RESUMO
BACKGROUND: Epithelial ovarian cancer, especially high grade serous ovarian cancer (HGSOC) is by far, the most lethal gynecological malignancy with poor prognosis and high relapse rate. Despite of availability of several therapeutic interventions including poly-ADP ribose polymerase (PARP) inhibitors, HGSOC remains unmanageable and identification of early detection biomarkers and therapeutic targets for this lethal malady is highly warranted. Aberrant expression of protein kinase C iota (PKCί) is implicated in many cellular and physiological functions involved in tumorigenesis including cell proliferation and cell cycle deregulation. METHODS AND RESULTS: Two high grade serous ovarian cancer cells SKOV3 and COV362 were employed in this study. PKCί was genetically knocked down or pharmacologically inhibited and several functional and biochemical assays were performed. We report that PKCί is overexpressed in HGSOC cells and patient tissue samples with a significant prognostic value. Pharmacological inhibition of PKCί by Na-aurothiomalate or its shRNA-mediated genetic knockdown suppressed HGSOC cell proliferation, EMT and induced apoptosis. Moreover, PKCί positively regulated GLUT1 and several other glycolytic genes including HK1, HK2, PGK1, ENO1 and LDHA to promote elevated glucose uptake and glycolysis in HGSOC cells. Mechanistically, PKCί drove glycolysis via PI3K/AKT/mTOR signalling. Na-aurothiomalate and highly selective, dual PI3K/mTOR inhibitor dactolisib could serve as novel anti-glycolytic drugs in HGSOC. CONCLUSION: Taken together, our results indicate PKCί/PI3K/AKT/mTOR signalling cascade could be a novel therapeutic target in a lethal pathology like HGSOC.
Assuntos
Proliferação de Células , Glicólise , Isoenzimas , Neoplasias Ovarianas , Fosfatidilinositol 3-Quinases , Proteína Quinase C , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Feminino , Humanos , Apoptose/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Regulação Neoplásica da Expressão Gênica , Isoenzimas/metabolismo , Isoenzimas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteína Quinase C/metabolismo , Proteína Quinase C/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: The main challenge in treating ovarian cancer is chemotherapy resistance. Previous studies have shown that PAK2 is highly expressed in various cancers. This research investigates whether increased PAK2 expression contributes to chemo-resistance and poor prognosis in ovarian cancer. METHODS: Initially, bioinformatics analysis was used to assess the importance of PAK2 mRNA up-regulation in ovarian cancer. This was then validated using tissue microarray to confirm PAK2 protein expression and localization in clinical samples. Univariate and multivariate logistic regression analyses were carried out to identify potential risk factors for chemo-resistance in serous epithelial ovarian cancer (EOC), while multivariate Cox regression and Kaplan-Meier analysis were conducted to ascertain prognostic factors for overall survival (OS) and disease-free survival (DFS) in patients with serous EOC. In vitro experiments were conducted to verify if inhibiting PAK2 expression could increase A2780/Taxol cells' sensitivity to paclitaxel, as shown by evaluating cell proliferation, apoptosis, transwell, and clone formation. Additionally, the interaction between PAK2, lnc-SNHG1, and miR-216b-5p was verified using RIP and luciferase reporter assays. Rescue experiments were undertaken to examine the influence of the lnc-SNHG1/miR-216b-5p/PAK2 axis on the development of paclitaxel resistance in A2780/Taxol cells. RESULTS: The bioinformatics analysis indicated a notable increase in PAK2 expression in ovarian malignant tumors compared to adjacent tissues, particularly in patients with stage III-IV disease compared to those with stage I-II disease (P = 0.0056). Elevated levels of PAK2 were linked to reduced OS in ovarian cancer patients, although no significant association was observed with DFS. Immunohistochemistry findings further supported these results, showing positive PAK2 protein expression in chemo-resistant serous EOC tissues, predominantly localized in the cytoplasm, which correlated with poorer OS and DFS outcomes. In vitro experiments demonstrated that the downregulation of PAK2 in A2780/Taxol cells led to a reduction in colony formation, an increase in apoptosis, and a diminished capacity for cell invasion. Subsequent analysis confirmed that lnc-SNHG1 functions as a competitive endogenous RNA (ceRNA) by interacting with miR-216b-5p and regulating PAK2 expression. Rescue experiments demonstrated that lnc-SNHG1 induces resistance to paclitaxel in A2780/Taxol cells by modulating the miR-216b-5p/PAK2 axis. CONCLUSIONS: PAK2 shows promise as a predictor of chemotherapy resistance and poor outcomes in ovarian cancer, indicating its potential use as a treatment target to overcome this resistance.
