RESUMEN
Loss of progesterone receptor (PR) expression is an established risk factor for unresponsiveness to progesterone therapy in patients with endometrial atypical hyperplasia and endometrioid carcinoma. ARID1A is one of the most commonly mutated genes in endometrioid carcinomas, and the loss of its expression is associated with tumor progression. In this study, we investigated the roles of ARID1A deficiency in PR expression in human and murine endometrial epithelial neoplasia. An analysis of genome-wide chromatin immunoprecipitation sequencing in isogenic ARID1A-/- and ARID1A+/+ human endometrial epithelial cells revealed that ARID1A-/- cells showed significantly reduced chromatin immunoprecipitation sequencing signals for ARID1A, BRG1, and H3K27AC in the PgR enhancer region. We then performed immunohistochemistry to correlate the protein expression levels of ARID1A, estrogen receptor, and PR in 50 human samples of endometrial atypical hyperplasia and 75 human samples of endometrial carcinomas. The expression levels of PR but not were significantly lower in ARID1A-deficient low-grade endometrial carcinomas and atypical hyperplasia (P = .0002). When Pten and Pten/Arid1a conditional knockout murine models were used, Pten-/-;Arid1a-/- mice exhibited significantly decreased epithelial PR expression in endometrial carcinomas (P = .003) and atypical hyperplasia (P < .0001) compared with that in the same tissues from Pten-/-;Arid1a+/+ mice. Our data suggest that the loss of ARID1A expression, as occurs in ARID1A-mutated endometrioid carcinomas, decreases PgR transcription by modulating the PgR enhancer region during early tumor development.
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Carcinoma Endometrioide , Hiperplasia Endometrial , Neoplasias Endometriales , Humanos , Animales , Ratones , Femenino , Progesterona , Receptores de Progesterona , Carcinoma Endometrioide/genética , Hiperplasia , Neoplasias Endometriales/genética , Hiperplasia Endometrial/genética , Proteínas de Unión al ADN/genética , Factores de Transcripción/genéticaRESUMEN
Serous carcinoma (SC) is an aggressive histologic type of endometrial carcinoma (EMC) with a poor prognosis. The development of novel therapeutics for SC is an important issue. PIM1 is a serine/threonine kinase involved in various cellular functions, such as cell cycle progression, apoptosis, and transcriptional activation via the phosphorylation of many target proteins, including MYC. PIM1 is overexpressed in several cancers and has been associated with treatment-resistance. We investigated the expression and function of PIM1 in EMC, particularly SC. Immunohistochemical analysis in 133 EMC cases [103 endometrioid carcinomas (EC) and 30 SC] revealed the significantly stronger expression of PIM1 in SC than in EC and significantly shorter survival of patients with overexpression of PIM1 in all EMC cases, as well as in only SC cases. A multivariate analysis identified overexpression of PIM1 as an independent prognostic factor. The knockdown of PIM1 by siRNA in the SC cell line, ARK1, decreased the expression of phosphorylated MYC and reduced proliferation, migration, and invasion. The PIM1 inhibitor, SGI-1776, reduced cell viability in SC cell lines (ARK1, ARK2, and SPAC1L) with IC50 between 1 and 5 µM. SGI-1776 also reduced the migration and invasion of ARK1 cells. Moreover, the oral administration of SGI-1776 significantly suppressed subcutaneous ARK1 xenograft tumor growth in nude mice without impairing health. These results indicate that PIM1 is involved in the acquisition of aggressiveness and suggest the potential of PIM1 as a novel therapeutic target and SGI-1776 as a therapeutic agent for SC.
