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1.
Anticancer Res ; 41(10): 4885-4894, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593436

RESUMO

BACKGROUND/AIM: Advanced undifferentiated pleomorphic sarcoma (UPS) has a poor prognosis and there are few treatments that can improve overall survival. Recently, Rapalink-1, a third-generation mammalian target of rapamycin (mTOR) kinase inhibitor, has been developed and shown to be effective against other tumours. However, mTOR inhibitors have been shown to induce autophagy and resistance to anti-cancer drugs. This study aimed to investigate the antitumor effects of Rapalink-1 with an autophagy inhibitor. MATERIALS AND METHODS: The antitumor effect of Rapalink-1 and/or hydroxychloroquine in three UPS cell lines was examined via cell viability analysis, western blotting, flow cytometry and immunofluorescence. RESULTS: Rapalink-1 decreased cell proliferation and inhibited the PI3K/mTOR pathway. Combined treatment with Rapalink-1 and hydroxychloroquine enhanced the antitumor effect compared to treatment with Rapalink-1 alone by blocking the autophagy-inducing effect of mTOR inhibitors. CONCLUSION: Combined treatment with Rapalink-1 and hydroxychloroquine may be used as a potential therapeutic agent against UPS.


Assuntos
Apoptose , Autofagia , Hidroxicloroquina/farmacologia , Sarcoma/patologia , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Humanos , Sarcoma/tratamento farmacológico , Sarcoma/metabolismo , Sirolimo/farmacologia , Células Tumorais Cultivadas
2.
APMIS ; 129(10): 607-615, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34342050

RESUMO

Tumors exhibiting DNA mismatch repair (MMR) deficiency and microsatellite instability (MSI) are responsive to immune checkpoint blockade. MSI is frequently diagnosed using five quasimonomorphic mononucleotide (pentaplex) markers; however, the assays have several technical limitations, including the lack of sensitivity of some of the markers. Although markers with increased sensitivity, such as CAT25 and BAT40, have been introduced, the majority of multiplex MSI tests have only been studied in Western populations and require further evaluation in an Asian cohort. This study tested the efficacy of BAT26, CAT25, and BAT40 mononucleotide MSI markers via triplex PCR on 300 samples from patients with advanced cancers from a Korean clinical population. The results were directly compared with those of a pentaplex MSI test and tumor mutation burden (TMB) status, and an additional 60 MSI-H cancers were used for further validation. Four (1.3%) out of 300 advanced tumors were MSI-high (MSI-H). In the pentaplex PCR assay, two colorectal cancers (0.7%) exhibited instability only with the BAT25 mononucleotide marker and were interpreted as MSI-low (MSI-L). In the triplex PCR assay, BAT40 was unstable in 64 cases (21%) and the results did not overlap with those of MSI-L from pentaplex. Given the high frequency of isolated BAT40 instability, we performed the same triplex PCR with DNA obtained from normal controls and found BAT40 polymorphisms in 37 cases (90%). Interestingly, the median TMB of the cases with BAT40 polymorphism was significantly higher (7.0 mt/Mb) than that of BAT40 wild-type cases (5.5 mt/Mb) (p = 0.003). The triplex PCR results from 60 additional MSI-H cancers correlated perfectly (100%) with those of pentaplex PCR, and the results were consistent for two (BAT26 and CAT25) markers. BAT40 germline polymorphism is common in the Korean population and is associated with higher TMB values. The simple duplex (BAT26 and CAT25) MSI test provided the same sensitivity and specificity as pentaplex PCR tests.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Marcadores Genéticos/genética , Mutação em Linhagem Germinativa , Instabilidade de Microssatélites , Repetições de Microssatélites/genética , Reação em Cadeia da Polimerase Multiplex/métodos , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Biblioteca Gênica , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex/normas , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Polimorfismo Genético , República da Coreia , Estudos Retrospectivos , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/metabolismo , Sarcoma/patologia , Sensibilidade e Especificidade , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
3.
Cells ; 10(8)2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34440844