Assuntos
Carcinoma Epitelial do Ovário , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias Ovarianas , Paclitaxel , Quinases Ativadas por p21 , Humanos , Quinases Ativadas por p21/metabolismo , Quinases Ativadas por p21/genética , Feminino , Resistencia a Medicamentos Antineoplásicos/genética , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Prognóstico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/mortalidade , MicroRNAs/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Pessoa de Meia-Idade , Proliferação de Células , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Apoptose/efeitos dos fármacos , Regulação para CimaRESUMO
Standard of care genetic testing has undergone significant changes in recent years. The British Gynecological Cancer Society and the British Association of Gynecological Pathologists (BGCS/BAGP) has re-assembled a multidisciplinary expert consensus group to update the previous guidance with the latest standard of care for germline and tumor testing in patients with ovarian cancer. For the first time, the BGCS/BAGP guideline group has incorporated a patient advisor at the initial consensus group meeting. We have used patient focused groups to inform discussions related to reflex tumor testing - a key change in this updated guidance. This report summarizes recommendations from our consensus group deliberations and audit standards to support continual quality improvement in routine clinical settings.
Assuntos
Carcinoma Epitelial do Ovário , Testes Genéticos , Neoplasias Ovarianas , Humanos , Feminino , Testes Genéticos/métodos , Testes Genéticos/normas , Reino Unido , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/diagnóstico , Sociedades Médicas , ConsensoRESUMO
Centrosome amplification is a feature of cancer cells associated with chromosome instability and invasiveness. Enhancing chromosome instability and subsequent cancer cell death via centrosome unclustering and multipolar divisions is an aimed-for therapeutic approach. Here, we show that centrosome amplification potentiates responses to conventional chemotherapy in addition to its effect on multipolar divisions and chromosome instability. We perform single-cell live imaging of chemotherapy responses in epithelial ovarian cancer cell lines and observe increased cell death when centrosome amplification is induced. By correlating cell fate with mitotic behaviors, we show that enhanced cell death can occur independently of chromosome instability. We identify that cells with centrosome amplification are primed for apoptosis. We show they are dependent on the apoptotic inhibitor BCL-XL and that this is not a consequence of mitotic stresses associated with centrosome amplification. Given the multiple mechanisms that promote chemotherapy responses in cells with centrosome amplification, we assess such a relationship in an epithelial ovarian cancer patient cohort. We show that high centrosome numbers associate with improved treatment responses and longer overall survival. Our work identifies apoptotic priming as a clinically relevant consequence of centrosome amplification, expanding our understanding of this pleiotropic cancer cell feature.
Assuntos
Apoptose , Centrossomo , Neoplasias Ovarianas , Humanos , Apoptose/efeitos dos fármacos , Centrossomo/metabolismo , Centrossomo/efeitos dos fármacos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Linhagem Celular Tumoral , Instabilidade Cromossômica/efeitos dos fármacos , Mitose/efeitos dos fármacos , Proteína bcl-X/metabolismo , Proteína bcl-X/genética , Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Análise de Célula Única/métodosRESUMO
Epithelial ovarian cancer is the deadliest gynecologic malignancy, characterized by high metastasis. Transforming growth factor-ß1 (TGF-ß1) drives epithelial- mesenchymal transformation (EMT), a key process in tumor metastasis. Tumor necrosis factor-α-induced protein 8 (TNFAIP8)-like 2 (TIPE2) acts as a negative regulator of innate and adaptive immunity and involves in various cancers. However, its relationship with TGF-ß1 in ovarian cancer and its role in reversing TGF-ß1-induced EMT remain unclear. This study examined TIPE2 mRNA and protein expression using quantitative RT-PCR (qRT-PCR), western blot and immunohistochemistry. The effects of TIPE2 overexpression and knockdown on the proliferation, migration and invasion of epithelial ovarian cancer cells were assessed through 5-ethynyl-2-deoxyuridine, colony-forming, transwell migration and invasion assays. The relationship between TIPE2 and TGF-ß1 was investigated using qRT-PCR and enzyme-linked immunosorbent assay, while the interaction between TIPE2 and Smad2 was identified via co-immunoprecipitation. The results revealed that TIPE2 protein was significantly down-regulated in epithelial ovarian cancer tissues and correlated with the pathological type of tumor, patients' age, tumor differentiation degree and FIGO stage. TIPE2 and TGF-ß1 appeared to play an opposite role to each other during the progression of human ovarian cancer cells. Furthermore, TIPE2 inhibited the metastasis and EMT of ovarian cancer cells by combining with Smad2 in vitro or in an intraperitoneal metastasis model. Consequently, these findings suggest that TIPE2 plays a crucial inhibitory role in ovarian cancer metastasis by modulating the TGF-ß1/Smad2/EMT signaling pathway and may serve as a potential target for ovarian cancer, providing important direction for future diagnostic and therapeutic strategies.