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Carcinoma , Neoplasias Endometriales , Animales , Ratones , Femenino , Humanos , Línea Celular Tumoral , Pronóstico , Ratones Desnudos , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Endometrio/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/genética , Proteínas Proto-Oncogénicas c-pim-1/metabolismoRESUMEN
Endometrium-related malignancies including uterine endometrioid carcinoma, ovarian clear cell carcinoma and ovarian endometrioid carcinoma are major types of gynecologic cancer, claiming more than 13,000 women's lives annually in the United States. In vitro cell models that recapitulate "normal" endometrial epithelial cells and their malignant counterparts are critically needed to facilitate the studies of pathogenesis in endometrium-related carcinomas. To achieve this objective, we have established a human endometrial epithelial cell line, hEM3, through immortalization and clonal selection from a primary human endometrium culture. hEM3 exhibits stable growth in vitro without senescence. hEM3 expresses protein markers characteristic of the endometrial epithelium, and they include PAX8, EpCAM, cytokeratin 7/8, and ER. hEM3 does not harbor pathogenic germline mutations in genes involving DNA mismatch repair (MMR) or homologous repair (HR) pathways. Despite its unlimited capacity of in vitro proliferation, hEM3 cells are not transformed, as they are not tumorigenic in immunocompromised mice. The cell line is amenable for gene editing, and we have established several gene-specific knockout clones targeting ARID1A, a tumor suppressor gene involved in the SWI/SNF chromatin remodeling. Drug screening demonstrates that both HDAC inhibitor and PARP inhibitor are effective in targeting cells with ARID1A deletion. Together, our data support the potential of hEM3 as a cell line model for studying the pathobiology of endometrium-related diseases and for developing effective precision therapies.
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Línea Celular , Evaluación Preclínica de Medicamentos , Endometrio/citología , Células Epiteliales , Animales , Femenino , Humanos , Ratones , Receptores de Estrógenos/metabolismoRESUMEN
In order to identify genes involved in the pathogenesis of clear cell carcinoma of the ovary (CCC), functional screening using a cDNA expression library was performed. We extracted mRNA from a CCC cell line (RMG-1), established a cDNA library using a retroviral vector, transfected that library into mouse NIH3T3 cells and sequenced the resultant foci. The tissue-type specific expression of isolated genes and their transforming activities were evaluated. Seven genes were isolated. Of these genes, the mRNA expression of SEC61B and DVL1 is significantly stronger in CCC than in other histological types (p < .05). Immunohistochemical staining reveals the stronger expression of SEC61B and C1ORF38 than normal ovarian tissues (p < .05). Focus formation is confirmed by the transfection of SEC61B, C1ORF38, and DVL1 into NIH3T3 cells. The present study identified novel genes including SEC61B, C1ORF38, and DVL1, involved in the pathogenesis of CCC. These genes may be additional therapeutic targets for CCC.Impact statementWhat is already known on this subject? Several important genetic abnormalities, including ARID1A and PIK3CA mutations, have been reported in ovarian clear cell carcinoma (CCC).What the results of this study add? SEC61B, C1ORF38, and DVL1 were newly detected as candidate genes involved in ovarian clear cell carcinogenesis.What the implications are of these findings for clinical practice and/or further research? Functional screening using a cDNA expression library may be a useful technique to identify functional genes for pathogenesis. The information obtained using this technique may provide new therapeutic targets of CCC.
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Adenocarcinoma de Células Claras/genética , Carcinogénesis/genética , Neoplasias Ováricas/genética , Animales , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Proteínas Dishevelled/metabolismo , Femenino , Biblioteca de Genes , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Células 3T3 NIH , Ovario/metabolismo , Canales de Translocación SEC/metabolismoRESUMEN
INTRODUCTION: Although lobular endocervical glandular hyperplasia is a benign disorder of the uterine cervix, its potential as a precursor of minimal deviation adenocarcinoma has been reported. However, the natural history of the disease and the frequency of malignant change are not fully understood. We evaluated the frequency of malignant change of clinical lobular endocervical glandular hyperplasia and explored useful parameters indicating malignant change. METHODS: The clinical courses of 175 patients with cervical multi-cystic lesions who visited Shinshu University Hospital between June 1995 and June 2019 were retrospectively analyzed. We examined the results of follow-up and outcomes of the patients diagnosed with lobular endocervical glandular hyperplasia and investigated the frequency of malignant transformation. RESULTS: Of the 175 patients, 15, 84, and 76 were clinically diagnosed with suspected malignancy, suspected lobular endocervical glandular hyperplasia, and suspected nabothian cyst, respectively. Of these patients, 69 patients with suspected lobular endocervical glandular hyperplasia were followed, and 12 underwent hysterectomy after a mean follow-up of 57.1 (range: 3-154) months due to lesion enlargement (increase in tumor diameter of >20%) and/or worsening cytology. Of these 12 patients, two had lobular endocervical glandular hyperplasia with atypia and one had minimal deviation adenocarcinoma. Of 69 patients, the rate of malignant change was 1.4% (1/69). The growth rates of the lesions for these three patients during follow-up were significantly higher than those of nine patients who underwent surgery with lobular endocervical glandular hyperplasia without atypia and 48 follow-up cases of suspected lobular endocervical glandular hyperplasia. The cut-off value of the growth rate suggesting malignant transformation was 38.1% (84.6% sensitivity and 100% specificity). Tumor size and cytology did not change in the remaining 57 cases continuing follow-up. CONCLUSION: An increase in tumor size and worsening cytology are important parameters for detecting malignant transformation of lobular endocervical glandular hyperplasia during follow-up. However, the frequency of malignant change of this disease may be limited. These results suggest that conservative management may be an option for clinical lobular endocervical glandular hyperplasia.