RESUMO

Aberrant bioactivity of the insulin-like growth factor (IGF) system results in the development and progression of several pathologic conditions including cancer. Preclinical studies have shown promising anti-cancer therapeutic potentials for anti-IGF targeted therapies. However, a clear but limited clinical benefit was observed only in a minority of patients with sarcomas. The molecular complexity of the IGF system, which comprises multiple regulators and interactions with other cancer-related pathways, poses a major limitation in the use of anti-IGF agents and supports the need of combinatorial therapeutic strategies to better tackle this axis. In this review, we will initially highlight multiple mechanisms underlying IGF dysregulation in cancer and then focus on the impact of the IGF system and its complexity in sarcoma development and progression as well as response to anti-IGF therapies. We will also discuss the role of Ephrin receptors, Hippo pathway, BET proteins and CXCR4 signaling, as mediators of sarcoma malignancy and relevant interactors with the IGF system in tumor cells. A deeper understanding of these molecular interactions might provide the rationale for novel and more effective therapeutic combinations to treat sarcomas.


Assuntos
Receptor IGF Tipo 1/metabolismo , Sarcoma/patologia , Anticorpos Monoclonais/uso terapêutico , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Receptores CXCR4/metabolismo , Receptores da Família Eph/metabolismo , Sarcoma/tratamento farmacológico , Sarcoma/metabolismo , Transdução de Sinais
4.
Cells ; 10(6)2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204560

RESUMO

Sarcomas are a heterogeneous group of rare malignancies originating from mesenchymal tissues with limited therapeutic options. Recently, alterations in components of the fibroblast growth factor receptor (FGFR) signaling pathway have been identified in a range of different sarcoma subtypes, most notably gastrointestinal stromal tumors, rhabdomyosarcomas, and liposarcomas. These alterations include genetic events such as translocations, mutations, and amplifications as well as transcriptional overexpression. Targeting FGFR has therefore been proposed as a novel potential therapeutic approach, also in light of the clinical activity shown by multi-target tyrosine kinase inhibitors in specific subtypes of sarcomas. Despite promising preclinical evidence, thus far, clinical trials have enrolled very few sarcoma patients and the efficacy of selective FGFR inhibitors appears relatively low. Here, we review the known alterations of the FGFR pathway in sarcoma patients as well as the preclinical and clinical evidence for the use of FGFR inhibitors in these diseases. Finally, we discuss the possible reasons behind the current clinical data and highlight the need for biomarker stratification to select patients more likely to benefit from FGFR targeted therapies.


Assuntos
Tumores do Estroma Gastrointestinal/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Sarcoma/metabolismo , Transdução de Sinais/fisiologia , Animais , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Inibidores de Proteínas Quinases/farmacologia , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/patologia
5.
Int J Cancer ; 149(9): 1691-1704, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34213775

RESUMO

Malignant sarcomas are rare accounting for <1% of all adult solid malignancies and approximately 11% to 13% of all pediatric malignancies. TRK-inhibitors have demonstrated robust and long-lasting responses in patients with NTRK fusion-positive solid tumors, including sarcoma. Access to these agents in many jurisdictions such as Canada remains limited. We undertook a modified Delphi consensus to articulate and convey the clinical importance of these agents for the Canadian sarcoma community. A systematic search of published and presented literature was conducted to identify clinical trials reporting outcomes on the use of TRK-inhibitors in relapsed/refractory NTRK fusion-positive sarcoma. Three main consensus questions were identified: (a) is there currently an unmet clinical need for systemic therapy options in relapsed/refractory sarcoma? (b) do TRK-inhibitors confer a clinical benefit to patients with NTRK fusion-positive sarcoma? (c) do phase I/II basket trials provide sufficient evidence to justify funding of TRK-inhibitors in NTRK fusion-positive sarcoma? Response rates to the first and second surveys were 57% (n = 30) and 42% (n = 22), respectively. There was strong agreement among the Canadian sarcoma community that there was unmet clinical need for effective systemic therapy options in relapsed/refractory sarcoma, that TRK-inhibitors are a safe and effective treatment option for patients with NTRK fusion-positive sarcoma, and that available phase I/II basket trials provide sufficient evidence to support funding of these agents in relapsed/refractory NTRK fusion-positive sarcoma. TRK-inhibitors are a safe and effective systemic therapy option for patients with relapsed/refractory NTRK fusion-positive sarcoma.