Assuntos
Carcinoma Epitelial do Ovário , Movimento Celular , Transição Epitelial-Mesenquimal , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Ovarianas , Proteína Smad2 , Fator de Crescimento Transformador beta1 , Proteína Smad2/metabolismo , Proteína Smad2/genética , Humanos , Feminino , Fator de Crescimento Transformador beta1/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Linhagem Celular Tumoral , Animais , Camundongos , Invasividade Neoplásica , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Camundongos Endogâmicos BALB C , Transdução de SinaisRESUMO
BACKGROUND: Epithelial ovarian cancer (EOC) is the deadliest gynaecological cancer with high mortality rates driven by the common development of resistance to chemotherapy. EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in promoting disease progression, metastasis and chemoresistance. The signalling mechanisms underpinning EOC omentum tropism have yet to be elucidated. METHODS: Three-dimensional co-culture models were used to explore adipocyte-EOC interactions. The impact of adipocytes on EOC proliferation, response to therapy and invasive capacity was assessed. Primary adipocytes and omental tissue were isolated from patients with ovarian malignancies and benign ovarian neoplasms. Exosomes were isolated from omentum tissue conditioned media and the effect of omentum-derived exosomes on EOC evaluated. Exosomal microRNA (miRNA) sequencing was used to identify miRNAs abundant in omental exosomes and EOC cells were transfected with highly abundant miRNAs miR-21, let-7b, miR-16 and miR-92a. RESULTS: We demonstrate the capacity of adipocytes to induce an invasive phenotype in EOC populations through driving epithelial-to-mesenchymal transition (EMT). Exosomes secreted by omental tissue of ovarian cancer patients, as well as patients without malignancies, induced proliferation, upregulated EMT markers and reduced response to paclitaxel therapy in EOC cell lines and HGSOC patient samples. Analysis of the omentum-derived exosomes from cancer patients revealed highly abundant miRNAs that included miR-21, let-7b, miR-16 and miR-92a that promoted cancer cell proliferation and protection from chemotherapy when transfected in ovarian cancer cells. CONCLUSIONS: These observations highlight the capacity of omental adipocytes to generate a pro-tumorigenic and chemoprotective microenvironment in ovarian cancer and other adipose-related malignancies.
Assuntos
Adipócitos , Exossomos , MicroRNAs , Invasividade Neoplásica , Neoplasias Ovarianas , Paclitaxel , Feminino , Exossomos/metabolismo , Humanos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Adipócitos/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Omento/patologia , Omento/metabolismo , Proliferação de Células/efeitos dos fármacos , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacosRESUMO
OBJECTIVE: The TGF-ß superfamily member activin, a dimer of the gene products of INHBA and/or INHBB, has been implicated in immune cell maturation and recruitment, but its immune impact within epithelial ovarian cancer (EOC) is not well characterized. We sought to explore differences in activin (INHBA/ Inhibin-ßA and INHBB/ Inhibin-ßB) between malignant and ovarian tissues at the RNA and protein level and assess the relationship between activin and immune cells in EOC. METHODS: Publicly available RNA sequencing data were accessed from GEO (#GSE143897) with normalization and quantification performed via DESeq2. Immune gene expression profile was further explored within the TCGA-OV cohort derived from The Cancer Genome Atlas (TCGA). Immunohistochemical analysis was performed to evaluate activin A and T-cell markers CD8 and FoxP3 at the protein level. ELISA to activin-A was used to assess levels in the ascites of advanced EOC patients. Kaplan-Meier curves were generated to visualize survival outcomes. RESULTS: Gene expression levels of components of the activin signaling pathway were elevated within EOC when compared to a benign cohort, with differences in activin type I/II receptor gene profiles identified. Additionally, INHBA gene expression was linked to lymphocytic immune markers in EOC samples. Immunohistochemistry analysis revealed a positive correlation of CD8 and FOXP3 staining with activin A at the protein level in both primary and metastatic epithelial ovarian cancer samples. Furthermore, Activin-A (inhibin-ßA) is significantly elevated in EOC patient ascites. CONCLUSION: INHBA expression is elevated within EOC, correlating with worse survival, with activin protein levels correlating with specific immune infiltration. Our findings suggest that activin-A may play a role in suppressing anti-tumor immunity in EOC, highlighting its potential as a therapeutic target.