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Adenocarcinoma/diagnóstico , Cuello del Útero/patología , Hiperplasia/patología , Lesiones Precancerosas/patología , Neoplasias del Cuello Uterino/diagnóstico , Adenocarcinoma/etiología , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Femenino , Humanos , Hiperplasia/complicaciones , Hiperplasia/cirugía , Histerectomía , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias del Cuello Uterino/etiología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/cirugíaRESUMEN
The targeting of glutamine metabolism specifically via pharmacological inhibition of glutaminase 1 (GLS1) has been translated into clinical trials as a novel therapy for several cancers. The results, though encouraging, show room for improvement in terms of tumor reduction. In this study, the glutaminase II pathway is found to be upregulated for glutamate production upon GLS1 inhibition in pancreatic tumors. Moreover, genetic suppression of glutamine transaminase K (GTK), a key enzyme of the glutaminase II pathway, leads to the complete inhibition of pancreatic tumorigenesis in vivo unveiling GTK as a new metabolic target for cancer therapy. These results suggest that current trials using GLS1 inhibition as a therapeutic approach targeting glutamine metabolism in cancer should take into account the upregulation of other metabolic pathways that can lead to glutamate production; one such pathway is the glutaminase II pathway via GTK.
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Inhibidores Enzimáticos/farmacología , Glutaminasa/genética , Liasas/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Transaminasas/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ácido Glutámico/metabolismo , Glutaminasa/antagonistas & inhibidores , Glutamina/genética , Glutamina/metabolismo , Humanos , Liasas/antagonistas & inhibidores , Redes y Vías Metabólicas/efectos de los fármacos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Transaminasas/antagonistas & inhibidoresRESUMEN
OBJECTIVES: Inactivating somatic mutations of ARID1A, a chromatin remodeling gene, are common in endometrioid endometrial carcinoma (EEC) but rare in complex atypical hyperplasia (CAH). Our objectives were to determine the clinical significance of ARID1A loss during tumor progression from CAH to EEC and to assess its role as a predictive cancer biomarker. METHODS: In cohort A, ARID1A immunoreactivity was evaluated in endometrial sampling (biopsy/curettage) specimens showing CAH to determine whether ARID1A expression correlates with the presence of EEC at subsequent hysterectomy. In cohort B, ARID1A immunoreactivity was evaluated in the hysterectomy specimens with concurrent CAH and EEC to assess for the concordance of ARID1A expression in both components. RESULTS: In cohort A, loss of ARID1A immunoreactivity was identified in the endometrial sampling specimen of 31% of patients undergoing hysterectomy for a preoperative diagnosis of CAH. EEC was identified in the hysterectomy specimen of 94% of patients with loss of ARID1A in the endometrial sampling specimen while only 15% of patients with retained ARID1A expression (Pâ¯<â¯0.0001). No association was observed between ARID1A expression and demographic characteristics. In cohort B, 14 (31%) of 45 patients with concurrent CAH/EEC in their hysterectomy specimens had complete loss of ARID1A expression in the EEC components. Among these 14 patients, 50% also had loss of ARID1A immunoreactivity in the CAH component. CONCLUSIONS: ARID1A immunostaining may correlate with malignant transformation and the presence of concurrent EEC in patients with CAH identified at pre-hysterectomy endometrial sampling. Further investigation to determine the potential utility of ARID1A expression as a tissue biomarker is warranted.