Assuntos
Proteínas de Fusão Oncogênica/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Receptor trkA/metabolismo , Receptor trkC/antagonistas & inibidores , Sarcoma/tratamento farmacológico , Inquéritos e Questionários/estatística & dados numéricos , Adolescente , Adulto , Idoso , Canadá , Consenso , Progressão da Doença , Humanos , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Receptor trkA/genética , Receptor trkC/genética , Receptor trkC/metabolismo , Sarcoma/genética , Sarcoma/metabolismo , Análise de Sobrevida , Adulto Jovem
6.
J Hematol Oncol ; 14(1): 114, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294128

RESUMO

Metabolic rewiring offers novel therapeutic opportunities in cancer. Until recently, there was scant information regarding soft tissue sarcomas, due to their heterogeneous tissue origin, histological definition and underlying genetic history. Novel large-scale genomic and metabolomics approaches are now helping stratify their physiopathology. In this review, we show how various genetic alterations skew activation pathways and orient metabolic rewiring in sarcomas. We provide an update on the contribution of newly described mechanisms of metabolic regulation. We underscore mechanisms that are relevant to sarcomagenesis or shared with other cancers. We then discuss how diverse metabolic landscapes condition the tumor microenvironment, anti-sarcoma immune responses and prognosis. Finally, we review current attempts to control sarcoma growth using metabolite-targeting drugs.


Assuntos
Redes e Vias Metabólicas , Metaboloma , Sarcoma/metabolismo , Animais , Regulação Neoplásica da Expressão Gênica , Humanos , Metabolômica , Sarcoma/genética , Transdução de Sinais , Transcriptoma , Microambiente Tumoral
7.
Hum Genet ; 140(8): 1241-1252, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34059954

RESUMO

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas with poor prognosis, developing either sporadically or in persons with neurofibromatosis type 1 (NF1). Loss of CDKN2A/B is an important early event in MPNST progression. However, many reported MPNSTs exhibit partial or no inactivation of CDKN2A/B, raising the question of whether there is more than one molecular path for MPNST initiation. We present here a comprehensive genomic analysis of MPNST cell lines and tumors to explore in depth the status of CDKN2A. After accounting for CDKN2A deletions and point mutations, we uncovered a previously unnoticed high frequency of chromosomal translocations involving CDKN2A in both MPNST cell lines and primary tumors. Most identified translocation breakpoints were validated by PCR amplification and Sanger sequencing. Many breakpoints clustered in an intronic 500 bp hotspot region adjacent to CDKN2A exon 2. We demonstrate the bi-allelic inactivation of CDKN2A in all tumors (n = 15) and cell lines (n = 8) analyzed, supporting a single molecular path for MPNST initiation in both sporadic and NF1-related MPNSTs. This general CDKN2A inactivation in MPNSTs has implications for MPNST diagnostics and treatment. Our findings might be relevant for other tumor types with high frequencies of CDKN2A inactivation.


Assuntos
Carcinogênese/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neurofibromatose 1/genética , Neurofibrossarcoma/genética , Polimorfismo de Nucleotídeo Único , Sarcoma/genética , Translocação Genética , Sequência de Bases , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Cromossomos Humanos Par 9 , Inibidor p16 de Quinase Dependente de Ciclina/deficiência , Éxons , Genoma Humano , Humanos , Neurofibromatose 1/complicações , Neurofibromatose 1/metabolismo , Neurofibromatose 1/patologia , Neurofibrossarcoma/etiologia , Neurofibrossarcoma/metabolismo , Neurofibrossarcoma/patologia , Sarcoma/etiologia , Sarcoma/metabolismo , Sarcoma/patologia , Células de Schwann/metabolismo , Células de Schwann/patologia , Sequenciamento Completo do Genoma
8.
Cancer Chemother Pharmacol ; 88(2): 323-334, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33978839

