RESUMO
Ovarian carcinoma is usually diagnosed at an advanced stage with peritoneal dissemination and/or lymph node metastasis, and the prognosis for such advanced carcinoma is very poor. Therefore, new biomarkers to predict patient prognosis are needed. Miyamoto et al. previously showed that keratan sulfate (KS) detected by the 5D4 monoclonal antibody was expressed in ovarian carcinoma. However, the detailed structure of such KS was not determined, and the biological significance of this finding remained to be clarified. We previously generated the 297-11A monoclonal antibody, which recognizes galactose (Gal)-6-O-sulfated N-acetyllactosamine (LacNAc) located at the nonreducing terminus. Because the 297-11A epitope overlaps with that of 5D4, here we chose to use the 297-11A antibody as a tool to analyze KS and related structures. We conducted immunohistochemical analysis of 98 ovarian carcinoma cases with 297-11A antibody combined with a series of glycosidases and performed mass spectrometry analysis of the human serous ovarian carcinoma cell line OVCAR-3 to deduce the glycan structure of 297-11A-sulfated glycans. We also performed western blot analysis to assess a potential association of 297-11A-sulfated glycans with the mucin core protein mucin 16 (MUC16; also known as cancer antigen 125 (CA125)). Finally, we examined the relationship between 297-11A expression and patient prognosis. Consequently, 297-11A-sulfated glycans were primarily expressed in serous and endometrioid carcinomas and poorly expressed in mucinous and clear cell carcinomas. We reveal that structurally, 297-11A-sulfated glycans expressed in ovarian carcinoma are O-glycans carrying partially sialylated, Gal-6-O-sulfated LacNAc and that these glycans are likely displayed on MUC16 mucin core proteins. Of clinical importance is that expression of 297-11A-sulfated glycans correlated with shorter progression-free survival in patients. Thus, 297-11A-sulfated glycans may serve as a predictor of ovarian carcinoma recurrence.
Assuntos
Neoplasias Ovarianas , Polissacarídeos , Humanos , Feminino , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/química , Polissacarídeos/metabolismo , Polissacarídeos/química , Prognóstico , Linhagem Celular Tumoral , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Idoso , Anticorpos Monoclonais/metabolismo , AdultoRESUMO
Therapeutic resistance is a notable cause of death in patients with ovarian carcinoma. Polyploid giant cancer cells (PGCCs), commonly arising in tumor tissues following chemotherapy, have recently been considered to contribute to drug resistance. As a type III deacetylase, Sirtuin1 (SIRT1) plays essential roles in the cell cycle, cellular senescence, and drug resistance. Accumulating evidence has suggested that alteration in its subcellular localization via nucleocytoplasmic shuttling is a critical process influencing the functions of SIRT1. However, the roles of SIRT1 subcellular localization in PGCC formation and subsequent senescence escape remain unclear. In this study, we compared the differences in the polyploid cell population and senescence state of PGCCs following paclitaxel treatment between tumor cells overexpressing wild-type SIRT1 (WT SIRT1) and those expressing nuclear localization sequence (NLS)-mutated SIRT1 (SIRT1NLSmt ). We investigated the involvement of cytoplasmic SIRT1 in biological processes and signaling pathways, including the cell cycle and cellular senescence, in ovarian carcinoma cells' response to paclitaxel treatment. We found that the SIRT1NLSmt tumor cell population contained more polyploid cells and fewer senescent PGCCs than the SIRT1-overexpressing tumor cell population. Comparative proteomic analyses using co-immunoprecipitation (Co-IP) combined with liquid chromatography-mass spectrometry (LC-MS)/MS showed the differences in the differentially expressed proteins related to PGCC formation, cell growth, and death, including CDK1 and CDK2, between SIRT1NLSmt and SIRT1 cells or PGCCs. Our results suggested that ovarian carcinoma cells utilize polyploidy formation as a survival mechanism during exposure to paclitaxel-based treatment via the effect of cytoplasmic SIRT1 on PGCC formation and survival, thereby boosting paclitaxel resistance. © 2023 The Pathological Society of Great Britain and Ireland.