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Carcinoma/metabolismo , Hiperplasia Endometrial/metabolismo , Neoplasias Endometriales/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma/genética , Carcinoma/patología , Carcinoma/cirugía , Proteínas de Unión al ADN , Progresión de la Enfermedad , Hiperplasia Endometrial/genética , Hiperplasia Endometrial/patología , Hiperplasia Endometrial/cirugía , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Neoplasias Endometriales/cirugía , Femenino , Humanos , Histerectomía , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Estadificación de Neoplasias , Proteínas Nucleares/genética , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de Riesgo , Factores de Transcripción/genéticaRESUMEN
In order to understand the role of gene mutations in endometrial carcinogenesis, whole exome sequencing via laser microdissection was performed in the normal endometrium, atypical endometrial hyperplasia and endometrial carcinoma in the same patient. A total of 4046 and 5746 mutations with amino acid substitution were detected in endometrial hyperplasia and endometrial carcinoma, respectively; 2252 were common in both tissues and might play crucial roles in early carcinogenesis. These common mutations included polymerase epsilon (POLE) and DNA mismatch repair (MMR) genes, indicating that an ultra-mutated phenotype, and also included PTEN and PIK3CA. The mutation-prone environment evoked by mutations in the POLE and MMR genes associated with the activated phosphatidylinositol-3 kinase pathway played a pivotal role in this case.
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Fosfatidilinositol 3-Quinasa Clase I/genética , ADN Polimerasa Dirigida por ADN/genética , Hiperplasia Endometrial/genética , Neoplasias Endometriales/genética , Secuenciación del Exoma/métodos , Transducción de Señal/genética , Adulto , Femenino , Humanos , MutaciónRESUMEN
Sirtuin 1 (SIRT1), originally identified as a longevity gene, is induced by caloric restriction, and regulates various cellular functions including DNA repair, cell survival and metabolism via the deacetylation of target proteins such as histone and p53. These functions are considered to act dualistically as preventing or facilitating cancer. This study aimed to clarify the expression and role of SIRT1 in endometrial carcinoma. Because a high-calorie diet was a well-known risk factor for endometrial carcinoma, we first hypothesized that SIRT1 might be downregulated in normal endometrial glandular cells of obese women. However, no correlation was observed between the expression of SIRT1 and body mass index (BMI). In contrast, regardless of BMI, the immunohistochemical expression of SIRT1 was significantly higher in endometrial carcinoma (108 cases) than in normal endometria (60 cases) (P<0.05), and its overexpression was associated with a shorter survival (P<0.05). Our experiments in vivo revealed that SIRT1 accelerated the proliferation of endometrial carcinoma cell lines (HHUA, HEC151, and HEC1B). SIRT1 overexpression significantly enhanced the resistance for cisplatin and paclitaxel in HHUA cells. Although p53 is an important target protein for SIRT1, the selective SIRT1 inhibitor (EX527) significantly suppressed the proliferation and cisplatin resistance of three endometrial carcinoma cell lines regardless of the p53 mutation status. In addition, SIRT1 overexpression in HHUA cells accelerated tumor growth and cisplatin resistance in nude mice, and EX527 significantly suppressed the growth of tumors of HHUA and HEC1B cells. No adverse effect of EX527 was observed in these mice. In conclusion, SIRT1 is involved in the acquisition of the aggressive behavior associated with endometrial carcinoma, and the SIRT1 inhibitor, EX527, may be a useful agent for the treatment of this malignancy.