RESUMO

AIM: The present study aims to examine the effects of apatinib combined with autophagy inhibitor 3-Methyladenine (3-MA) on the proliferation and apoptosis of human uterine sarcoma in FU-MMT-1 and MES-SA cells and its tumor inhibition effect in xenograft model of uterine sarcoma. METHODS: Different concentrations of 3-MA and apatinib were used to treat the uterine sarcoma cell lines (MES-SA and FU-MMT-1 cells). The cell viability was detected by CCK8 method. Flow cytometry was used to detect the apoptosis and cell cycle. Wound closure assay and Transwell assay were performed to measure the migration ability of cells. Western blot was used to determine the apoptosis proteins and autophagy proteins. A nude mice sarcoma xenograft model was established and treated with apatinib alone, 3-MA alone, or combined incubation of them. Tumor size of xenograft and the mice survival rate were measured. RESULTS: Combination of 3-MA and apatinib significantly inhibited the proliferation and migration ability, but increased the apoptosis rate of uterine sarcoma cells compared to apatinib. The combination of 3-MA and apatinib significantly limited the tumor size of xenograft and increased the survival rate of mice compared to apatinib alone. Apatinib inhibited the PI3K/Akt/mTOR pathway, while 3-MA and the combination of 3-MA and apatinib significantly activated the PI3K/Akt/mTOR pathway and inhibited autophagy. Combination of 3-MA and apatinib increased apoptosis compared to apatinib alone. The expression of VEGFR-2 was not impacted by 3-MA. CONCLUSION: Combination of apatinib and autophagy inhibitor 3-MA significantly inhibited the growth and migration of uterine sarcoma cells and xenograft. Autophagy inhibition may increase the antitumor effect of apatinib via the PI3K/Akt/mTOR pathway.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Sarcoma/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Neoplasias Uterinas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Sarcoma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Uterinas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
9.
Cell Death Dis ; 12(6): 515, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34016958

RESUMO

The EMX (Empty Spiracles Homeobox) genes EMX1 and EMX2 are two homeodomain gene members of the EMX family of transcription factors involved in the regulation of various biological processes, such as cell proliferation, migration, and differentiation, during brain development and neural crest migration. They play a role in the specification of positional identity, the proliferation of neural stem cells, and the differentiation of certain neuronal cell phenotypes. In general, they act as transcription factors in early embryogenesis and neuroembryogenesis from metazoans to higher vertebrates. The EMX1 and EMX2's potential as tumor suppressor genes has been suggested in some cancers. Our work showed that EMX1/EMX2 act as tumor suppressors in sarcomas by repressing the activity of stem cell regulatory genes (OCT4, SOX2, KLF4, MYC, NANOG, NES, and PROM1). EMX protein downregulation, therefore, induced the malignance and stemness of cells both in vitro and in vivo. In murine knockout (KO) models lacking Emx genes, 3MC-induced sarcomas were more aggressive and infiltrative, had a greater capacity for tumor self-renewal, and had higher stem cell gene expression and nestin expression than those in wild-type models. These results showing that EMX genes acted as stemness regulators were reproduced in different subtypes of sarcoma. Therefore, it is possible that the EMX genes could have a generalized behavior regulating proliferation of neural crest-derived progenitors. Together, these results indicate that the EMX1 and EMX2 genes negatively regulate these tumor-altering populations or cancer stem cells, acting as tumor suppressors in sarcoma.


Assuntos
Genes Homeobox , Proteínas de Homeodomínio/genética , Sarcoma/genética , Fatores de Transcrição/genética , Animais , Carcinogênese , Linhagem Celular Tumoral , Xenoenxertos , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Sarcoma/metabolismo , Sarcoma/patologia , Fatores de Transcrição/metabolismo
10.
Medicine (Baltimore) ; 100(20): e26040, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011115

RESUMO

BACKGROUND: Tumor-specific DNA methylation can potentially be a useful indicator in cancer diagnostics and monitoring. Sarcomas comprise a heterogeneous group of mesenchymal neoplasms which cause life-threatening tumors occurring throughout the body. Therefore, potential molecular detection and prognostic evaluation is very important for early diagnosis and treatment. METHODS: We performed a retrospective study analyzing DNA methylation of 261 patients with sarcoma from The Cancer Genome Atlas (TCGA) database. Cox regression analyses were conducted to identify a signature associated with the overall survival (OS) of patients with sarcoma, which was validated in a validation dataset. RESULTS: Three DNA methylation signatures were identified to be significantly associated with OS. Kaplan-Meier analysis showed that the 3-DNA methylation signature could significantly distinguish the high- and low-risk patients in both training (first two-thirds) and validation datasets (remaining one-third). Receiver operating characteristic (ROC) analysis confirmed that the 3-DNA methylation signature exhibited high sensitivity and specificity in predicting OS of patients. Also, the Kaplan-Meier analysis and the area under curve (AUC) values indicated that the 3-DNA methylation signature was independent of clinical characteristics, including age at diagnosis, sex, anatomic location, tumor residual classification, and histological subtypes. CONCLUSIONS: The current study showed that the 3-DNA methylation model could efficiently function as a novel and independent prognostic biomarker and therapeutic target for patients with sarcoma.


