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1.
J Ovarian Res ; 15(1): 69, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35668504

RESUMO

BACKGROUND: Dysregulation of Ectonucleoside Triphospahate Diphosphohydrolase 5 (ENTPD5) in tumors might be associated with tumor progression, while the role of ENTPD5 in the growth and metastasis of serous ovarian cancer (SOC) is still unclear. METHODS: ENTPD5 expression patterns in ovarian cancer tissues were analyzed by qRT-PCR and immunohistochemistry assay (IHC). Two SOC cell lines, SKOV3 and OVCAR8, were stably transfected with lentivirus to build knockdown and overexpression cell lines. Clone formation assay, collagen gel droplet culture technology, wound healing assay and flow cytometry were used to assess the migration and growth traits of SOC cells. Expression levels of ENTPD5, glucose regulated protein 78 (GRP78), eukaryotic translation initiation factor 2 alpha (eIF-2α), phosphorylated -eIF-2α and, C/EBP homologous protein (CHOP) in SOC cells were detected by Western blot. RESULTS: Compared to fallopian tube tissues, the expression of ENTPD5 was significantly higher in tumor tissues obtained from SOC patients, and positively correlated with clinical stage and metastasis. ENTPD5 knockdown robustly inhibited cell proliferation, migration, whereas ENTPD5 overexpression elicited the opposite effect on SOC cells. ENTPD5 knockdown arrested cell cycle in G0/G1 phase and increased apoptosis. Importantly, ENTPD5 knockdown was associated with significantly decreased protein levels for GRP78, CHOP, and p-eIF-2α, suggesting possible involvement of ENTPD5 in endoplasmic reticulum stress (ERS). CONCLUSIONS: Our study demonstrates that ENTPD5 knockdown inhibited SOC cell proliferation, migration and restrained the activation of the GRP78/p-eIF-2α/CHOP pathway, which provides a potentially effective therapeutic target for the treatment of SOC.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Apoptose , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/patologia , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Fator de Iniciação 2 em Eucariotos/farmacologia , Feminino , Glucose , Humanos , Proteínas Oncogênicas , Neoplasias Ovarianas/patologia , Proteína C/farmacologia , Pirofosfatases/farmacologia
2.
Int J Mol Sci ; 23(11)2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35682896

RESUMO

Background: Recently, new paradigms for the etiology and origin of ovarian high-grade serous carcinoma (HGSC) have emerged. The carcinogens released during ovulation transform fallopian tube epithelial cells, exfoliating and metastasizing to the peritoneal organs, including the ovaries. Solid in vivo evidence of the paradigms in a mouse model is urgently needed but is hampered by the differing tubo-ovarian structures. In mice, there is a bursa structure surrounding the distal oviduct and ovary. This, on one hand, prevents the direct influence of ovulatory follicular fluid (FF) on the exfoliated tumor cells. On the other hand, it hinders the seeding of exfoliated tumor cells into the ovary. Methods: In this study, we created a bursa-free mouse xenograft model to examine the effect of superovulation on peritoneal and ovarian metastases of transformed human tubal epithelial cells after intraperitoneal injection in NSG mice. Results: The bursa-free mouse model showed a better effect of ovulation on peritoneal metastasis. In this model, superovulation increased the number of transformed human tubal epithelial cell seedlings after intraperitoneal injection. Compared to the bursa-intact state, bursa-free ovaries were more vulnerable to external tumor seeding in either normal ovulation or superovulation state. Conclusions: This study provides the first in vivo evidence that intraperitoneal spreading of tubal HGSC cells is enhanced by ovulation. This study also demonstrated a mouse model for studying ovary-peritoneum interaction in cancer development.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Animais , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Modelos Animais de Doenças , Neoplasias das Tubas Uterinas/patologia , Tubas Uterinas/patologia , Feminino , Xenoenxertos , Humanos , Camundongos , Neoplasias Ovarianas/patologia , Ovulação
3.
In Vivo ; 36(4): 1903-1910, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35738605