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Carbazoles/uso terapéutico , Carcinoma Endometrioide/metabolismo , Cisplatino , Resistencia a Antineoplásicos , Neoplasias Endometriales/metabolismo , Sirtuina 1/metabolismo , Animales , Carbazoles/farmacología , Carcinoma Endometrioide/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular , Neoplasias Endometriales/tratamiento farmacológico , Endometrio/metabolismo , Femenino , Humanos , Inmunohistoquímica , Ratones Endogámicos BALB C , Ratones Desnudos , Sirtuina 1/antagonistas & inhibidores , Estrés Fisiológico , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIMS: It has been reported that the expression of core 2 ß1,6-N-acetylglucosaminyl transferase 1 (C2GnT1), which synthesizes the core 2 branching structure on O-glycans, may be associated with the biological aggressiveness of tumour cells. Therefore, the aim of this study was to examine the relationship between the expression of C2GnT1 and clinicopathological parameters of patients with endometrial carcinoma. METHODS AND RESULTS: The immunohistochemical expression of C2GnT1 was examined in 84 cases of endometrioid-type endometrial carcinoma, 15 cases of endometrial hyperplasia, and 30 normal endometria. The staining intensity was reported according to a positivity index (PI, full score 100), calculated from the percentage of positive cells. The expression of C2GnT1 was significantly higher in endometrial carcinoma (PI = 8.31 ± 15.29) than in normal endometrium (PI = 0.52 ± 1.24) (P < 0.0005). In carcinomas, the PI was higher in high-grade or advanced-stage tumours, but not significantly. Topologically, C2GnT1 was strongly expressed at sites of deep myometrial invasion. In addition, patients with C2GnT1 overexpression (PI ≥ 10) had significantly shorter survival (P < 0.0005). Multivariable analysis also indicated that C2GnT1 overexpression was an independent prognostic factor (P = 0.017). CONCLUSIONS: C2GnT1 appears to be involved in the biological aggressiveness of endometrial carcinoma. C2GnT1 might become a novel prognostic factor for endometrial carcinoma.
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Carcinoma Endometrioide/diagnóstico , Neoplasias Endometriales/diagnóstico , N-Acetilglucosaminiltransferasas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/mortalidad , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/mortalidad , Femenino , Humanos , Japón/epidemiología , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Tasa de SupervivenciaRESUMEN
Relapses negatively impact cancer patient survival due to the tumorigenesis ability of surviving cancer cells post-therapy. Efforts are needed to better understand and combat this problem. This study hypothesized that dead cell debris post-radiation therapy creates an advantageous microenvironment rich in metabolic materials promoting the growth of remaining live cancer cells. In this study, live cancer cells are co-cultured with dead cancer cells eradicated by UV radiation to mimic a post-therapy environment. Isotopic labeling metabolomics is used to investigate the metabolic behavior of cancer cells grown in a post-radiation-therapy environment. It is found that post-UV-eradicated dead cancer cells serve as nutritional sources of "off-the-shelf" and precursor metabolites for surviving cancer cells. The surviving cancer cells then take up these metabolites, integrate and upregulate multiple vital metabolic processes, thereby significantly increasing growth in vitro and probably in vivo beyond their intrinsic fast-growing characteristics. Importantly, this active metabolite uptake behavior is only observed in oncogenic but not in non-oncogenic cells, presenting opportunities for therapeutic approaches to interrupt the active uptake process of oncogenic cells without affecting normal cells. The process by which living cancer cells re-use vital metabolites released by dead cancer cells post-therapy is coined in this study as "metabolic recycling" of oncogenic cells.
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Linfoma de Células B , Recurrencia Local de Neoplasia , Humanos , Metabolómica , Transformación Celular Neoplásica/patología , Proliferación Celular , Microambiente TumoralRESUMEN
PURPOSE: Wasabi is a traditional plant seasoning with an anti-septic function. Recent studies revealed several functions of Wasabi, such as anti-inflammation; however, the anti-tumor effect against endometrial carcinoma (EMC) cells has not been examined. In the present study, we investigated the anti-tumor effect of 6-(methylsulfinyl) hexyl isothiocyanate (6-MITC), a major chemical compound of Wasabi, against various EMC cell lines in vitro and in vivo. METHODS: The effect of 6-MITC on cell viability was measured by the WST-1 assay in EMC and HUVEC cells. The impact of 6-MITC oral administration in nude mice was measured to assess the growth of the EMC xenograft and natural killer (NK) cell activity in the spleen. RESULTS: The addition of 6-MITC suppressed the proliferation of EMC cells (Ishikawa, HEC265, HEC108, KLE, and HEC1B) dose-dependently, but not HUVEC cells. 6-MITC (5 µM) enhanced the cisplatin sensitivity of EMC cells. 6-MITC induced apoptosis in a dose-dependent fashion in EMC cells other than HEC1B cells and was associated with increased expression of cleaved-caspase3 and decreased expression of BCL2. Oral administration of 6-MITC (2 and 4 µmol/kg) to Ishikawa and HEC1B xenografting mice resulted in a reduced tumor volume compared with the control (P < 0.05, 4 µmol/kg). Immunohistochemical staining of resected tumors revealed increased expression of Ki-67 and reduced cleaved-caspase3. Furthermore, 6-MITC treatment enhanced NK cell activity, especially when administered before tumor xenografting. CONCLUSION: These results indicate that 6-MITC has a marked anti-tumor effect against EMC cells and a novel effect to enhance NK cell activity. These effects suggest the therapeutic potential of 6-MITC.