Assuntos
Metilação de DNA/fisiologia , Sarcoma/diagnóstico , Sarcoma/metabolismo , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Sarcoma/mortalidade , Neoplasias de Tecidos Moles/mortalidade , Adulto Jovem
11.
PLoS One ; 16(4): e0250643, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33886686

RESUMO

Soft tissue sarcoma (STS) is a rare cancer that develops from soft tissues in any part of the body. Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improve the clinical outcome of STS patients. We previously revealed that the tumor-specific, replication-competent oncolytic adenovirus OBP-301 kills human sarcoma cells. In this study, we investigated the radiosensitizing effect of OBP-301 in human STS cells. The in vitro antitumor effect of OBP-301 and ionizing radiation in monotherapy or combination therapy was assessed using highly radiosensitive (RD-ES and SK-ES-1) and moderately radiosensitive (HT1080 and NMS-2) STS cell lines. The expression of markers for apoptosis and DNA damage were evaluated in STS cells after treatment. The therapeutic potential of combination therapy was further analyzed using SK-ES-1 and HT1080 cells in subcutaneous xenograft tumor models. The combination of OBP-301 and ionizing radiation showed a synergistic antitumor effect in all human STS cell lines tested, including those that show different radiosensitivity. OBP-301 was found to enhance irradiation-induced apoptosis and DNA damage via suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1), which was expressed at higher levels in moderately radiosensitive cell lines. The combination of OBP-301 and ionizing radiation showed a more profound antitumor effect compared to monotherapy in SK-ES-1 (highly radiosensitive) and HT1080 (moderately radiosensitive) subcutaneous xenograft tumors. OBP-301 is a promising antitumor reagent to improve the therapeutic potential of radiotherapy by increasing radiation-induced apoptosis in STS.


Assuntos
Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Tolerância a Radiação , Sarcoma/terapia , Neoplasias de Tecidos Moles/terapia , Adenoviridae/genética , Animais , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Terapia Combinada , Dano ao DNA/efeitos da radiação , Feminino , Humanos , Camundongos , Camundongos Nus , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Terapia Viral Oncolítica , Radiação Ionizante , Sarcoma/metabolismo , Sarcoma/patologia , Sarcoma/radioterapia , Neoplasias de Tecidos Moles/metabolismo , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/radioterapia , Transplante Heterólogo
12.
Aging (Albany NY) ; 13(9): 12395-12409, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33872216

RESUMO

Budding Uninhibited By Benzimidazoles are a group of genes encoding proteins that play central roles in spindle checkpoint during mitosis. Improper mitosis may lead to aneuploidy which is found in many types of tumors. As a key mediator in mitosis, the dysregulated expression of BUBs has been proven to be highly associated with various malignancies, such as leukemia, gastric cancer, breast cancer, and liver cancer. However, bioinformatic analysis has not been applied to explore the role of the BUBs in sarcomas. Herein, we investigate the transcriptional and survival data of BUBs in patients with sarcomas using Oncomine, Gene Expression Profiling Interactive Analysis, Cancer Cell Line Encyclopedia, Kaplan-Meier Plotter, LinkedOmics, and the Database for Annotation, Visualization and Integrated Discovery. We found that the expression levels of BUB1, BUB1B and BUB3 were higher in sarcoma samples and cell lines than in normal controls. Survival analysis revealed that the higher expression levels of BUB1, BUB1B and BUB3 were associated with lower overall and disease-free survival in patients with sarcomas. This study implies that BUB1, BUB1B and BUB3 are potential treatment targets for patients with sarcomas and are new biomarkers for the prognosis of sarcomas.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Sarcoma/metabolismo , Proteínas de Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Mitose , Prognóstico , Sarcoma/diagnóstico , Sarcoma/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética
13.
Chin J Physiol ; 64(1): 43-50, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33642343

RESUMO

Focal adhesion (FA) turnover has been demonstrated to play an important role in cell migration; however, the mechanism of FA turnover is complicated and requires further investigation. In this study, Rab11, which is involved in endosome recycling, was examined in terms of a direct regulatory function in FA formation during cell migration. Wild-type and dominant negative (DN) Rab11 or shRab11 were transfected into human HT1080 fibrosarcoma cells; the cell motility and migration abilities were determined, and localization of Rab11 and FA molecules was monitored by confocal microscopy. The results showed that Rab11 deficiency or the DN form inhibited sarcoma cell migration. Rab11 was also found to be co-localized with recycled ß1 integrin and affected FA formation. We further employed immunofluorescence and immunoprecipitation to examine the physical interaction between Rab11 and focal adhesion kinase (FAK), and the results suggested that Rab11 affected cell migration by regulating FAK recycling to aid formation of an FA complex on the cell membrane.