RESUMO

BACKGROUND/AIM: Mutations of BRCA1/2 improve cancer prognosis due to their better response to platinum-based chemotherapy. This study evaluated overall survival (OS) and progression-free survival (PFS) under similar conditions of first-line adjuvant chemotherapy within seven years in high-grade serous ovarian cancer (HGSOC). PATIENTS AND METHODS: A total of 160 patients were enrolled. The pathogenic BRCA1/2 variant group included pathogenic variant and likely-pathogenic variant, while the non-pathogenic group included wild-type and variant of uncertain significance. For first-line chemotherapy, delivered dose intensity, relative dose intensity, and delay of duration were calculated in all patients. RESULTS: Of the tested variants, 108 (67.5%) were non-pathogenic and 52 (32.5%) were pathogenic. No significant difference was found in various clinical factors of cancer stage, surgery, or chemotherapy. There was no significance for OS or PFS within five or seven years. CONCLUSION: In patients with HGSOC, the OS and PFS for germline BRCA1/2 pathogenic and non-pathogenic variants were not significantly different under similar conditions of first-line adjuvant chemotherapy within seven years.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Proteína BRCA1/genética , Quimioterapia Adjuvante , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Mutação , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia
4.
Gynecol Oncol ; 166(1): 90-99, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35624045

RESUMO

OBJECTIVES: Develop conditional survival and risk-assessment estimates for uterine serous carcinoma (USC) overall and stratified by stage as tools for annual survivorship counseling and care planning. METHODS: Patients in the National Cancer Data Base diagnosed between 2004 and 2014 with stage I-IV USC were eligible. Individuals missing stage or survival data or with multiple malignancies were excluded. Five-year conditional survival was estimated using the stage-stratified Kaplan-Meier method annually during follow-up. A standardized mortality ratio (SMR) estimated the proportion of observed to expected deaths in the U.S. adjusted for year, age, and race. The relationships between prognostic factors and survival were studied using multivariate Cox modeling at diagnosis and conditioned on surviving 5-years. RESULTS: There were 14,575 participants, including 43% with stage I, 8% with stage II, 29% with stage III, and 20% with stage IV USC. Five-year survival at diagnosis vs. after surviving 5-years was 52% vs. 75% overall, 77% vs. 81% for stage I, 57% vs. 72% for stage II, 40% vs. 66% for stage III, and 17% vs. 60% for stage IV USC, respectively (P < 0.0001). Incremental improvements in 5-year conditional survival and reductions in SMR tracked with annual follow-up and higher stage. The adjusted risk of death at diagnosis vs. after surviving 5-years was 1.15 vs. 1.40 per 5-year increase of age, 1.26 vs. 1.68 for Medicaid insurance, 3.92 vs. 2.48 for stage III disease, and 6.65 vs. 2.79 for stage IV disease, respectively (P < 0.0001). CONCLUSION: In USC, the evolution of conditional survival permits annual reassessments of prognosis to tailor survivorship counseling and care planning.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias do Endométrio , Neoplasias Uterinas , Idoso , Aconselhamento , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Sobrevivência , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/patologia
5.
Medicina (Kaunas) ; 58(5)2022 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-35630004

RESUMO

Background: It has been demonstrated that Egfl7 promotes tumor cell escape from immunity by downregulating the activation of tumor blood vessels. Aim: to analyze mRNA expression of EGFL7 within the tumor microenvironment of high-grade ovarian serous carcinoma and its association with a number of intraepithelial CD4+/CD8+ lymphocytes and ICAM-1 expression. Methods: qPCR analysis of EGFL7 mRNA in cancer cells and adjacent stromal endothelium microdissected from formalin-fixed paraffin-embedded tumors of 59 high-grade ovarian serous carcinoma patients, was performed. Infiltration of intraepithelial lymphocytes (CD4+/CD8+) and expression of ICAM-1 were evaluated by immunohistochemistry and compared between tumors with different statuses of EGFL7 expression. Results: EGFL7 was expressed in cancer cells (9/59, 15.25%), endothelium (8/59, 13.56%), or both cancer cells and adjacent endothelium (4/59, 6.78%). ICAM-1 was expressed on cancer cells (47/59, 79.66%), stromal endothelium (46/59, 77.97%), or both epithelium and endothelium (40 of 59, 67.8%). EGFL7-positivity of cancer cells and endothelium was associated with lower intraepithelial inflow of CD4+ (p = 0.022 and p = 0.029, respectively) and CD8+ lymphocytes (p = 0.004 and p = 0.031, respectively) but impact neither epithelial nor endothelial ICAM-1 expression (p = 0.098 and p = 0.119, respectively). The patients' median follow-up was 23.83 months (range 1.07-78.07). Lack of prognostic significance of EGFL7-status and ICAM-1 expression was notified. Conclusion: EGFL7 is activated in the cancer cells as frequently as in the endothelium of human high-grade ovarian serous carcinoma. Activation of EGFL7 in cancer cells and/or endothelial cells could negatively impact diapedesis regardless of localization.