RESUMEN
Although endometriosis is primarily benign, it has been identified as a risk factor for endometriosis-associated ovarian cancer (EAOC). Genetic alterations in ARID1A, PTEN, and PIK3CA have been reported in EAOC; however, an appropriate EAOC animal model has yet to be established. Therefore, the present study aimed to create an EAOC mouse model by transplanting uterine pieces from donor mice, in which Arid1a and/or Pten was conditionally knocked out (KO) in Pax8-expressing endometrial cells by the administration of doxycycline (DOX), onto the ovarian surface or peritoneum of recipient mice. Two weeks after transplantation, gene KO was induced by DOX and endometriotic lesions were thereafter removed. The induction of only Arid1a KO did not cause any histological changes in the endometriotic cysts of recipients. In contrast, the induction of only Pten KO evoked a stratified architecture and nuclear atypia in the epithelial lining of all endometriotic cysts, histologically corresponding to atypical endometriosis. The induction of Arid1a; Pten double-KO evoked papillary and cribriform structures with nuclear atypia in the lining of 42 and 50% of peritoneal and ovarian endometriotic cysts, respectively, which were histologically similar to EAOC. These results indicate that this mouse model is useful for investigating the mechanisms underlying the development of EAOC and the related microenvironment.
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Modelos Animales de Enfermedad , Endometriosis , Neoplasias Ováricas , Trasplantes , Animales , Femenino , Humanos , Ratones , Proteínas de Unión al ADN , Doxiciclina , Ratones Noqueados , Fosfohidrolasa PTEN , Factores de Transcripción , Microambiente Tumoral , ÚteroRESUMEN
In 2020, the WHO published a new system for classifying invasive endocervical adenocarcinoma based on histological features and high-risk human papillomavirus (HPV) infection. However, immunophenotypes of each histological subtype require further investigation. We immunohistochemically analyzed 66 invasive endocervical adenocarcinomas using three cell-lineage-specific markers: claudin 18 (CLDN18) for gastric, cadherin 17 (CDH17) for intestinal, and PAX8 for Müllerian epithelial cells. We identified five immunophenotypes of endocervical adenocarcinoma: gastric (21%); intestinal (14%); gastrointestinal (11%); Müllerian (35%); and not otherwise specified (NOS) (20%). Adenocarcinomas with gastric immunophenotype, characterized by aging (p = 0.0050), infrequent HPV infection (p < 0.0001), concurrent lobular endocervical glandular hyperplasia (p = 0.0060), lymphovascular invasion (p = 0.0073), advanced clinical stage (p = 0.0001), and the poorest progression-free (p < 0.0001) and overall (p = 0.0023) survivals, were morphologically compatible with gastric-type adenocarcinoma of the WHO 2020 classification. Conversely, most adenocarcinomas with Müllerian (91%) and intestinal (89%) immunophenotypes were HPV associated and morphologically compatible with usual- or intestinal-type adenocarcinomas of the WHO 2020 classification. The morphology of adenocarcinomas with gastrointestinal immunophenotype was intermediate or mixed between those of gastric and intestinal immunophenotypes; 57% were HPV associated. Adenocarcinomas with NOS immunophenotype were mainly HPV associated (85%) and histologically poorly differentiated. Multivariate analysis revealed that gastric (p = 0.008), intestinal + gastrointestinal (p = 0.0103), and NOS (p = 0.009) immunophenotypes were independent predictors of progression-free survival. Immunophenotypes characterized by CLDN18, CDH17, and PAX8 exhibited clinicopathological relevance and may improve the diagnostic accuracy and prognostic value of conventional histological classification.