Assuntos
Adesões Focais , Sarcoma , Adesão Celular , Movimento Celular , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Adesões Focais/metabolismo , Humanos , Fosforilação , Sarcoma/metabolismo
14.
BMC Cancer ; 21(1): 210, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648449

RESUMO

BACKGROUND: A number of studies have linked positive Ki-67 expression with the prognosis of osteosarcoma (OS) patients. However, the results have been conflicting. To address this controversy, we conducted an analysis using a meta-analysis and a TCGA dataset to estimate the value of Ki-67 expression in the prognosis of OS. METHODS: A comprehensive search for relevant papers was conducted using NCBI PubMed, Embase, Springer, ISI Web of Knowledge, the Cochrane Library, and CNKI regardless of the publication year. The associations between Ki-67 expression and the clinical features and main prognostic outcomes of OS were measured. The TCGA dataset was also analyzed. The pooled odds ratio (OR) and its 95% confidential intervals (CIs) were utilized for statistical analysis. RESULTS: Overall, a total of 12 studies with 500 cases were included, and the results indicated that the expression of Ki-67 was significantly associated with Enneking stage (OR = 6.88, 95% CI: 2.92-16.22, p < 0.05), distant metastasis (OR = 3.04, 95% CI: 1.51-6.12, p < 0.05) and overall survival (OR = 8.82, 95% CI: 4.68-16.65, p < 0.05) in OS patients. Additionally, we observed no significant heterogeneity among all retrieved studies. Associations between Ki-67 expression and overall survival and disease-free survival of sarcoma were confirmed using the TCGA and Kaplan-Meier plotter datasets. CONCLUSION: The present study strongly suggests that positive Ki-67 expression was associated with Enneking stage, distant metastasis, and overall survival of OS, and it may be used as a potential biomarker to predict prognosis and guide clinical therapy for OS.


Assuntos
Antígenos de Neoplasias/análise , Neoplasias Ósseas/metabolismo , Antígeno Ki-67/análise , Osteossarcoma/metabolismo , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-67/biossíntese , Antígeno Ki-67/genética , Metástase Neoplásica , Estadiamento de Neoplasias , Osteossarcoma/genética , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Prognóstico , Viés de Publicação , Sarcoma/genética , Sarcoma/metabolismo , Sarcoma/mortalidade , Sarcoma/patologia , Regulação para Cima
15.
Bioengineered ; 12(1): 496-506, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33587010

RESUMO

Soft tissue sarcomas (STSs) are rare, heterogeneous mesenchymal neoplasias. Understanding the tumor microenvironment (TME) and identifying potential biomarkers for prognosis associated with the TME of STS might provide effective clues for immune therapy. We evaluated the immune scores and stromal scores of STS patients by using the RNA sequencing dataset from The Cancer Genome Atlas (TCGA) database and the ESTIMATE algorithm. Then, the differentially expressed mRNAs (DEGs), miRNAs (DEMs) and lncRNAs (DELs) were identified after comparing the high- and low-score groups. Next, we established a competing endogenous RNA (ceRNA) network and explored the prognostic values of biomarkers involved in the network with the help of bioinformatics analysis. High immune score was significantly associated with favorable overall survival in STS patients. A total of 328 DEGs, 18 DEMs and 67 DELs commonly regulated in the immune and stromal score groups were obtained. A ceRNA network and protein-protein interaction (PPI) network identified some hub nodes with considerable importance in the network. Kaplan-Meier survival analysis demonstrated that nine mRNAs, two miRNAs and three lncRNAs were closely associated with overall survival of STS patients. Gene set enrichment analysis (GSEA) suggested that these three lncRNAs were mainly involved in immune response-associated pathways in STS patients. Finally, the expression levels of five mRNAs (APOL1, EFEMP1, LYZ, RARRES1 and TNFAIP2) were verified, which were consistent with the results of the TCGA cohort. The results of our study confirmed the prognostic value of immune scores for STS patients. We also identified several TME-related biomarkers that might contribute to prognostic prediction and immune therapy.