Assuntos
Ativinas , Carcinoma Epitelial do Ovário , Subunidades beta de Inibinas , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/genética , Subunidades beta de Inibinas/genética , Subunidades beta de Inibinas/metabolismo , Ativinas/metabolismo , Ativinas/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genéticaRESUMO
BACKGROUND AND AIMS: CircRNAs and autophagy are closely involved in the physiological and pathological processes of ovarian cancer; however, their exact mechanisms are still undetermined. This investigation aimed to elucidate the function and associated pathways of circFAM188A, which modulates proliferation, autophagy, and invasion in ovarian cancer (EOC). METHODS: The expression of circFAM188A in the tissues of EOC patients was assessed via RT-PCR. To elucidate proliferation, invasion, and autophagy in the tumor cells, Transwell, 5-ethynyl-2'-deoxyuridine (EdU), and mRFP-GFP-LC3 reporter assays were conducted. The binding sites between circ-FAM188A and the miR-670-3p, miR-670-3p and YY1 were predicted using bioinformatics and verified by dual-luciferase reporter assays. Pulldown assays demonstrated binding between ULK1 and circ-FAM188A. ULK1 was found to be crucial in the initial stage of autophagy. Moreover, an in vivo xenograft model was established by subcutaneous injection of nude mice with EOC cells. RESULT: Expression of circ-FAM188A was increased in EOC tissues relative to normal ovarian tissues and circ-FAM188A overexpression promoted proliferation, invasion, and autophagy; these effects were reversed by circ-FAM188A silencing. miR-670-3p and circ-FAM188A co-localized in the cytoplasm. circ-FAM188A enhanced YY1 expression by sponging miR-670-3p and was also shown to interact with ULK1. CONCLUSION: It is thus suggested that circ-FAM188A modulates autophagy by sponging miR-670-3p as well as interacting with ULK1.
Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Autofagia , Carcinoma Epitelial do Ovário , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos Nus , MicroRNAs , Neoplasias Ovarianas , RNA Circular , Humanos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Feminino , MicroRNAs/genética , Autofagia/genética , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/metabolismo , Animais , Camundongos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Proliferação de Células/genética , RNA Circular/genética , RNA Circular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linhagem Celular Tumoral , Fator de Transcrição YY1/genética , Fator de Transcrição YY1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Movimento Celular/genética , Pessoa de Meia-IdadeRESUMO
BACKGROUND/AIM: Epithelial ovarian cancer (EOC) is a lethal disease that is the fifth leading cause of cancer-related death in women. BAF312 (siponimod) is a potent and selective sphingosine-1-phosphate (S1P) receptor modulator that has been approved as a treatment for multiple sclerosis. In addition to its immunomodulatory action, BAF312 shows preclinical antitumor effects in several cancer types. This study sought to determine whether BAF312 had anticancer properties against EOC using in vitro and in vivo models. MATERIALS AND METHODS: EOC cell lines A2780, SKOV3ip1, A2780-CP20, and SKOV3-TR were treated with BAF312 and tested for cell proliferation, apoptosis, and migration using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, fluorescence-activated cell sorting, and migration assays. We investigated the expression of sphingosine-1-phosphate receptor 1 (S1PR1) in most EOC cell lines through western blot analysis. To investigate potential mechanisms, western blot analysis was used to assess the expression of AKT serine/threonine kinase 1 (AKT) and extracellular-regulated kinase (ERK) after BAF312 treatment. We also created poly(D,L-lactide-co-glycolide) nanoparticles encapsulating BAF312 (PLGA-NP-BAF312) for in vivo therapy. The average size and zeta potential of PLGA-NP-BAF312 were determined using dynamic light scattering. The therapeutic efficacy of PLGA-NP-BAF312 was tested in an A2780 tumor-bearing orthotopic mouse model of EOC. RESULTS: S1PR1 was overexpressed in most EOC cell lines. BAF312 significantly reduced cell proliferation and migration while inducing significant apoptosis in all EOC cell lines. PLGA-NP-BAF312 treatment significantly reduced tumor weights in A2780 tumor-bearing mice. Furthermore, the anticancer effects of BAF312 were associated with reduced phosphorylation of ERK and AKT. CONCLUSION: Our findings show that BAF312 has significant anticancer effects in EOC cells by inhibiting the ERK and AKT pathways, and might potentially be used to treat EOCs.
Assuntos
Apoptose , Carcinoma Epitelial do Ovário , Movimento Celular , Proliferação de Células , Neoplasias Ovarianas , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Feminino , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/genética , Linhagem Celular Tumoral , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Camundongos , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Compostos de Benzil/farmacologia , Antineoplásicos/farmacologia , Azetidinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos Nus , Receptores de Esfingosina-1-Fosfato/metabolismo , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologiaRESUMO
Epithelial ovarian cancer (EOC) is the deadliest women's cancer and has a poor prognosis. Early detection is the key for improving survival (a 5-year survival rate in stage I/II is over 70% compared to that of 25% in stage III/IV) and can be achieved through methylation markers from circulating cell-free DNA (cfDNA) using a liquid biopsy. In this study, we first identify top 500 EOC markers differentiating EOC from healthy female controls from 3.3 million methylome-wide CpG sites and validated them in 1,800 independent cfDNA samples. We then utilize a pretrained AI transformer system called MethylBERT to develop an EOC diagnostic model which achieves 80% sensitivity and 95% specificity in early-stage EOC diagnosis. We next develop a simple digital droplet PCR (ddPCR) assay which archives good performance, facilitating early EOC detection.