Assuntos
Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Proteínas de Ligação ao Cálcio , Cistadenocarcinoma Seroso , Família de Proteínas EGF , Neoplasias Ovarianas , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Cistadenocarcinoma Seroso/patologia , Família de Proteínas EGF/metabolismo , Células Endoteliais/metabolismo , Feminino , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , RNA Mensageiro , Microambiente Tumoral
6.
J Ovarian Res ; 15(1): 50, 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35501919

RESUMO

BACKGROUND: Patients treated with neoadjuvant chemotherapy (NACT) for advanced high-grade serous ovarian carcinoma (HGSC) have a higher rate and shorter time to platinum-resistant recurrence compared to patients treated with primary cytoreductive surgery (PCS) and adjuvant chemotherapy. The purpose of this study is to determine the impact of NACT on somatic mutation status in platinum-sensitive and resistant HGSC. Patients with advanced HGSC who had a documented response to platinum-based NACT, a banked blood sample, and a banked tumor sample before and after NACT were identified. Whole exome and/or targeted deep sequencing was performed in matched normal and pre/post-NACT tumor samples from 3 platinum-resistant and 2 platinum-sensitive patients to identify somatic non-synonymous mutations at each time point. RESULTS: When comparing exonic non-synonymous mutations in pre-NACT and post-NACT samples from the same patient, an average of 41% (1-68%) of genes were mutated at both time points. There were no trends detected in the mutational burden following exposure to NACT in platinum-resistant vs. platinum-sensitive cases. The majority of mutated genes were unique to each case. We identified several genes that were commonly mutated in pre-NACT samples specific to platinum-resistant (CSPG4, SLC35G5, TUBA3D) or sensitive (CYP2D6, NUTM1, DNAH5) cases. Four mutated genes emerged exclusively in the platinum-resistant cases (ADGRV1, MUC17, MUC20, PAK2) following NACT. CONCLUSIONS: Patients with advanced HGSC present with significant intra-tumor heterogeneity. NACT significantly impacts the somatic mutation status irrespective of the time to recurrence. The mutated genes detected in chemo-naive pre-NACT tumor samples from either resistant or sensitive cases could potentially have a role in the prediction of chemotherapy response in patients scheduled to receive NACT; larger studies are required to further validate these genes.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Epiteliais e Glandulares , Neoplasias Ovarianas , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Mutação , Terapia Neoadjuvante , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia
7.
Methods Mol Biol ; 2429: 445-454, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35507180

RESUMO

Identification of serous tubal intraepithelial carcinomas (STIC) in the fallopian tubes of women who are carriers of germ line pathogenic variants in tubo-ovarian cancer predisposition genes (i.e., BRCA1 and BRCA2) has led to the hypothesis that many high-grade serous carcinomas (HGSC) arise from the fimbria of the fallopian tube. However, the primitive (stem and progenitor) tubal epithelial cells that give rise to STIC and HGSC have not been defined. Further, as putative HGSC precursors are discovered at salpingectomy, the natural history of such lesions is truncated at diagnosis. Thus, living cultures of human fallopian tubes suitable for experimental studies are needed to define and characterize the cellular origin of HGSCs and thereby advance the discovery of improved methods to assess risk, develop effective early detection tests and identify novel prevention approaches. Accordingly, patient-derived tissue-organoids and isolated epithelial stem cell derived-organoids generated from average and high-risk patients are vital resources to understand the developmental biology of aging fallopian tubes and pathogenesis of HGSCs. With a vision to boost HGSC prevention research, we have established state-of-the-art protocols for the collection, processing, storage, distribution, and management of fallopian tube tissues. Here we describe the protocol for preparing these organoids, with emphasis on the key steps that require meticulous attention to achieve success.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Células Epiteliais/metabolismo , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/metabolismo , Neoplasias das Tubas Uterinas/patologia , Tubas Uterinas/metabolismo , Feminino , Humanos , Organoides/metabolismo , Neoplasias Ovarianas/metabolismo
8.
J Ovarian Res ; 15(1): 64, 2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35610701