Assuntos
Neoplasias Ovarianas , Paclitaxel , Feminino , Humanos , Paclitaxel/farmacologia , Sirtuína 1/genética , Proteômica , Linhagem Celular Tumoral , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/química , Carcinoma Epitelial do Ovário , PoliploidiaRESUMO
Ovarian cancer is the most common type of gynecologic cancer. One of the leading causes of high mortality is chemoresistance, developed primarily or during treatment. Different mechanisms of drug resistance appear at the cellular and cancer tissue organization levels. We examined the differences in response to the cytotoxic drugs CIS, MTX, DOX, VIN, PAC, and TOP using 2D (two-dimensional) and 3D (three-dimensional) culture methods. We tested the drug-sensitive ovarian cancer cell line W1 and established resistant cell lines to appropriate cytotoxic drugs. The following qualitative and quantitative methods were used to assess: 1) morphology - inverted microscope and hematoxylin & eosin staining; 2) viability - MTT assay; 3) gene expression - a quantitative polymerase chain reaction; 4) identification of proteins - immunohistochemistry, and immunofluorescence. Our results indicate that the drug-sensitive and drug-resistant cells cultured in 3D conditions exhibit stronger resistance than the cells cultured in 2D conditions. A traditional 2D model shows that drug resistance of cancer cells is caused mainly by changes in the expression of genes encoding ATP-binding cassette transporter proteins, components of the extracellular matrix, "new" established genes related to drug resistance in ovarian cancer cell lines, and universal marker of cancer stem cells. Whereas in a 3D model, the drug resistance in spheroids can be related to other mechanisms such as the structure of the spheroid (dense or loose), the cell type (necrotic, quiescent, proliferating cells), drug concentrations or drug diffusion into the dense cellular/ECM structure.
Assuntos
Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas , Neoplasias Ovarianas/química , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Linhagem Celular Tumoral , Humanos , Feminino , Esferoides Celulares , Técnicas de Cultura de Células em Três Dimensões , Antineoplásicos/farmacologiaRESUMO
Mucin domains are densely O-glycosylated modular protein domains found in various extracellular and transmembrane proteins. Mucin-domain glycoproteins play important roles in many human diseases, such as cancer and cystic fibrosis, but the scope of the mucinome remains poorly defined. Recently, we characterized a bacterial O-glycoprotease, StcE, and demonstrated that an inactive point mutant retains binding selectivity for mucin-domain glycoproteins. In this work, we leverage inactive StcE to selectively enrich and identify mucin-domain glycoproteins from complex samples like cell lysate and crude ovarian cancer patient ascites fluid. Our enrichment strategy is further aided by an algorithm to assign confidence to mucin-domain glycoprotein identifications. This mucinomics platform facilitates detection of hundreds of glycopeptides from mucin domains and highly overlapping populations of mucin-domain glycoproteins from ovarian cancer patients. Ultimately, we demonstrate our mucinomics approach can reveal key molecular signatures of cancer from in vitro and ex vivo sources.
Assuntos
Mucinas , Neoplasias Ovarianas , Feminino , Glicopeptídeos/química , Glicoproteínas/metabolismo , Glicosilação , Humanos , Mucinas/metabolismo , Neoplasias Ovarianas/química , Neoplasias Ovarianas/genéticaRESUMO
Primary peritoneal malignant mesothelioma (MM) can demonstrate morphologic overlap with low-grade and high-grade tubo-ovarian serous neoplasms; it is also biologically and prognostically distinct from benign mesothelial proliferations. Currently, there is no single biomarker that can definitively distinguish these neoplasms. Sex-determining region Y box 6 (SOX6) immunohistochemistry has been recently described to differentiate pleural epithelioid MM from lung adenocarcinoma, but it has not been evaluated in the peritoneum. SOX6 immunohistochemistry was performed on 43 peritoneal epithelioid MM, 7 peritoneal biphasic MM, 5 well-differentiated papillary mesotheliomas, 5 serous borderline tumors, 29 low-grade serous carcinomas (LGSCs), 20 high-grade serous carcinomas (HGSCs), and 25 cases of peritoneal reactive mesothelial hyperplasia. Quantitative SOX6 expression in epithelioid MM (median, 100% of tumor cells) was significantly greater than in LGSC/serous borderline tumor (median, 90%; P=0.004) and HGSC (median, 45%; P=0.0001). However, when SOX6 is expression is defined as ≥10% of tumor cells, there was no significant difference in the rate of SOX6 positivity between epithelioid MM (41/43, 95%), LGSC (28/29, 97%; P=1.0), and HGSC (17/20, 85%; P=0.16). Quantitative extent of SOX6 expression in epithelioid MM was significantly greater than in biphasic MM (median, 0%; P=0.0001), well-differentiated papillary mesothelioma (median, 20%; P=0.001), and reactive mesothelial hyperplasia (median, 20%; P=0.0001), but not significantly different from flat quiescent mesothelium (median, 90%; P=0.82). SOX6 immunohistochemistry is 95% sensitive for peritoneal epithelioid MM, but is also consistently expressed in LGSC and HGSC, negating its usefulness in this common differential diagnosis. SOX6 also shows variable expression across the spectrum of reactive, benign neoplastic, and malignant mesothelial lesions of the peritoneum, and does not appear to be diagnostically useful in distinguishing benign from malignant mesothelial proliferations.