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Adenocarcinoma , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Adenocarcinoma/patología , Biomarcadores de Tumor/análisis , Cadherinas , Claudinas , Femenino , Humanos , Factor de Transcripción PAX8 , Pronóstico , Neoplasias del Cuello Uterino/patologíaRESUMEN
OBJECTIVE: Vasa previa is a condition in which fetal blood vessels are located on fetal membranes within 2 cm of the internal cervical os. Vasa previa has been classified into two types: Type 1, in which vessels connect a velamentous umbilical cord to the placenta, and Type 2, in which vessels connect the lobes of a bilobed placenta or the placenta to a succenturiate lobe. However, there are also atypical cases that cannot be classified into these two types. These cases are manifested by a center or marginal cord insertion with a normal shaped placenta, and fetal vessels were also located on membranes around the internal cervical os. These cases were recently proposed as Type 3 vasa previa. The present study investigated the incidence of Type 3 vasa previa and elucidated differences in clinical and ultrasonographical characteristics between traditional types and Type 3. METHODS: This was a single-center observational study using a cohort of all vasa previa cases between January 2010 and April 2020. RESULTS: Among 8,723 deliveries, there were 14 cases (0.16%) of vasa previa, all of which were diagnosed prenatally by US, not after vaginal delivery or CS. There were 9 (64%), 0, and 5 (36%) cases of Types 1, 2, and 3, respectively. All 5 Type 3 cases had only one fetal aberrant vessel of vasa previa, while 6 out of 9 Type 1 cases (67%) had two or more aberrant vessels. Seven Type 1 cases (78%) possessed two or more known risk factors, such as velamentous cord insertion, whereas all Type 3 cases only had one. Difficulties were associated with diagnosing two out of the 14 cases of vasa previa using routine transvaginal ultrasonography (TVUS). In these cases, the aberrant fetal vessel of vasa previa was only one vein with a thin wall that was not clearly visualized by gray-scale TVUS as well as slow flow that was easily misread by color-Doppler. These cases were ultimately diagnosed as vasa previa based on non-pulsatile flow detected by color and pulsed Doppler. CONCLUSIONS: The present results suggest that Type 3 may account for a large proportion of vasa previa cases. Most Type 3 cases may present with only one fetal aberrant vessel of vasa previa and fewer risk factors, suggesting that the diagnosis of vasa previa may be more challenging in Type 3 cases than in the other types. Vasa previa with a venous vasa previa needs to be considered because of the difficulties associated with an antenatal diagnosis due to unclear imaging of the vasculature or the lack of specific color Doppler flow patterns. Pulsed Doppler imaging may be helpful for the diagnosis of these cases.
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Vasa Previa , Femenino , Embarazo , Humanos , Vasa Previa/diagnóstico por imagen , Vasa Previa/epidemiología , Ultrasonografía Prenatal , Cordón Umbilical/diagnóstico por imagen , Placenta/diagnóstico por imagen , Diagnóstico PrenatalRESUMEN
Somatic inactivating mutations of ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human endometrium-related malignancies. To elucidate the mechanisms underlying how ARID1A deleterious mutation contributes to tumorigenesis, we establish genetically engineered murine models with Arid1a and/or Pten conditional deletion in the endometrium. Transcriptomic analyses on endometrial cancers and precursors derived from these mouse models show a close resemblance to human uterine endometrioid carcinomas. We identify transcriptional networks that are controlled by Arid1a and have an impact on endometrial tumor development. To verify findings from the murine models, we analyze ARID1AWT and ARID1AKO human endometrial epithelial cells. Using a system biology approach and functional studies, we demonstrate that ARID1A-deficiency lead to loss of TGF-ß tumor suppressive function and that inactivation of ARID1A/TGF-ß axis promotes migration and invasion of PTEN-deleted endometrial tumor cells. These findings provide molecular insights into how ARID1A inactivation accelerates endometrial tumor progression and dissemination, the major causes of cancer mortality.