Assuntos
Biomarcadores Tumorais , Ácidos Nucleicos Livres , Metilação de DNA , Detecção Precoce de Câncer , Neoplasias Ovarianas , Humanos , Feminino , Metilação de DNA/genética , Biomarcadores Tumorais/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/sangue , Detecção Precoce de Câncer/métodos , Ácidos Nucleicos Livres/genética , Ácidos Nucleicos Livres/sangue , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/patologia , Inteligência Artificial , Ilhas de CpG/genética , Pessoa de Meia-Idade , Biópsia Líquida/métodosRESUMO
Ovarian carcinoma remains the most lethal gynaecologic malignancy. Half of all high-grade serous ovarian cancers (HGSOCs) have a homologous recombination deficiency (HRD) with regard to the repair of double-strand DNA breaks and are candidate to receive maintenance treatment with PARP inhibitors. While a wealth of literature exists regarding the therapeutic guidance of patients from a medical standpoint, the influence of the HRD status on the surgical outlook has been comparatively limited. In this review, the clinical and biological features of advanced ovarian cancers with BRCA1/2 mutation and/or HRD status are considered with particular reference to their impact on the surgical management and on the medico-surgical sequence. The modification of the surgical indications according to the results of molecular testing in first-line and recurrent settings are discussed.
Assuntos
Carcinoma Epitelial do Ovário , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/cirurgia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/diagnóstico , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/diagnóstico , Proteína BRCA1/genética , Mutação , Proteína BRCA2/genética , Gerenciamento Clínico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêuticoRESUMO
Our study explores the role of cancer-derived extracellular exosomes (EXs), particularly focusing on collagen alpha-3 (VI; COL6A3), in facilitating tumor dissemination and metastasis in epithelial ovarian cancer (EOC). We found that COL6A3 is expressed in aggressive ES2 derivatives, SKOV3 overexpressing COL6A3 (SKOV3/COL6A3), and mesenchymal-type ovarian carcinoma stromal progenitor cells (MSC-OCSPCs), as well as their EXs, but not in less aggressive SKOV3 cells or ES2 cells with COL6A3 knockdown (ES2/shCOL6A3). High COL6A3 expression correlates with worse overall survival among EOC patients, as evidenced by TCGA and GEO data analysis. In vitro experiments showed that EXs from MSC-OCSPCs or SKOV3/COL6A3 cells significantly enhance invasion ability in ES2 or SKOV3/COL6A3 cells, respectively (both, p <0.001). In contrast, ES2 cells with ES2/shCOL6A3 EXs exhibited reduced invasion ability (p < 0.001). In vivo, the average disseminated tumor numbers in the peritoneal cavity were significantly greater in mice receiving intraperitoneally injected SKOV3/COL6A3 cells than in SKOV3 cells (p < 0.001). Furthermore, mice intravenously (IV) injected with SKOV3/COL6A3 cells and SKOV3/COL6A3-EXs showed increased lung colonization compared to mice injected with SKOV3 cells and PBS (p = 0.007) or SKOV3/COL6A3 cells and PBS (p = 0.039). Knockdown of COL6A3 or treatment with EX inhibitor GW4869 or rapamycin-abolished COL6A3-EXs may suppress the aggressiveness of EOC.
Assuntos
Carcinoma Epitelial do Ovário , Colágeno Tipo VI , Exossomos , Neoplasias Ovarianas , Exossomos/metabolismo , Exossomos/genética , Feminino , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Humanos , Colágeno Tipo VI/metabolismo , Colágeno Tipo VI/genética , Animais , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Camundongos , Linhagem Celular Tumoral , Metástase Neoplásica , Invasividade Neoplásica , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Movimento CelularRESUMO
Bisphenol A (BPA) has been a substantial additive in plastics until the reports on its adverse effects have led to its restrictions and replacement. Monitoring studies document the increasing occurrence of bisphenol analogs, however, data on their effects and risks is still insufficient. Based on the indications that BPA might contribute to ovarian cancer pathogenesis, we examined effects of the analogs AF (BPAF), S (BPS) and F (BPF) (10-9-10-4 M) on the Caov-3 epithelial cancer cells, including the impact on cell viability, proliferation, oxidative stress, and production and expression of several factors and genes related to ovarian cancer. At environmentally relevant doses, bisphenols did not exert significant effects. At the highest concentration, BPAF caused varied alterations, including decreased cell viability and proliferation, caspase activation, down-regulation of PCNA and BIRC5, elevation of IL8, VEGFA, MYC, PTGS2 and ABCB1 expressions. Only BPA (10-4 M) increased IL-6, IL-8 and VEGFA output by the Caov-3 cells. Each bisphenol induced generation of reactive oxygen species and decreased superoxide dismutase activity at the highest concentration. Although the effects were observed only in the supraphysiological doses, the results indicate that certain bisphenol analogs might affect several ovarian cancer cell characteristics and merit further investigation.