Assuntos
Biomarcadores Tumorais/análise , Células Epitelioides/química , Neoplasias das Tubas Uterinas/química , Mesotelioma Maligno/química , Neoplasias Císticas, Mucinosas e Serosas/classificação , Neoplasias Ovarianas/química , Neoplasias Peritoneais/química , Fatores de Transcrição SOXD/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células , Bases de Dados Factuais , Diagnóstico Diferencial , Células Epitelioides/patologia , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Mesotelioma Maligno/patologia , Pessoa de Meia-Idade , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Valor Preditivo dos Testes , Adulto JovemRESUMO
Mesonephric-like adenocarcinomas (MLA) are rare neoplasms arising in the uterine corpus and ovary which have been added to the recent 2020 World Health Organization Classification of Female Genital Tumors. They have similar morphology and immunophenotype and exhibit molecular aberrations similar to cervical mesonephric adenocarcinomas. It is debated as to whether they are of mesonephric or Mullerian origin. We describe the clinical, pathologic, immunohistochemical, and molecular features of 5 cases of extrauterine mesonephric-like proliferations (4 ovary, 1 extraovarian), all with novel and hitherto unreported features. These include an origin of MLA in extraovarian endometriosis, an association of ovarian MLA with high-grade serous carcinoma, mixed germ cell tumor and mature teratoma, and a borderline ovarian endometrioid tumor exhibiting mesonephric differentiation. Four of the cases exhibited a KRAS variant and 3 also a PIK3CA variant. In reporting these cases, we expand on the published tumor types associated with MLA and report for the first time a borderline tumor exhibiting mesonephric differentiation. We show the value of molecular testing in helping to confirm a mesonephric-like lesion and in determining the relationship between the different neoplastic components. We provide further evidence for a Mullerian origin, rather than a true mesonephric origin, in some of these cases. We also speculate that in the 2 cases associated with germ cell neoplasms, the MLA arose out of the germ cell tumor.
Assuntos
Adenocarcinoma/patologia , Ductos Paramesonéfricos/patologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Ductos Mesonéfricos/patologia , Adenocarcinoma/química , Adenocarcinoma/genética , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Diferenciação Celular , Proliferação de Células , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Humanos , Mesocolo/química , Mesocolo/patologia , Pessoa de Meia-Idade , Ductos Paramesonéfricos/química , Mutação , Neoplasias Ovarianas/química , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Neoplasias Peritoneais/química , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/terapia , Proteínas Proto-Oncogênicas p21(ras)/genética , Resultado do Tratamento , Ductos Mesonéfricos/químicaRESUMO
Ovarian clear cell carcinoma (OCCC) and ovarian endometrioid carcinoma (OEC) are both associated with endometriosis but differ in histologic phenotype, biomarker profile, and survival. Our objectives were to refine immunohistochemical (IHC) panels that help distinguish the histotypes and reassess the prevalence of mismatch repair deficiency (MMRd) in immunohistochemically confirmed OCCC. We selected 8 candidate IHC markers to develop first-line and second-line panels in a training set of 344 OCCC/OEC cases. Interobserver reproducibility of histotype diagnosis was assessed in an independent testing cohort of 100 OCC/OEC initially without and subsequently with IHC. The prevalence of MMRd was evaluated using the testing cohort and an expansion set of 844 ovarian carcinomas. The 2 prototypical combinations (OCCC: Napsin A+/HNF1B diffusely+/PR-; OEC: Napsin A-/HNF1B nondiffuse/PR+) occurred in 75% of cases and were 100% specific. A second-line panel (ELAPOR1, AMACR, CDX2) predicted the remaining cases with 83% accuracy. Integration of IHC improved interobserver reproducibility (κ=0.778 vs. 0.882, P<0.0001). The prevalence of MMRd was highest in OEC (11.5%, 44/383), lower in OCCC (1.7%, 5/297), and high-grade serous carcinomas (0.7%, 5/699), and absent in mucinous (0/126) and low-grade serous carcinomas (0/50). All 5 MMRd OCCC were probable Lynch syndrome cases with prototypical IHC profile but ambiguous morphologic features: 3/5 with microcystic architecture and 2/5 with intratumoral stromal inflammation. Integration of first-line and second-line IHC panels increases diagnostic precision and enhances prognostication and triaging for predisposing/predictive molecular biomarker testing. Our data support universal Lynch syndrome screening in all patients with OEC when the diagnosis of other histotypes has been vigorously excluded.