RESUMO

Circulating leukocytes are an important part of the immune system. The aim of this work is to explore the role of preoperative circulating leukocytes in serous ovarian carcinoma and investigate whether they can be used to predict survival prognosis. Routine blood test results and clinical information of patients with serous ovarian carcinoma were retrospectively collected. And to predict survival according to the blood routine test result the decision tree method was applied to build a machine learning model.The results showed that the number of preoperative white blood cells (p = 0.022), monocytes (p < 0.001), lymphocytes (p < 0.001), neutrophils (p < 0.001), and eosinophils (p < 0.001) and the monocyte to lymphocyte (MO/LY) ratio in the serous ovarian cancer group were significantly different from those in the control group. These factors also showed a correlation with other clinicopathological characteristics. The MO/LY was the root node of the decision tree, and the predictive AUC for survival was 0.69. The features involved in the decision tree were the MO/LY, differentiation status, CA125 level, neutrophils (NE,) ascites cytology, LY% and age.In conclusion, the number and percentage of preoperative leukocytes in patients with ovarian cancer is changed significantly compared to those in the normal control group, as well as the MO/LY. A decision tree was built to predict the survival of patients with serous ovarian cancer based on the CA125 level, white blood cell (WBC) count, presence of lymph node metastasis (LNM), MO count, the MO/LY ratio, differentiation status, stage, LY%, ascites cytology, and age.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Inteligência Artificial , Ascite , Antígeno Ca-125 , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/cirurgia , Feminino , Humanos , Linfócitos , Neoplasias Ovarianas/patologia , Prognóstico , Estudos Retrospectivos
9.
Gynecol Oncol ; 165(3): 560-567, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35606067

RESUMO

OBJECTIVE: Low-grade serous carcinoma (LGSOC) is a rare epithelial ovarian/peritoneal cancer characterized by younger age at diagnosis, relative chemoresistance, prolonged overall survival (OS), and mutations in the mitogen activated protein kinase (MAPK) pathway compared to high-grade serous carcinoma. We describe the genomic profile of LGSOC by next generation sequencing (NGS) and evaluated its potential relationship to clinical outcomes. METHODS: The study included 215 women with LGSOC with: 1) pathologically confirmed LGSOC, 2) availability of NGS data, and 3) adequate clinical data. Clinical subgroups were compared for progression-free survival (PFS) and OS. Multivariable Cox regression analysis was performed. RESULTS: Median age at diagnosis was 46.6 years. The majority had a stage III ovarian primary. One or more mutations were identified in 140 (65.1%) cases; 75 (34.9%) had none. The most common mutations were KRAS (n = 71; 33.0%), NRAS (n = 24; 11.2%), and BRAF (n = 18; 8.4%). Patients with MAPK-mutated tumors (n = 113) (52.6%) had a significantly longer OS compared to those with tumors lacking MAPK pathway mutations (n = 102) (47.4%) [median OS, 147.8 months (95% CI,119.0-176.6) versus 89.5 months (95% CI, 61.4-117.7) (p = 0.01)], respectively. Median OS for patients with MAPK-mutated tumors was also significantly better than for patients whose tumors had no mutations (n = 75) [median OS, 147.8 months (95% CI, 119.0-176.6) versus 78.0 months (95% CI, 57.6-98.3)], respectively (p = 0.001). Median OS for patients with non-MAPK-mutated tumors (n = 27) was 125.1 months (95% CI, 83.9-166.3). In multivariable analysis, having a MAPK mutation was associated with improved OS. CONCLUSIONS: Patients with MAPK-mutated tumors have a significantly improved OS compared to those without MAPK-mutated tumors.