Assuntos
Compostos Benzidrílicos , Proliferação de Células , Sobrevivência Celular , Neoplasias Ovarianas , Fenóis , Humanos , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Feminino , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Linhagem Celular Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Sulfonas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Survivina/genética , Survivina/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Interleucina-8/metabolismo , Interleucina-8/genética , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , FluorocarbonosRESUMO
MicroRNAs (miRNAs) are a class of small RNA genes with important roles in cancer biology regulation. There are considerable studies regarding the roles of microRNA-505-3p (miR-505-3p) in cancer development and progression, but the function of miR-505-3p in epithelial ovarian cancer (EOC) has not been fully clarified. Comparative analysis of miRNA expression data set was used to select differentially expressed miRNAs. Quantitative real-time polymerase chain reaction was applied to detect expression levels of RNAs, while western blot and immunofluorescence staining were performed to detect expression levels of proteins of interest. The motility of EOC cells was assessed by wound healing and transwell assays. The binding and regulating relationship between miRNA and its direct target gene was investigated by dual-luciferase assay. Our results show that miR-505-3p was upregulated in recurrent EOC, which significantly inhibits EOC cell motility via modulating cell epithelial-mesenchymal transition. Furthermore, our results indicated that PEAK1 expression was inhibited by direct binding of miR-505-3p into its 3'-URT in EOC cells. Importantly, knockdown of PEAK1 attenuated the effect of mi-505-3p inhibitor on EOC cell migration and invasion. In conclusion, our findings indicate that miRNA-505-3p inhibits EOC cell motility by targeting PEAK1.
Assuntos
Carcinoma Epitelial do Ovário , Movimento Celular , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias Ovarianas , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genéticaRESUMO
BACKGROUND: There is no consensus regarding the specific genes included in the homologous recombination repair (HRR) gene panel for identifying the HRR deficiency (HRD) status and predicting the prognosis of epithelial ovarian cancer (EOC) patients. OBJECTIVE: We aimed to explore a 15-gene panel involving the HRR pathway as a predictive prognostic indicator in Chinese patients newly diagnosed with EOC. PATIENTS AND METHODS: We reviewed the previously published reports about different HRR gene panels and prespecified the 15-gene panel. The genetic testing results in a 15-gene panel from 308 EOC patients diagnosed between 2014 and 2022 from six centers were collected. The association of clinicopathologic characteristics, the use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) and progression-free survival (PFS) with 15-gene panel HRR mutations (HRRm) status was assessed. RESULTS: 43.2% (133/308) of patients were determined to carry 144 deleterious HRRm, among which 68.1% (98/144) were germline mutations and 32.8% (101/308) were BRCA1/2 gene lethal mutations. The hazard ratio (HR) (95% confidence interval, CI) for PFS (HRRm v HRR wild type, HRRwt) using the 15-gene panel HRRm was 0.42 (0.28-0.64) at all stages and 0.42 (0.27-0.65) at stages IIIC-IV. However, a prognostic difference was observed only between the BRCA mutation group and the HRRwt group, not between the non-BRCA HRRm group and the HRRwt group. For the subgroups of patients not using PARPis, the HR (95% CI) was 0.41 (0.24-0.68) at stages IIIC-IV. CONCLUSIONS: This study provides evidence that 15-gene panel HRRm can predict the prognosis of EOC, of these only the BRCA1/2 mutations, not non-BRCA HRRm, contribute to prognosis prediction. Among patients without PARPis, the HRRm group presented a better PFS. This is the first study of this kind in the Chinese population.