Assuntos
RNA Mensageiro , RNA não Traduzido , Sarcoma , Microambiente Tumoral/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biologia Computacional , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Mapas de Interação de Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/metabolismo , Adulto Jovem
17.
Diagn Pathol ; 16(1): 2, 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33419470

RESUMO

BACKGROUND: IL4Rα and IL13Rα1 are constituents of the type II IL4 receptor. Recently, IL4Rα and IL13Rα1 were reported to have roles in cancer progression and suggested as potential prognostic markers. However, studies on IL4Rα and IL13Rα1 in soft-tissue sarcomas have been limited. METHODS: This study investigated the immunohistochemical expression of IL4Rα and IL13Rα1 in 89 soft-tissue sarcomas of the extremities, superficial trunk, and retroperitoneum. Immunohistochemical staining for IL4Rα and IL13Rα1 were scored according to a combination of staining intensity and staining area in tissue microarray samples. Positivity for the immunohistochemical expression of IL4Rα and IL13Rα1 were determined using receiver operating curve analysis. Statistical analysis was performed using regression analysis and a chi-square test. RESULTS: In human soft-tissue sarcomas, immunohistochemical expression of IL4Rα was significantly associated with IL13Rα1 expression. Nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were significantly associated with shorter survival of soft-tissue sarcoma patients in univariate analysis. Multivariate analysis indicated that nuclear expression of IL4Rα and IL13Rα1 were independent indicators of shorter overall survival (IL4Rα; p = 0.002, IL13Rα1; p = 0.016) and relapse-free survival (IL4Rα; p = 0.022, IL13Rα1; p < 0.001) of soft-tissue sarcoma patients. Moreover, the co-expression pattern of nuclear IL4Rα and IL13Rα1 was an independent indicator of shorter survival of soft-tissue sarcoma patients (overall survival; overall p < 0.001, relapse-free survival; overall p < 0.001). CONCLUSIONS: This study suggests IL4Rα and IL13Rα1 are associated with the progression of soft-tissue sarcoma, and the expression of IL4Rα and IL13Rα1 might be novel prognostic indicators of soft-tissue sarcoma patients.


Assuntos
Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Neoplasias Retroperitoneais/diagnóstico , Sarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Extremidades/patologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Retroperitoneais/metabolismo , Neoplasias Retroperitoneais/patologia , Espaço Retroperitoneal/patologia , Sarcoma/metabolismo , Sarcoma/patologia , Neoplasias de Tecidos Moles/metabolismo , Neoplasias de Tecidos Moles/patologia , Análise de Sobrevida , Adulto Jovem
18.
Ann Diagn Pathol ; 51: 151706, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33516059

RESUMO

Two cases of primary intrapulmonary hyalinizing spindle cell tumor with giant rosettes are presented. The patients are one woman and one man ages 37 and 42 years respectively. Both patients presented with non-specific symptoms of cough, dyspnea, and chest pain. Imaging revealed the presence of an intrapulmonary mass. One tumor was located in the left lower lobe while the other tumor was in the right upper lobe. Both patients underwent lobectomy. The tumors ranged from 2.4 to 3.0 cm in greatest dimension and were characterized by the presence of a bland spindle cell proliferation with areas of hyalinization and the presence of the so-called giant rosettes. Immunohistochemical stains were performed and the spindle cell component show positive staining for vimentin and negative staining for Bcl-2, CD34, STAT6, p40. Keratin immunohistochemical stain highlighted the entrapped alveolar epithelium while S-100 protein showed weak focal staining in the spindle cells. Both patients have remained alive and well without evidence of recurrence or metastasis for a period of 6 to 14 months post-surgical resection. The cases herein presented highlight the ubiquitous distribution of this tumor and underscores the importance of keeping this particular tumor in the differential diagnosis of spindle cell tumors of the lung.