Assuntos
Cistadenocarcinoma Papilar , Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Neoplasias Peritoneais , Carcinoma Epitelial do Ovário/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Genômica , Humanos , Mutação , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/patologia
10.
J Cancer Res Ther ; 18(1): 301-304, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35381807

RESUMO

Although papillary serous cyst adenocarcinoma of the ovary is a common tumor, the incidence of ovarian-type papillary serous cyst adenocarcinoma in the testis is rare. Based on medical documents, there are only about 50 cases reported about testicular and paratesticular serous tumors.[1],[2],[3] Herein, we report a case of low-grade serous cyst adenocarcinoma of the testis that did unilateral orchiectomy and then came with retroperitoneal mass and lung metastasis. Chemotherapy was well tolerated, and now, after 1 year, he does not have any complaint.


Assuntos
Adenocarcinoma , Cistadenocarcinoma Seroso , Cistos , Neoplasias Testiculares , Adenocarcinoma/diagnóstico , Adenocarcinoma/cirurgia , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/patologia , Neoplasias Testiculares/cirurgia
12.
Gynecol Oncol ; 165(3): 552-559, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35414426

RESUMO

OBJECTIVES: The "incessant ovulation" hypothesis links increased risk for tubo-ovarian high-grade serous carcinoma (HGSC) due to more ovulations and reduced risk conferred by pre-menopausal exposures like oral contraceptive use, multiparity, and breastfeeding. However, most women diagnosed with HGSC are postmenopausal, implying age is a major risk factor for HGSC. Our mouse model for HGSC, based on tamoxifen (TAM)-induced somatic inactivation of the Brca1, Trp53, Rb1, and Nf1 (BPRN) tumor suppressor genes in oviductal epithelium, recapitulates key genetic, histopathologic, and biological features of human HGSCs. We aimed to credential the model for future efforts to define biological and risk modification factors in HGSC pathogenesis. METHODS: BPRN mice were treated with TAM to induce tumors at defined ages and parity status. RESULTS: BPRN mice aged 9-months prior to tumor induction had markedly shorter survival than 6-8 week old mice induced to form tumors (median 46.5 weeks versus 61.5 weeks, log-rank test P = 0.0006). No significant differences in cancer phenotypes were observed between multiparous versus nulliparous BPRN mice. However, using a modified tumor model with one wild-type Nf1 allele (BPRNfl/+), nulliparous mice had more advanced tumors than multiparous mice (Mantel-Haenszel Chi-square test of association, P = 0.01). CONCLUSIONS: Our findings show aging is associated with significantly shortened survival post tumor induction in the BRPN model and multiparity delays development and/or progression of HGSC in certain genetic contexts. The findings support relevance of our mouse model to gain mechanistic insights into how known factors exert their protective effects and to test novel approaches for HGSC prevention.


Assuntos
Carcinoma , Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Envelhecimento , Animais , Transformação Celular Neoplásica/patologia , Cistadenocarcinoma Seroso/patologia , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/patologia , Paridade , Gravidez
13.
J Ovarian Res ; 15(1): 48, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35477477

RESUMO

BACKGROUND: Taxol resistance in serous ovarian cancer is responsible for its poor prognosis, yet the underlying mechanism is still poorly understood. Thus, we probed the mechanism of Taxol resistance in serous ovarian cancer with multiple bioinformatic methods to provide novel insights into potential therapies. METHODS: The differentially expressed genes (DEGs) in Taxol-sensitive and Taxol-resistant cell lines and their relationship with the overall survival (OS) and progression-free interval (PFI) of ovarian cancer patients were analyzed using gene expression datasets from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The role of receptor interacting serine/threonine kinase 2 (RIPK2) was validated via identification of its coexpressed genes, functional analysis and generation of a protein-protein interaction (PPI) network. The single sample gene set enrichment analysis (ssGSEA) was used to explore immune infiltration, and genomic alterations of RIPK2 were also analyzed via cBio Cancer Genomics Portal (cBioProtal). RESULTS: RIPK2 was highly expressed in Taxol resistant ovarian cancer cell lines, and its high expression was also linked with shorter OS and PFI in serous ovarian cancer patients. The PPI network analysis and pathway analysis demonstrated that RIPK2 might participate in the positive regulation of NF-κB transcription factor activity. RIPK2 expression was related to tumor microenvironment alterations, which might participate in the formation of Taxol resistance. CONCLUSIONS: Our studies suggested that high expression of RIPK2 is related to Taxol resistance in serous ovarian cancer, and that RIPK2 induces Taxol resistance through NOD1/RIPK2/NF-κB inflammatory pathway activation and tumor microenvironment changes.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , NF-kappa B/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Microambiente Tumoral/genética
14.
J Exp Clin Cancer Res ; 41(1): 157, 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35477522