Assuntos
Carcinoma Epitelial do Ovário , Mutação , Neoplasias Ovarianas , Reparo de DNA por Recombinação , Humanos , Feminino , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Prognóstico , Pessoa de Meia-Idade , Reparo de DNA por Recombinação/genética , Adulto , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Mutação em Linhagem Germinativa , Idoso de 80 Anos ou maisRESUMO
The association of BRCA1 and BRCA2 mutations with increased risk for developing epithelial ovarian cancer is well established. However, the observed clinical differences, particularly the improved therapy response and patient survival in BRCA2-mutant patients, are unexplained. Our objective is to identify molecular pathways that are differentially regulated upon the loss of BRCA1 and BRCA2 functions in ovarian cancer. Transcriptomic and pathway analyses comparing BRCA1-mutant, BRCA2-mutant, and homologous recombination wild-type ovarian tumors showed differential regulation of the Wnt/ß-catenin pathway. Using Wnt3A-treated BRCA1/2 wild-type, BRCA1-null, and BRCA2-null mouse ovarian cancer cells, we observed preferential activation of canonical Wnt/ß-catenin signaling in BRCA1/2 wild-type ovarian cancer cells, whereas noncanonical Wnt/ß-catenin signaling was preferentially activated in the BRCA1-null ovarian cancer cells. Interestingly, BRCA2-null mouse ovarian cancer cells demonstrated a unique response to Wnt3A with the preferential upregulation of the Wnt signaling inhibitor Axin2. In addition, decreased phosphorylation and enhanced stability of ß-catenin were observed in BRCA2-null mouse ovarian cancer cells, which correlated with increased inhibitory phosphorylation on GSK3ß. These findings open venues for the translation of these molecular observations into modalities that can impact patient survival. SIGNIFICANCE: We show that BRCA1 and BRCA2 mutation statuses differentially impact the regulation of the Wnt/ß-catenin signaling pathway, a major effector of cancer initiation and progression. Our findings provide a better understanding of molecular mechanisms that promote the known differential clinical profile in these patient populations.
Assuntos
Proteína BRCA1 , Proteína BRCA2 , Carcinoma Epitelial do Ovário , Neoplasias Ovarianas , Via de Sinalização Wnt , Animais , Feminino , Humanos , Camundongos , Proteína Axina/genética , Proteína Axina/metabolismo , beta Catenina/metabolismo , beta Catenina/genética , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Via de Sinalização Wnt/genética , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt3A/metabolismo , Proteína Wnt3A/genéticaRESUMO
BACKGROUND: Epithelial ovarian carcinoma (EOC) is a prevalent gynaecological malignancy. The prognosis of patients with EOC is related to acetylation modifications and immune responses in the tumour microenvironment (TME). However, the relationships between acetylation-related genes, patient prognosis, and the tumour immune microenvironment (TIME) are not yet understood. Our research aims to investigate the link between acetylation and the tumour microenvironment, with the goal of identifying new biomarkers for estimating survival of patients with EOC. METHODS: Using data downloaded from the tumour genome atlas (TCGA), genotypic tissue expression (GTEx), and gene expression master table (GEO), we comprehensively evaluated acetylation-related genes in 375 ovarian cancer specimens and identified molecular subtypes using unsupervised clustering. The prognosis, TIME, stem cell index and functional concentration analysis were compared among the three groups. A risk model based on differential expression of acetylation-related genes was established through minimum absolute contraction and selection operator (LASSO) regression analysis, and the predictive validity of this feature was validated using GEO data sets. A nomogram is used to predict a patient's likelihood of survival. In addition, different EOC risk groups were evaluated for timing, tumour immune dysfunction and exclusion (TIDE) score, stemness index, somatic mutation, and drug sensitivity. RESULTS: We used the mRNA levels of the differentially expressed genes related to acetylation to classify them into three distinct clusters. Patients with increased immune cell infiltration and lower stemness scores in cluster 2 (C2) exhibited poorer prognosis. Immunity and tumourigenesis-related pathways were highly abundant in cluster 3 (C3). We developed a prognostic model for ten differentially expressed acetylation-related genes. Kaplan-Meier analysis demonstrated significantly worse overall survival (OS) in high-risk patients. Furthermore, the TIME, tumour immune dysfunction and exclusion (TIDE) score, stemness index, tumour mutation burden (TMB), immunotherapy response, and drug sensitivity all showed significant correlations with the risk scores. CONCLUSIONS: Our study demonstrated a complex regulatory mechanism of acetylation in EOC. The assessment of acetylation patterns could provide new therapeutic strategies for EOC immunotherapy to improve the prognosis of patients.
Assuntos
Carcinoma Epitelial do Ovário , Neoplasias Ovarianas , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Feminino , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/metabolismo , Acetilação , Prognóstico , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-IdadeRESUMO
Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Brain metastasis (BM) is quite an uncommon presentation. However, the likelihood of central nervous system (CNS) metastasization should be considered in the context of disseminated disease. The therapeutic management of BMs is an unmet clinical need, to date. We identified, across different cancer centers, six cases of both BRCA wild-type and BRCA-mutated EOCs spreading to the CNS. They presented either with a single brain lesion or with multiple lesions and most of them had intracranial-only disease. All cases received Poly-ADP ribose polymerase inhibitor (PARPi) maintenance, as per clinical practice, for a long time within a multimodal treatment approach. We also provide an insight into the available body of work regarding the management of this intriguing disease setting, with a glimpse of future therapeutic challenges. Despite the lack of unanimous guidelines, multimodal care pathways should be encouraged for the optimal disease control of this unfortunate patient subset. Albeit not being directly investigated in BM patients, PARPi maintenance is deemed to have a valuable role in this setting. Prospective research, aimed to implement worthwhile strategies in the multimodal patient journey of BMs from EOC, is eagerly awaited.