Assuntos
Fibroma/diagnóstico , Hialina/metabolismo , Neoplasias Pulmonares/patologia , Sarcoma/diagnóstico , Adulto , Proliferação de Células , Dor no Peito/diagnóstico , Dor no Peito/etiologia , Tosse/diagnóstico , Tosse/etiologia , Diagnóstico Diferencial , Dispneia/diagnóstico , Dispneia/etiologia , Feminino , Fibroma/metabolismo , Fibroma/patologia , Fibroma/cirurgia , Humanos , Hialina/ultraestrutura , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/cirurgia , Masculino , Proteínas S100/metabolismo , Sarcoma/metabolismo , Sarcoma/patologia , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia , Resultado do Tratamento , Vimentina/metabolismo
19.
Mol Cancer Ther ; 20(1): 132-141, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33177152

RESUMO

This phase Ib study enumerated whole blood circulating tumor cells (CTC) and evaluated biomarkers in patients with potentially resectable soft-tissue sarcoma (STS) treated with olaratumab monotherapy (20 mg/kg) for one cycle followed by up to six cycles of olaratumab (20 mg/kg, cycles 1-2; 15 mg/kg, cycles 3-7) plus doxorubicin (75 mg/m2 on day 1). CTCs, platelet-derived growth factor receptors (PDGFR), and PDGF ligand expression in tumor tissue pre- and post-olaratumab monotherapy were evaluated. Antitumor activity, safety, pharmacokinetics, and PET/biomarker association with clinical outcome were assessed. Of 51 treated patients, 35, 43, and 37 were evaluable for CTC enumeration, PDGFRs, and PDGF ligand expression, respectively. An increase in CTCs at cycle 1 day 8 was observed, followed by a significant reduction by cycle 3 day 1 or 30-day follow-up. Decrease in CTC counts after olaratumab monotherapy was higher in patients with disease control than without disease control (57.9% vs. 31.2%). Baseline IHC expression was positive in most patients for PDGFRα [n = 31 (72.1%)] and PDGFRß [n = 36 (83.7%)]. Similar rates were observed post-olaratumab monotherapy [PDGFRα, n = 30 (69.8%); PDGFRß, n = 33 (76.7%)]. Eleven patients (29.7%) showed a 30% reduction by RT-PCR in PDGFRα at cycle 2. PDGFR expression and PET response showed no correlation with clinical outcome. Safety and pharmacokinetic profiles were consistent with previous reports. This study, the first to use a validated method for CTC detection, confirms that CTC enumeration in STS is feasible. However, no correlation was observed between PDGFRα expression and clinical outcome.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Biomarcadores Tumorais/metabolismo , Doxorrubicina/uso terapêutico , Células Neoplásicas Circulantes/patologia , Sarcoma/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Ligantes , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/metabolismo , Tomografia por Emissão de Pósitrons , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Sarcoma/diagnóstico por imagem , Sarcoma/metabolismo , Resultado do Tratamento
20.
J Cutan Pathol ; 48(2): 207-210, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32583897

RESUMO

BACKGROUND: Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) share clinical, pathological, immunohistochemical and molecular features, though PDS is associated with a more aggressive behavior. METHODS: We reviewed 71 tumors fulfilling criteria for AFX and PDS to further stratify their biological potential. RESULTS: Lesions were mainly located on the scalps of elderly men, and were often ulcerated. One case was necrotic, one showed vascular invasion, and one showed perineural invasion. Fifty-one tumors were limited to reticular dermis (71.8%), 20 invaded subcutaneous tissue, focally in 13 cases (18.3%), and diffusely in seven (9.9%). Subcutaneous invasion was present significantly more often in tumors showing predominantly spindle compared to pleomorphic/mixed cell morphology (P = 0.02). At a follow-up of 17-125 months, 4 cases recurred locally, 4, 6, 10 and 13 months after surgery; no metastases were observed. Three tumors were composed of spindle cells, and one of clear cells. Three cases had margins focally involved, while the fourth case had clear margins. CONCLUSION: Depth of invasion and state of margins are criteria predicting prognosis in AFX/PDS; in addition, spindle cell morphology seems to be related to a more infiltrative pattern of growth and to aggressiveness. Grouping these tumors on a morphologic base could help to clarify their different biological behavior.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias de Cabeça e Pescoço , Sarcoma , Neoplasias Cutâneas , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Neoplasias de Cabeça e Pescoço/classificação , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Sarcoma/classificação , Sarcoma/diagnóstico , Sarcoma/metabolismo , Sarcoma/patologia , Neoplasias Cutâneas/classificação , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
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