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma Endometrioide/química , Neoplasias Colorretais Hereditárias sem Polipose/química , Reparo de Erro de Pareamento de DNA , Imuno-Histoquímica , Neoplasias Ovarianas/química , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Diagnóstico Diferencial , Feminino , Predisposição Genética para Doença , Humanos , Variações Dependentes do Observador , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fenótipo , Valor Preditivo dos Testes , Reprodutibilidade dos TestesAssuntos
Biomarcadores Tumorais/genética , Fusão Gênica , Coativador 2 de Receptor Nuclear/genética , Neoplasias Ovarianas/genética , Tumor Rabdoide/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Neoplasias Uterinas/genética , Adulto , Biomarcadores Tumorais/análise , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia , Fenótipo , Tumor Rabdoide/química , Tumor Rabdoide/patologia , Tumor Rabdoide/cirurgia , Tumores do Estroma Gonadal e dos Cordões Sexuais/química , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Resultado do Tratamento , Neoplasias Uterinas/química , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgiaRESUMO
Separating extracellular vesicles (EV) from blood plasma is challenging and complicates their biological understanding and biomarker development. In this study, we fractionate blood plasma by combining size-exclusion chromatography (SEC) and OptiPrep density gradient centrifugation to study clinical context-dependent and time-dependent variations in the biomolecular landscape of systemically circulating EV. Using pooled blood plasma samples from breast cancer patients, we first demonstrate the technical repeatability of blood plasma fractionation. Using serial blood plasma samples from HIV and ovarian cancer patients (n = 10) we next show that EV carry a clinical context-dependent and/or time-dependent protein and small RNA composition, including miRNA and tRNA. In addition, differential analysis of blood plasma fractions provides a catalogue of putative proteins not associated with systemically circulating EV. In conclusion, the implementation of blood plasma fractionation allows to advance the biological understanding and biomarker development of systemically circulating EV.
Assuntos
Centrifugação com Gradiente de Concentração/métodos , Fracionamento Químico/métodos , Vesículas Extracelulares/química , Lipoproteínas/análise , Plasma/química , Proteoma , Biomarcadores/análise , Neoplasias da Mama/sangue , Neoplasias da Mama/química , Cromatografia em Gel , Feminino , Infecções por HIV/sangue , Humanos , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/químicaRESUMO
BACKGROUND: Hormonal therapies are commonly prescribed to patients with metastatic granulosa cell tumours (GCT), based on high response rates in small retrospective studies. Aromatase inhibitors (AIs) are reported to have high response rates and an accepted treatment option. We report the results of a phase 2 trial of an AI in recurrent/metastatic GCTs. METHODS: 41 patients with recurrent ER/PR + ve GCT received anastrozole 1 mg daily until progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) at 12 weeks, evaluated by RECIST1.1 criteria. Secondary endpoints included progression-free survival (PFS), CBR duration, quality of life and toxicity. RESULTS: The CBR at 12 weeks in 38 evaluable patients was 78.9%, which included one (2.6%; 95% CI: 0.5-13.5%) partial response and 76.3% stable disease. Two additional patients without measurable disease were stable, based on inhibin. Median PFS was 8.6 m (95% CI 5.5-13.5 m). There were delayed responses observed after 12 weeks with a total of 4 pts. (10.5%; 95% CI 4.2%-24.1%) with a RECIST partial response; 23 (59%) patients were progression-free at 6 months. The adverse effects were predominantly low grade. CONCLUSIONS: This is the first prospective trial of hormonal therapy in GCTs. Although there was a high CBR, the objective response rate to anastrozole was much lower than the pooled response rates of >70% to AIs reported in most retrospective series and case reports. PARAGON demonstrates the importance of prospective trials in rare cancers and the need to reconsider the role of AIs as single agents in GCTs.
