of primary cutaneous synovial sarcoma in a 58-year-old woman that presented as a nodule involving the left occipital scalp. A complete radiologic evaluation of the patient failed to reveal any other mass lesion. Histologic sections showed a densely cellular, diffuse spindle cell proliferation within the subcutis. The lesion was composed of uniform, plump spindled cells with nuclei and vesicular chromatin, arranged in haphazard fascicles. There was admixed hemorrhage and a hemangiopericytoma-like vasculature. Immunohistochemically, the spindled cells showed focal strong positivity for cytokeratin (CK) OSCAR, CK5/6, CK34BE12, and pan-CK. Fluorescence in situ hybridization was positive for a rearrangement of SYT (SS18), confirming the diagnosis of monophasic synovial sarcoma. Synovial sarcoma should be considered in the differential diagnosis of monomorphous spindle cell tumors, especially if the tumors have a hemangiopericytoma-like vasculature or express keratins. In such cases, confirmatory molecular testing should be performed to confirm the diagnosis.
Assuntos
Biomarcadores Tumorais , Rearranjo Gênico , Neoplasias de Cabeça e Pescoço , Proteínas Proto-Oncogênicas , Proteínas Repressoras , Sarcoma Sinovial , Neoplasias Cutâneas , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND AND AIMS: Synovial sarcoma (SS) is a spindled cell sarcoma demonstrating varying degrees of epithelial differentiation and characterized by a pathognomonic t(X;18) translocation. SS most frequently involves deep soft tissue of the extremities in young adults. Superficial SS involving dermis and/or subcutaneous tissue is exceedingly rare. METHODS AND RESULTS: We identified eight cases of primary superficial synovial sarcomas across three tertiary institutions. All cases were confined to the dermis/subcutis based on imaging or gross and microscopic examination. The average patient age was 36 years (range 14-50). The average tumor size was 2.4 cm (range 0.9-3.9 cm) and lesions showed classic monophasic (n = 4) or biphasic (n = 4) morphology. All tumors expressed keratin AE1/AE3 and/or epithelial membrane antigen (EMA), but were negative for CD34. The diagnosis for each case was confirmed by molecular detection of t(X;18). Six of the eight cases were treated with curative excision while the other two received additional radiotherapy. Follow-up was available for six patients (mean 68 months, range 2-108 months) and no patient experienced recurrence or metastatic disease. CONCLUSIONS: We present the largest series to date of primary superficial SS with molecular confirmation for all cases. SS should be considered when evaluating a cutaneous monomorphic spindle cell neoplasm.