Assuntos
Neoplasias Encefálicas , Carcinoma Epitelial do Ovário , Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/genética , Terapia Combinada , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêuticoRESUMO
Epithelial ovarian cancer (EOC) is a deadly disease with limited diagnostic biomarkers and therapeutic targets. Here we conduct a comprehensive proteomic profiling of ovarian tissue and plasma samples from 813 patients with different histotypes and therapeutic regimens, covering the expression of 10,715 proteins. We identify eight proteins associated with tumor malignancy in the tissue specimens, which are further validated as potential circulating biomarkers in plasma. Targeted proteomics assays are developed for 12 tissue proteins and 7 blood proteins, and machine learning models are constructed to predict one-year recurrence, which are validated in an independent cohort. These findings contribute to the understanding of EOC pathogenesis and provide potential biomarkers for early detection and monitoring of the disease. Additionally, by integrating mutation analysis with proteomic data, we identify multiple proteins related to DNA damage in recurrent resistant tumors, shedding light on the molecular mechanisms underlying treatment resistance. This study provides a multi-histotype proteomic landscape of EOC, advancing our knowledge for improved diagnosis and treatment strategies.
Assuntos
Carcinoma Epitelial do Ovário , Proteínas , Proteoma , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Biomarcadores Tumorais/sangue , Aprendizado de Máquina , Mutação , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Prognóstico , Reparo do DNA/genética , Proteínas/genética , Proteínas/metabolismo , ChinaRESUMO
Dormancy in cancer is a clinical state in which residual disease remains undetectable for a prolonged duration. At a cellular level, rare cancer cells cease proliferation and survive chemotherapy and disseminate disease. We created a suspension culture model of high-grade serous ovarian cancer (HGSOC) dormancy and devised a novel CRISPR screening approach to identify survival genes in this context. In combination with RNA-seq, we discovered the Netrin signaling pathway as critical to dormant HGSOC cell survival. We demonstrate that Netrin-1, -3, and its receptors are essential for low level ERK activation to promote survival, and that Netrin activation of ERK is unable to induce proliferation. Deletion of all UNC5 family receptors blocks Netrin signaling in HGSOC cells and compromises viability during the dormancy step of dissemination in xenograft assays. Furthermore, we demonstrate that Netrin-1 and -3 overexpression in HGSOC correlates with poor outcome. Specifically, our experiments reveal that Netrin overexpression elevates cell survival in dormant culture conditions and contributes to greater spread of disease in a xenograft model of abdominal dissemination. This study highlights Netrin signaling as a key mediator HGSOC cancer cell dormancy and metastasis.
High-grade serous ovarian cancer (or HGSOC for short) is the fifth leading cause of cancer-related deaths in women. It is generally diagnosed at an advanced stage of disease when the cancer has already spread to other parts of the body. Surgical removal of tumors and subsequent treatment with chemotherapy often reduces the signs and symptoms of the disease for a time but some cancer cells tend to survive so that patients eventually relapse. The HGSOC cells typically spread from the ovaries by moving through the liquid surrounding organs in the abdomen. The cells clump together and enter an inactive state known as dormancy that allows them to survive chemotherapy and low-nutrient conditions. Understanding how to develop new drug therapies that target dormant cancer cells is thought to be an important step in prolonging the life of HGSOC patients. Cancer cells are hardwired to multiply and grow, so Perampalam et al. reasoned that becoming dormant poses challenges for HGSOC cells, which may create unique vulnerabilities not shared by proliferating cancer cells. To find out more, the researchers used HGSOC cells that had been isolated from patients and grown in the laboratory. The team used a gene editing technique to screen HGSOC cells for genes required by the cells to survive when they are dormant. The experiments found that genes involved in a cell signaling pathway, known as Netrin signaling, were critical for the cells to survive. Previous studies have shown that Netrin signaling helps the nervous system form in embryos and inhibits a program of controlled cell death in some cancers. Perampalam et al. discovered that Netrins were present in the environment immediately surrounding dormant HGSOC cells. Human HGSOC patients with higher levels of Netrin gene expression had poorer prognoses than patients with lower levels of Netrin gene expression. Further experiments demonstrated that Netrins help dormant HGSOC cells to spread around the body. These findings suggest that Netrin signalling may provide useful targets for future drug therapies against dormant cells in some ovarian cancers. This could include repurposing drugs already in development or creating new inhibitors of this pathway.