Assuntos
Anastrozol/uso terapêutico , Tumor de Células da Granulosa/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Tumores do Estroma Gonadal e dos Cordões Sexuais/tratamento farmacológico , Adulto , Idoso , Feminino , Tumor de Células da Granulosa/química , Tumor de Células da Granulosa/mortalidade , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/química , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/química , Neoplasias Ovarianas/mortalidade , Qualidade de Vida , Tumores do Estroma Gonadal e dos Cordões Sexuais/química , Tumores do Estroma Gonadal e dos Cordões Sexuais/mortalidadeRESUMO
Ovarian carcinoma histotypes are distinct diseases with variable clinical outcomes and response to treatment. There is a need for new subtype-specific treatment modalities, especially for women with widespread and chemo-resistant disease. Stimulator of interferon genes (STING) is a part of the cGAS-STING pathway that mediates innate immune defence against infectious DNA-containing pathogens and also detects tumour-derived DNA and generates intrinsic antitumour immunity. The STING signalling pathway is suppressed by several mechanisms in a variety of malignant diseases and, in some cancers that may be a requirement for cellular transformation. The aim of this study was to use immunohistochemistry to evaluate STING protein expression across normal tissue, paratubal and ovarian cysts, and ovarian tumour histotypes including ovarian carcinomas. Herein, we show that the fallopian tube ciliated cells express STING protein, whereas the secretory cells are negative. STING expression differs among ovarian cancer histotypes; low-grade serous ovarian carcinomas and serous borderline tumours have uniform high STING expression, while high-grade serous and endometrioid carcinomas have heterogeneous expression, and clear cell and mucinous carcinomas show low expression. As low-grade serous carcinomas are known to be genomically stable and typically lack a prominent host immune response, the consistently high STING expression is unexpected. High STING expression may reflect pathway activation or histogenesis and the mechanisms may be different in different ovarian carcinoma histotypes. Further studies are needed to determine whether the STING signalling pathway is active and whether these tumours would be candidates for therapeutic interventions that trigger innate immunity activation.
Assuntos
Biomarcadores Tumorais/análise , Proteínas de Membrana/análise , Neoplasias Císticas, Mucinosas e Serosas/química , Neoplasias Ovarianas/química , Feminino , Humanos , Imunidade Inata , Imunoterapia , Gradação de Tumores , Neoplasias Císticas, Mucinosas e Serosas/imunologia , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Císticas, Mucinosas e Serosas/terapia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Transdução de SinaisRESUMO
PURPOSE: Due to the lack of effective screening approaches and early detection biomarkers, ovarian cancer has the highest mortality rates among gynecologic cancers. Herein, we undertook a systematic biomarker discovery and validation approach to identify microRNA (miRNA) biomarkers for the early detection of ovarian cancer. EXPERIMENTAL DESIGN: During the discovery phase, we performed small RNA sequencing in stage I high-grade serous ovarian cancer (n = 31), which was subsequently validated in multiple, independent data sets (TCGA, n = 543; GSE65819, n = 87). Subsequently, we performed multivariate logistic regression-based training in a serum data set (GSE106817, n = 640), followed by its independent validation in three retrospective data sets (GSE31568, n = 85; GSE113486, n = 140; Czech Republic cohort, n = 192) and one prospective serum cohort (n = 95). In addition, we evaluated the specificity of OCaMIR, by comparing its performance in several other cancers (GSE31568 cohort, n = 369). RESULTS: The OCaMIR demonstrated a robust diagnostic accuracy in the stage I high-grade serous ovarian cancer patients in the discovery cohort (AUC = 0.99), which was consistently reproducible in both stage I (AUC = 0.96) and all stage patients (AUC = 0.89) in the TCGA cohort. Logistic regression-based training and validation of OCaMIR achieved AUC values of 0.89 (GSE106817), 0.85 (GSE31568), 0.86 (GSE113486), and 0.82 (Czech Republic cohort) in the retrospective serum validation cohorts, as well as prospective validation cohort (AUC = 0.92). More importantly, OCaMIR demonstrated a significantly superior diagnostic performance compared with CA125 levels, even in stage I patients, and was more cost-effective, highlighting its potential role for screening and early detection of ovarian cancer. CONCLUSIONS: Small RNA sequencing identified a robust noninvasive miRNA signature for early-stage serous ovarian cancer detection.