Asunto(s)
Carcinogénesis/genética , Carcinoma Endometrioide/genética , Reprogramación Celular/genética , Proteínas de Unión al ADN/genética , Neoplasias Endometriales/genética , Factores de Transcripción/genética , Animales , Carcinogénesis/metabolismo , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Endometrio/citología , Endometrio/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Ratones de la Cepa 129 , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Mutación , Factores de Transcripción/metabolismoRESUMEN
Amplification and overexpression of the MYC oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a target of MYC and a key enzyme in glutaminolysis, are intrinsically resistant to platinum-based chemotherapy and are enriched with intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not in low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLShigh cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. These findings suggest consideration of applying a combined therapy of GLS inhibitor and PARP inhibitor to treat chemoresistant ovarian cancers, especially those with high GLS expression. SIGNIFICANCE: Targeting glutaminase disturbs redox homeostasis and nucleotide synthesis and causes replication stress in cancer cells, representing an exploitable vulnerability for the development of effective therapeutics. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4514/F1.large.jpg.
Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Glutaminasa/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-myc/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bencenoacetamidas/administración & dosificación , Bencenoacetamidas/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Glutaminasa/antagonistas & inhibidores , Glutamina/genética , Glutamina/metabolismo , Glutatión/metabolismo , Humanos , Ratones Desnudos , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Ftalazinas/administración & dosificación , Ftalazinas/farmacología , Piperazinas/administración & dosificación , Piperazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Proteínas Proto-Oncogénicas c-myc/genética , Tiadiazoles/administración & dosificación , Tiadiazoles/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We uncovered the neurotransmitter N-acetyl-aspartyl-glutamate (NAAG) as a reservoir providing glutamate to promote cancer growth, and demonstrated that inhibition of NAAG hydrolysis by targeting glutamate carboxypeptidase II is a viable strategy for cancer therapy. Our study also suggests that NAAG concentration in plasma could be a non-invasive measurement to monitor cancer progression.
RESUMEN
Lobular endocervical glandular hyperplasia (LEGH) was first reported as a benign proliferative disorder of the uterine cervix. However, it currently remains unclear whether it has the biological characteristics of pyloric metaplasia or precursor of minimal deviation adenocarcinoma (MDA)/gastric-type mucinous cervical adenocarcinoma (GAS). Therefore, in the present study we performed whole-exome sequencing on three cases of LEGH collected by laser-microdissection from the frozen tissue sections of surgically removed uteri. Analysis of the results identified 50 somatic variants. After several filtering processes, we identified 13 functional variants, including 12 missense and one insertion-deletion variants. Of these mutations, keratinocyte proline-rich protein, olfactory receptor M4 and zinc finger protein 645 mutations were found in the Catalogue Of Somatic Mutations In Cancer but were not related to carcinogenic diseases. We did not detect any significant copy number alterations or signatures. Although this was a limited case series, we did not identify any variants relevant to the tumorigenesis of LEGH to MDA/GAS, suggesting a metaplastic aspect of LEGH.
RESUMEN
BACKGROUND: The sawtooth fetal heart rate pattern is rare, and has been reported as a possible indicator of neurological sequelae in newborns. However, we observed this fetal heart rate pattern in an infant with normal neurological function. CASE PRESENTATION: A 29-year-old primigravida Japanese woman presented to our hospital at 40 weeks and 1 day of gestation with marked vaginal bleeding. Since admission, fetal heart rate tracing consistently demonstrated a sawtooth-like pattern. There were 3-4 oscillations per minute, and their amplitude was 30-40 beats per minute. An emergency cesarean section was performed because of non-reassuring fetal status. Evidence of placental abruption was not observed. The newborn was a male weighing 2936 g, with an Apgar score of 1 and 3 at 1 minute and 5 minutes, respectively. The infant received brain cooling, but was discharged uneventfully. A follow-up examination at age 3 years demonstrated no developmental restriction. CONCLUSION: Although the Apgar score of the newborn was low, the infant had no neurological sequelae. Thus, the sawtooth fetal heart rate pattern may not be linked to in utero irreversible fetal central nervous system injury.