RESUMO

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) encompasses a highly dynamic and complex key process which leads to metastatic progression. In high-grade serous ovarian carcinoma (HG-SOC), endothelin-1 (ET-1)/endothelin A receptor (ETAR) signaling promotes EMT driving tumor progression. However, the complex nature of intertwined regulatory circuits activated by ET-1 to trigger the metastatic process is not fully elucidated. METHODS: The capacity of ET-1 pathway to guide a critical transcriptional network that is instrumental for metastatic growth was identified in patient-derived HG-SOC cells and cell lines through immunoblotting, q-RT-PCR, co-immunoprecipitation, in situ proximity ligation, luciferase reporter, chromatin immunoprecipitation assays and publicly available databases. Functional assays in HG-SOC cells and HG-SOC xenografts served to test the inhibitory effects of ET-1 receptors (ET-1R) antagonist in vitro and in vivo. RESULTS: We demonstrated that ET-1/ETAR axis promoted the direct physical ZEB1/YAP interaction by inducing their nuclear accumulation in HG-SOC cells. Moreover, ET-1 directed their engagement in a functional transcriptional complex with the potent oncogenic AP-1 factor JUN. This led to the aberrant activation of common target genes, including EDN1 (ET-1) gene, thereby creating a feed-forward loop that sustained a persistent ET-1/ZEB1 signaling activity. Notably, ET-1-induced Integrin-linked kinase (ILK) signaling mediated the activation of YAP/ZEB1 circuit driving cellular plasticity, invasion and EMT. Of therapeutic interest, treatment of HG-SOC cells with the FDA approved ET-1R antagonist macitentan, targeting YAP and ZEB1-driven signaling, suppressed metastasis in vivo in mice. High gene expression of ETAR/ILK/YAP/AP-1/ZEB1 was a strong predictor of poor clinical outcome in serous ovarian cancer patients, indicating the translational relevance of this signature expression. CONCLUSIONS: This study provides novel mechanistic insights of the ET-1R-driven mediators that support the ability of HG-SOC to acquire metastatic traits which include the cooperation of YAP and ZEB1 regulatory circuit paving the way for innovative treatment of metastatic ovarian cancer.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Animais , Plasticidade Celular , Cistadenocarcinoma Seroso/patologia , Endotelina-1/genética , Endotelina-1/metabolismo , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/patologia , Receptor de Endotelina A/genética , Receptor de Endotelina A/metabolismo , Fator de Transcrição AP-1 , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
15.
BMC Cancer ; 22(1): 376, 2022 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-35397601

RESUMO

BACKGROUND: Ovarian cancer (OC) is the fifth most common malignant female cancer with a high mortality, mainly because of aggressive high-grade serous carcinomas (HGSOC), but also due to absence of specific early symptoms and effective detection strategies. The CXCL12-CXCR4 axis is considered to have a prognostic impact and to serve as potential therapeutic target. Therefore we investigated the role of pCXCR4 and CXCR4 expression of the tumor cells and of tumor infiltrating immune cells (TIC) in high-grade serous OC and their association with the recurrence-free (RFS) and overall survival (OS). METHODS: A tissue microarray of 47 primary high grade ovarian serous carcinomas and their recurrences was stained with primary antibodies directed against CXCR4 and pCXCR4. Beside the evaluation of the absolute tumor as well as TIC expression in primary and recurrent cancer biopsies the corresponding ratios for pCXCR4 and CXCR4 were generated and analyzed. The clinical endpoints were response to chemotherapy, OS as well as RFS. RESULTS: Patients with a high pCXCR4/CXCR4 TIC ratio in primary cancer biopsies showed a significant longer RFS during the first two years (p = 0.025). However, this effect was lost in the long-term analysis including a follow-up period of 5 years (p = 0.128). Interestingly, the Multivariate Cox regression analysis showed that a high pCXCR4/CXCR4 TIC ratio in primary cancer independently predicts longer RFS (HR 0.33; 95CI 0.13 - 0.81; p = 0.015). Furthermore a high dichotomized distribution of CXCR4 positive tumor expression in recurrent cancer biopsies showed a significantly longer 6-month RFS rate (p = 0.018) in comparison to patients with low CXCR4 positive tumor expression. However, this effect was not independent of known risk factors in a Multivariate Cox regression (HR 0.57; 95CI 0.24 - 1.33; p = 0.193). CONCLUSIONS: To the best of our knowledge we show for the first time that a high pCXCR4/CXCR4 TIC ratio in primary HGSOC biopsies is indicative for better RFS and response to chemotherapy. HIGHLIGHTS: • We observed a significant association between high pCXCR4/CXCR4 TIC ratio and better RFS in primary cancer biopsies, especially during the early postoperative follow-up and independent of known risk factors for recurrence. • High CXCR4 tumor expression in recurrent HGSOC biopsies might be indicative for sensitivity to chemotherapy. We found evidence that at the beginning of the disease (early follow-up) the role of the immune response seems to be the most crucial factor for progression. On the other hand in recurrent/progressive disease the biology of the tumor itself becomes more important for prognosis. • We explored for the first time the predictive and prognostic role of pCXCR4/CXCR4 TIC ratio in high-grade serous ovarian cancer.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Receptores CXCR4 , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Recidiva Local de Neoplasia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Prognóstico , Receptores CXCR4/genética , Transdução de Sinais
16.
J Pathol ; 257(3): 255-261, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35238033

RESUMO

The current theory of carcinogenesis for the deadliest of 'ovarian' cancers-high-grade serous carcinoma (HGSC)-holds that the malignancy develops first in the fallopian tube and spreads to the ovaries, peritoneum, and/or regional lymph nodes. This is based primarily on the observation of early forms of serous neoplasia (serous tubal intraepithelial lesions [STILs], and serous tubal intraepithelial carcinomas [STICS]) in the fimbria of women undergoing risk reduction surgery. However, these lesions are uncommon in the general population, confer a low risk (5%) of HGSC following their removal in at-risk women with germ-line BRCA1/2 mutations, and require 4 or more years to recur as intraperitoneal HGSC. These features suggest that isolated STILs and STICs behave as precursors, with uncertain cancer risk rather than carcinomas. Their evolution to HGSC within, or after, escape from the tube could proceed stepwise with multiple biologic events; however, it is unclear whether tubal or ovarian HGSCs encountered in the setting of advanced disease evolved in the same fashion. The latter scenario could also be explained by a 'catastrophic' model in which STICs suddenly develop with invasive and metastatic potential, overwhelming or obscuring the site of origin. Moreover, a similar model might explain the sudden emergence of HGSC in the peritoneal cavity following escape of precursor cells years before. Long-term follow-up data from opportunistic or prophylactic salpingectomy should shed light on where malignant transformation occurs, as well as the timeline from precursor to metastatic HGSC. © 2022 The Pathological Society of Great Britain and Ireland.


Assuntos
Carcinoma in Situ , Carcinoma , Cistadenocarcinoma Seroso , Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Carcinoma in Situ/patologia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/prevenção & controle , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/patologia , Neoplasias das Tubas Uterinas/prevenção & controle , Feminino , Genômica , Humanos , Recidiva Local de Neoplasia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/prevenção & controle , Cavidade Peritoneal/patologia
17.
Exp Biol Med (Maywood) ; 247(11): 910-920, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35285286

RESUMO

Platinum-based chemotherapy, especially carboplatin, is the primary measure to treat patients with ovarian cancer (OC). However, OC patients still have an adverse prognosis due to emergency of chemotherapy resistance. Ovarian serous cystadenocarcinoma (OSC) is the most common histological subtype of OC. Therefore, identifying the key factors that affect chemotherapy resistance and searching novel treatments had become a top priority. In this study, we analyzed carboplatin response-related mRNA, miRNA, DNA methylation, and alternative splicing (AS) and established a drug-resistant signature for carboplatin in OSC. This drug-resistant signature was obviously higher in resistant group than in non-resistant group and had accuracy predictive performance, which demonstrated that this signature could be considered as a superior indicator for OSC patients with carboplatin resistance. Furthermore, we selected three potential small molecule drugs including liranaftate, siguazodan, and tramiprostate to inhibit carboplatin resistance of OSC. In addition, we also identified ZINC00000205417, ZINC00000140928, and ZINC00021908260 were potential small molecule compounds for SLC17A7 based on Molecular Operating Environment (MOE) virtual screening. Finally, we confirmed the drug-like properties of these small molecule drugs via evaluating absorption, distribution, metabolism, elimination, and toxicity (ADMET) property. In summary, the signature could be used as biomarker for carboplatin resistance and small molecule drugs targeting these genes could improve clinical treatment for OSC in the future.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Proteína Vesicular 1 de Transporte de Glutamato
18.
J Clin Oncol ; 40(17): 1879-1891, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35302882

RESUMO

PURPOSE: After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO. METHODS: Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA-PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study. RESULTS: From 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P < .001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO. CONCLUSION: BRCA-PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events.


Assuntos
Neoplasias da Mama , Cistadenocarcinoma Seroso , Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Neoplasias Peritoneais , Cistadenocarcinoma Seroso/patologia , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/prevenção & controle , Neoplasias das Tubas Uterinas/cirurgia , Feminino , Heterozigoto , Humanos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Ovariectomia/efeitos adversos , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/prevenção & controle , Salpingo-Ooforectomia/efeitos adversos
19.
Sci Rep ; 12(1): 4445, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35292711

RESUMO

Despite recent advances in the management of BRCA1 mutated high-grade serous ovarian cancer (HGSC), the physiology of these tumors remains poorly understood. Here we provide a comprehensive molecular understanding of the signaling processes that drive HGSC pathogenesis with the addition of valuable ubiquitination profiling, and their dependency on BRCA1 mutation-state directly in patient-derived tissues. Using a multilayered proteomic approach, we show the tight coordination between the ubiquitination and phosphorylation regulatory layers and their role in key cellular processes related to BRCA1-dependent HGSC pathogenesis. In addition, we identify key bridging proteins, kinase activity, and post-translational modifications responsible for molding distinct cancer phenotypes, thus providing new opportunities for therapeutic intervention, and ultimately advance towards a more personalized patient care.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Reparo do DNA , Feminino , Humanos , Mutação , Neoplasias Ovarianas/patologia , Proteômica
20.
Sci Rep ; 12(1): 3153, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35210538

RESUMO

Intra-tumoral budding (ITB) has been well demonstrated to be an independent risk factor for adverse outcomes in colorectal carcinoma. This study investigated the prognostic significance of ITB in high-grade serous ovarian carcinomas (HGSOCs). The medical records and slides of 84 SOCs, including 13 with neoadjuvant chemotherapy (NAC), were retrospectively reviewed. The histopathologic examination with scoring of p53 expression showed them to be 80 HGSOCs and 4 low-grade serous ovarian carcinomas (LGSOCs). ITB was found in 64 (80.0%) of the 80 HGSOCs and 1 (25.0%) of 4 LGSOCs. The presence of ITB in HGSOC was significantly correlated with a higher level of CA125, an advanced 2014 FIGO stage, the presence of Lymph node metastasis, and the presence of lymphovascular space invasion (LVSI). The median progression-free survival (PFS) was 18 months in patients with HGSOC with ITB and 36 months in patients with HGSOC without ITB (P = 0.006), and their median overall survival (OS) was 50 months and 60 months (P = 0.060). The multivariate analysis revealed that ITB was not an independent prognostic factor. ITB is a cost-effective prognostic indicator for patients with HGSOC and ITB in ovarian tumor tissue is considered a useful histological biomarker of the progression of HGSOCs.


Assuntos
Biomarcadores Tumorais , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Estudos Retrospectivos , Proteína Supressora de Tumor p53/metabolismo
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