Assuntos
Biomarcadores Tumorais/análise , Cistadenocarcinoma Seroso/química , Cistadenocarcinoma Seroso/diagnóstico , Detecção Precoce de Câncer/métodos , MicroRNAs/análise , Neoplasias Ovarianas/química , Neoplasias Ovarianas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Estudos Prospectivos , Estudos RetrospectivosRESUMO
PURPOSE: To analyze the role of six human epididymis protein 4 (HE4)-related mitochondrial ribosomal proteins (MRPs) in ovarian cancer and selected MRPL15, which is most closely related to the tumorigenesis and prognosis of ovarian cancer, for further analyses. METHODS: Using STRING database and MCODE plugin in Cytoscape, six MRPs were identified among genes that are upregulated in response to HE4 overexpression in epithelial ovarian cancer cells. The Cancer Genome Atlas (TCGA) ovarian cancer, GTEX, Oncomine, and TISIDB were used to analyze the expression of the six MRPs. The prognostic impact and genetic variation of these six MRPs in ovarian cancer were evaluated using Kaplan-Meier Plotter and cBioPortal, respectively. MRPL15 was selected for immunohistochemistry and GEO verification. TCGA ovarian cancer data, gene set enrichment analysis, and Enrichr were used to explore the mechanism of MRPL15 in ovarian cancer. Finally, the relationship between MRPL15 expression and immune subtype, tumor-infiltrating lymphocytes, and immune regulatory factors was analyzed using TCGA ovarian cancer data and TISIDB. RESULTS: Six MRPs (MRPL10, MRPL15, MRPL36, MRPL39, MRPS16, and MRPS31) related to HE4 in ovarian cancer were selected. MRPL15 was highly expressed and amplified in ovarian cancer and was related to the poor prognosis of patients. Mechanism analysis indicated that MRPL15 plays a role in ovarian cancer through pathways such as the cell cycle, DNA repair, and mTOR 1 signaling. High expression of MRPL15 in ovarian cancer may be associated with its amplification and hypomethylation. Additionally, MRPL15 showed the lowest expression in C3 ovarian cancer and was correlated with proliferation of CD8+ T cells and dendritic cells as well as TGFßR1 and IDO1 expression. CONCLUSION: MRPL15 may be a prognostic indicator and therapeutic target for ovarian cancer. Because of its close correlation with HE4, this study provides insights into the mechanism of HE4 in ovarian cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Proteínas Mitocondriais/metabolismo , Neoplasias Ovarianas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Ribossômicas/metabolismo , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Linfócitos T CD8-Positivos/citologia , Carcinoma Epitelial do Ovário/química , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Proliferação de Células/genética , Bases de Dados Genéticas , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Proteínas Mitocondriais/análise , Proteínas Mitocondriais/genética , Neoplasias Ovarianas/química , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ovário/química , Ovário/metabolismo , Prognóstico , RNA Mensageiro/análise , Proteínas de Ligação a RNA/análise , Proteínas de Ligação a RNA/genética , Proteínas Ribossômicas/análise , Proteínas Ribossômicas/genética , Regulação para Cima , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/análise , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/genética , Adulto JovemRESUMO
High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy. While immune checkpoint inhibitors against PD-L1 and CTLA-4 have shown significant effects in multiple tumor types, the response rate to single-agent immune checkpoint inhibitors is low in HGSC. Alternative biomarkers and targets must be identified to guide patient selection and new therapeutic strategies in HGSC. Here, we aim to investigate the clinical significance of novel immune modulators, including B7-H4, IDO1, Tim3, IL6, and IL-8, in patients with HGSC. A total of 48 patients with HGSCs, comprising 24 cases that were sensitive and 24 that were resistant to standard paclitaxel and carboplatin chemotherapy, were selected for our initial analysis. A NanoString assay including 33 immune-related genes was used to compare the expression of different immune regulatory molecules in the sensitive and resistant groups. Differentially expressed proteins were verified using multiplex immunohistochemical staining on tissue arrays of 202 patients with HGSCs who underwent primary surgery at MDACC. We analyzed the expression levels of immune checkpoints and compared expression profiles with clinicopathologic features including response, progression-free survival, and overall survival. HGSC tumors resistant to therapy expressed higher levels of B7-H4 (69.3%), IDO1 (71.8%), Tim3 (89.1%), and inflammatory factors IL-6 and IL-8, and expressed higher Tim3 in stromal components. High expression of B7-H4 and IDO1 was associated with significantly lower overall survival and progression-free survival. B7-H4 and IDO1 were co-expressed in 49.1% of studied cases. A panel of immunomodulatory proteins including B7-H4, IDO1, Tim3, IL-6, and IL-8 are expressed at high levels in HGSCs. These modulators represent novel targets to enhance immunotherapy in patients with HGSCs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Resistencia a Medicamentos Antineoplásicos , Indolamina-Pirrol 2,3,-Dioxigenase/análise , Neoplasias Císticas, Mucinosas e Serosas/química , Neoplasias Ovarianas/química , Inibidor 1 da Ativação de Células T com Domínio V-Set/análise , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/genética , Carboplatina/uso terapêutico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Gradação de Tumores , Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Císticas, Mucinosas e Serosas/mortalidade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Paclitaxel/uso terapêutico , Valor Preditivo dos Testes , Fatores de TempoAssuntos
Tumor Carcinoide/etiologia , Síndrome do Carcinoide Maligno/complicações , Neoplasias Ovarianas/etiologia , Teratoma/complicações , Doença Cardíaca Carcinoide/diagnóstico por imagem , Tumor Carcinoide/química , Tumor Carcinoide/diagnóstico por imagem , Tumor Carcinoide/patologia , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/química , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
Liquid biopsies constitute a minimally invasive means of managing cancer patients, entailing early diagnosis, follow-up and prediction of response to therapy. Their use in the germ cell tumor field is invaluable since diagnostic tissue biopsies (which are invasive) are often not performed, and therefore only a presumptive diagnosis can be made, confirmed upon examination of the surgical specimen. Herein, we provide an overall review of the current liquid biopsy-based biomarkers of this disease, including the classical, routinely used serum tumor markers-the promising microRNAs rapidly approaching the introduction into clinical practice-but also cell-free DNA markers (including DNA methylation) and circulating tumor cells. Finally, and importantly, we also explore novel strategies and challenges for liquid biopsy markers and methodologies, providing a critical view of the future directions for liquid biopsy tests in this field, highlighting gaps and unanswered questions.
Assuntos
Biópsia Líquida , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Procedimentos Clínicos , DNA de Neoplasias/química , Gerenciamento Clínico , Feminino , Humanos , Masculino , MicroRNAs/análise , Proteínas de Neoplasias/análise , Neoplasias Embrionárias de Células Germinativas/sangue , Neoplasias Embrionárias de Células Germinativas/química , Neoplasias Embrionárias de Células Germinativas/patologia , Células Neoplásicas Circulantes , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/química , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , RNA Neoplásico/análise , Neoplasias Testiculares/sangue , Neoplasias Testiculares/química , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/patologiaRESUMO
The association of Brenner tumor (BT) with rete ovarii (RO) has been rarely alluded to in the literature. Both entities have debatable histogenesis. In this study of six cases of BT associated with RO, we describe the morphologic features and performed immunohistochemical staining for markers of Mullerian, Wolffian, mesothelial, and sex cord stromal derivation to explore the relationship between these entities. Histologically, all BTs were benign, microscopic, and incidental. RO was prominent and hyperplastic with gradual or abrupt transition to BT. In addition, focal areas of rete entrapped between BT nests were seen. All BTs were positive for GATA-3 and negative for PAX-8. Conversely, the RO in all cases was negative for GATA-3 and positive for PAX-8. WT-1 was positive in both entities. Sex cord stromal and mesothelial markers (other than WT-1) were negative in BT and RO. Although morphologically, BTs seem to arise from RO in these cases, they have a distinct immunophenotype. It is possible that at least some BTs arise from metaplastic changes in RO epithelium.
Assuntos
Biomarcadores Tumorais/análise , Tumor de Brenner/patologia , Linhagem da Célula , Imuno-Histoquímica , Neoplasias Ovarianas/patologia , Ovário/patologia , Adulto , Idoso , Biópsia , Tumor de Brenner/química , Tumor de Brenner/cirurgia , Feminino , Humanos , Metaplasia , Pessoa de Meia-Idade , Neoplasias Ovarianas/química , Neoplasias Ovarianas/cirurgia , Ovário/química , Ovário/cirurgia , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
In this paper, we present a method to distinguish neoplastic tissues from non-neoplastic ones using calibration-free laser-induced breakdown spectroscopy (CF-LIBS). For this propose, plasma emission was collected from neoplastic and non-neoplastic tissues taken from the ovarian cancer mice models. Results were obtained by utilizing the characteristic plasma emission lines of different elements that have been confirmed in the investigated samples. From the temporal evolution of plasma emission, the optimum temporal-observation-windows are identified for LIBS investigation. The concentrations of the detected elements in tissues were measured by a calibration-free approach based on data process of plasma parameters at the local thermodynamic equilibrium. The neoplastic specimens provided more energetic plasma than non-neoplastic ones that resulting in higher peaks intensities, electron density and electron temperature especially in the early windows (between 0.1 µs to 0.8 µs). Results demonstrated higher concentrations of major and trace elements such as Mg, Fe, Ca, Na, and K in the neoplastic tissues. Finally, the results using CF-LIBS method were found to be in good agreement with that of Inductive coupled plasma-optical emission spectroscopy (ICP-OES).
Assuntos
Neoplasias Ovarianas/química , Análise Espectral/métodos , Oligoelementos/análise , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Sex cord tumor with annular tubules (SCTAT) is a highly rare type of ovarian sex cord-stromal tumor (SCST), the diagnosis of which remains to be challenging. The aim of this study was to scrutinize the utility of three immunohistochemical markers including Forkhead box protein 2 (FOXL2), SOX9, and ß-catenin and DICER1 mutation status in distinguishing SCTATs from other ovarian SCSTs. Nine cases of SCTAT, 10 Sertoli-Leydig cell tumor (SCLT), 10 adult-type granulosa cell tumor (AGCT), and 8 juvenile-type granulosa cell tumor (JGCT) were included in the study. SCTATs were characterized by diffuse and strong expression of SOX9, focal and weak expression of FOXL2, and the absence of DICER1 mutation. However, AGCTs and JGCTs displayed strong and diffuse expression of FOXL2, focal/no immunoreaction for SOX9. SLCTs generally showed moderate intensity of FOXL2 and SOX9 expression. Nuclear ß-catenin expression was observed in none of SLCT, 1/9 of SCTAT, 6/8 JGCT, and 4/10 AGCT cases, respectively. DICER1 hotspot mutation was detected in only 3 cases of SLCT and 2 cases of JGCT. We conclude that in addition to strong and diffuse SOX9 expression, weak/absent expression of FOXL2 is suggestive for the diagnosis of SCTAT. Hence, we suggest that inclusion of these two markers, SOX-9 and FOXL2, to the immunohistochemical panel helps in differentiation of SCTAT from other SCSTs in addition to morphologic findings. We also conclude that SCTATs of the ovary do not harbor DICER1 hotspot mutation.
Assuntos
Biomarcadores Tumorais , RNA Helicases DEAD-box/genética , Proteína Forkhead Box L2/análise , Mutação , Neoplasias Ovarianas , Ribonuclease III/genética , Fatores de Transcrição SOX9/análise , Tumores do Estroma Gonadal e dos Cordões Sexuais , beta Catenina/análise , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Tumor de Células da Granulosa/química , Tumor de Células da Granulosa/genética , Tumor de Células da Granulosa/patologia , Humanos , Imuno-Histoquímica , Neoplasias Ovarianas/química , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Valor Preditivo dos Testes , Tumor de Células de Sertoli-Leydig/química , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/química , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologiaRESUMO
Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy.