RESUMEN
The aim of this study was to compare the diagnostic efficacy of colposcopic-directed biopsy and four-quadrant biopsy in detecting high-grade cervical intra-epithelial neoplasia (CIN). Women attending three women's clinics for routine cervical screening were recruited. Colposcopy was arranged for women with any cytologic abnormalities greater than atypical squamous cells of undetermined significance (ASCUS), two consecutive ASCUS results or positive HPV testing. During colposcopy, a cervical biopsy was taken from the most suspicious area, but more than one biopsy was allowed. Four-quadrant biopsies at 3, 6, 9 and 12 o'clock and an endocervical curettage were also taken in all cases. A total of 1522 colposcopies were performed in 1311 subjects from June 2010 to August 2017, with 118 cases of high-grade CIN diagnosed. Colposcopic-directed biopsy detected 50.8% of the 118 high-grade CIN, while four-quadrant biopsy detected 86.4% (p < 0.0001). Twenty-seven cases (22.9%) of high-grade CIN were diagnosed in women with normal or unsatisfactory colposcopy. Among the 64 cases with low-grade colposcopic impression, four-quadrant biopsy detected significantly more high-grade CIN (53 cases, 82.8%) than colposcopic-directed biopsy (35 cases, 56.3%) (p = 0.0011). Four-quadrant cervical biopsies should be considered for all women with an abnormal smear or positive HPV testing, especially in patients with low-grade/normal/unsatisfactory colposcopy.
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Frozen sections of uterine smooth muscle tumors are infrequently required, and related diagnostic difficulties are seldom discussed. We analyzed the clinicopathologic features of 112 frozen sections of uterine smooth muscle tumors and determined the accuracy, reasons for deferrals, and causes of interpretational errors. Most patients (median age, 45 y) presented with pelvic mass symptoms (53%). The main reasons for a frozen section examination were an abnormal gross appearance including loss of the usual whorled pattern of leiomyoma (36 cases, 32.1%), and intraoperative discovery of an abnormal growth pattern and extrauterine extension of a uterine tumor (28 cases, 25%). There were 9 leiomyosarcomas and 103 leiomyomas, including 18 benign histologic variants. An accurate diagnosis of malignancy was achieved in all leiomyosarcomas, with the exception of a myxoid leiomyosarcoma. In 99 cases (88%), the frozen section diagnosis concurred with the permanent section diagnosis (false positives, 0.9%; false negatives, 0%). Misinterpretation of stromal hyalinization as tumor cell necrosis in a leiomyoma with amianthoid-like fibers was a major discrepancy. Two minor discrepancies did not lead to a change in management. The diagnosis was deferred in 10 cases (8.9%) because of stromal alterations, unusual cellular morphology, uncertain type of necrosis, and abnormal growth patterns. Thus, although various stromal and cellular alterations can cause diagnostic uncertainty, leading to deferrals, frozen section diagnosis of uterine smooth muscle tumors has a high accuracy rate. While a definitive frozen section diagnosis of malignancy may be made when there is unequivocal atypia, indisputable mitotic figures, and tumor cell necrosis, it is important to remember that nonmyogenic mesenchymal tumors may also mimic uterine smooth muscle tumors. In a frozen section setting, it would be sufficient to issue a diagnosis of "malignant mesenchymal tumor." For tumors that do not meet the criteria for malignancy, issuing a frozen section diagnosis of "atypical mesenchymal tumor and defer the histologic subtyping to the permanent sections" is appropriate.
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Secciones por Congelación/métodos , Leiomioma/diagnóstico , Leiomiosarcoma/diagnóstico , Neoplasias Uterinas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Humanos , Periodo Intraoperatorio , Leiomioma/patología , Leiomiosarcoma/patología , Persona de Mediana Edad , Tumor de Músculo Liso/diagnóstico , Tumor de Músculo Liso/patología , Neoplasias Uterinas/patologíaRESUMEN
BACKGROUND: The existing staging systems of uterine leiomyosarcoma (uLMS) cannot classify the patients into four non-overlapping prognostic groups. This study aimed to develop a prediction model to predict the three-year survival status of uLMS. METHODS: In total, 201 patients with uLMS who had been treated between June 1993 and January 2014, were analyzed. Potential prognostic indicators were identified by univariate models followed by multivariate analyses. Prediction models were constructed by binomial regression with 3-year survival status as a binary outcome, and the final model was validated by internal cross-validation. RESULTS: Nine potential parameters, including age, log tumor diameter, log mitotic count, cervical involvement, parametrial involvement, lymph node metastasis, distant metastasis, tumor circumscription and lymphovascular space invasion were identified. 110 patients had complete data to build the prediction models. Age, log tumor diameter, log mitotic count, distant metastasis, and circumscription were significantly correlated with the 3-year survival status. The final model with the lowest Akaike's Information Criterion (117.56) was chosen and the cross validation estimated prediction accuracy was 0.745. CONCLUSION: We developed a prediction model for uLMS based on five readily available clinicopathologic parameters. This might provide a personalized prediction of the 3-year survival status and guide the use of adjuvant therapy, a cancer surveillance program, and future studies.
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Human papillomavirus (HPV) is the etiological agent of cervical cancer; however, the mechanisms underlying HPV-mediated carcinogenesis remain poorly understood. Here, we showed that nuclear receptor related-1 protein (Nurr1) was upregulated in primary cervical cancer tissue-derived spheroid cells and HPV-positive cell lines, and Nurr1 upregulation was correlated with cancer grade. Nurr1 promoted cell proliferation, migration, invasion, and anchorage-independent cell growth. In addition to its effect on cancer aggressiveness, Nurr1 enhanced the self-renewal ability of cells in vitro and in vivo, underscoring the importance of Nurr1 in maintaining the stemness of cancer stem-like cells (CSLCs). Mechanistically, Nurr1 independently activated the MEK/ERK and PI3K/Akt/mTOR signaling cascades. The MEK inhibitor trametinib (GSK) and PI3K/mTOR dual inhibitor dactolisib (BEZ) were shown to abrogate Nurr1-augmented tumorigenesis by upregulating p21 and p27 expression and by suppressing MMP9 and KLF4 expression. We provided further evidence that BEZ, but not GSK, could abolish Nurr1-enhanced radioresistance, suggesting its potential value for radiosensitizing CSLCs in the clinical setting. This study highlights the unprecedented roles of Nurr1 and elucidates mechanisms by which Nurr1 promotes tumor progression and radioresistance, providing a novel therapeutic strategy for cervical cancer treatment.
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Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Células Madre Neoplásicas/patología , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Proteínas Oncogénicas Virales/metabolismo , Tolerancia a Radiación , Neoplasias del Cuello Uterino/patología , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Femenino , Humanos , Factor 4 Similar a Kruppel , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de la radiación , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Proteínas Oncogénicas Virales/genética , Papillomaviridae/fisiología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/virología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/radioterapia , Neoplasias del Cuello Uterino/virología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Due to its high ability to disseminate, ovarian cancer remains one of the largest threats to women's health, worldwide. Evidence showed that the immune cells infiltrating the tumor microenvironment are crucial in mediating metastasis. Therefore, it is necessary to understand which types of immune cells are involved in metastasis, and to determine the mechanisms by which they influence the process. By immunohistochemistry, we found that higher concentrations of intratumoral CD8+ T cells were found to be correlated with an advanced grade and stage of ovarian cancer. Additionally, the infiltration of stromal CD8+ T cells was also significantly higher in tissues with advanced stages and metastatic tumors. A positive correlation between the infiltration of FoxP3+ Treg cells and histological grade was also observed, regardless of location. PD-L1 expression in metastatic tumors was also higher than that in paired primary ovarian tumors. Transwell migration and invasion assays revealed the increased migration and invasion of ovarian cancer cell lines (A2780CP and ES2) and ascites-derived ovarian cancer cells following co-culturing with CD8+ T cells. Enhanced expression of MMP-9, uPA, VEGF, bFGF, IL-8, IL-10, and PD-L1 by cancer cells following co-culturing with CD8+ T cells were also detected by qPCR, ELISA or flow cytometry. In conclusion, our findings suggest that the infiltrated T cells could promote the development of ovarian cancer, and provide another mechanism of immune evasion mediated by T cells.
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Antígeno B7-H1/metabolismo , Carcinoma Epitelial de Ovario/patología , Linfocitos Infiltrantes de Tumor/inmunología , Invasividad Neoplásica/patología , Escape del Tumor/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Carcinoma Epitelial de Ovario/inmunología , Carcinoma Epitelial de Ovario/metabolismo , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/metabolismo , Persona de Mediana Edad , Invasividad Neoplásica/genética , Células Tumorales Cultivadas , Microambiente Tumoral/inmunología , Adulto JovenRESUMEN
BACKGROUND: CD109 was involved in the tumorigenesis and progression of various cancers via TGF-ß1 signalling and STAT3 activation. As CD109 is strongly expressed in cervical squamous cell carcinoma, this study was conducted to investigate its functional characteristics in cervical cancer. METHODS: CD109 expression was examined by immunohistochemistry (IHC) with cervical tissue microarray. The effects of CD109 expression were examined on migration, cell proliferation, spheroid formation and soft-agar colony-formation assay. Meanwhile, cervical cancer cell lines with high CD109 expression were chosen for the functional study using siRNA knockdown and CRISPR/Cas9 knockout. RESULTS: IHC demonstrated an upregulation of CD109 in the cell membrane of cervical squamous cell carcinoma. CD109( + ) cells isolated by flow-cytometric sorting displayed enhanced migration, cell proliferation, sphere-forming and anchorage-independent cell growth ability. In contrast, silencing of CD109 expression could reverse the in vitro and in vivo tumorigenic and aggressive properties. Furthermore, CD109 induced EGFR-mediated STAT3 phosphorylation known to be responsible for cell migration, proliferation and maintenance of CSC phenotype. CONCLUSION: Abundant CD109( + ) populations in cervical cancer cells potentially contributed to carcinogenesis and aggressiveness, whereas silencing of CD109 expression could reverse those properties. CD109 mediates cervical tumorigenicity and aggressiveness via CD109/EGFR/STAT3 signalling.
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Antígenos CD/metabolismo , Carcinoma de Células Escamosas/metabolismo , Proteínas de Neoplasias/metabolismo , Factor de Transcripción STAT3/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Animales , Antígenos CD/biosíntesis , Antígenos CD/genética , Secuencia de Bases , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Receptores ErbB/metabolismo , Femenino , Proteínas Ligadas a GPI/biosíntesis , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Técnicas de Inactivación de Genes , Xenoinjertos , Humanos , Inmunohistoquímica , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Fosforilación , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Transducción de Señal , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: Ovarian cancer is characterised by frequent recurrence due to persistent presence of residual cancer stem cells (CSCs). Here, we identify and characterise tumour subsets from ascites-derived tumour cells with stemness, metastasis and metabolic switch properties and to delineate the involvement of pyruvate dehydrogenase kinase 4 (PDK4) in such process. METHODS: Ovarian cancer cells/cell lines derived from ascites were used for tumourspheres/ALDH+CD44+ subset isolation. The functional roles and downstream signalling of PDK4 were explored. Its association with clinical outcome of ovarian cancer was analysed. RESULTS: We demonstrated enhanced CSC characteristics of tumour cells derived from ovarian cancer ascites, concomitant with ALDH and CD44 subset enrichment and high PDK4 expression, compared to primary tumours. We further showed tumourspheres/ALDH+CD44+ subsets from ascites-derived tumour cells/cell lines with CSC properties and enhanced glycolysis. Clinically, PDK4 expression was correlated with aggressive features. Notably, blockade of PDK4 in tumourspheres/ALDH+CD44+ subsets led to inhibition of CSC characteristics, glycolysis and activation of STAT3/AKT/NF-κB/IL-8 (signal transducer and activator of transcription 3/protein kinases B/nuclear factor-κB/interleukin-8) signalling. Conversely, overexpression of PDK4 in ALDH-CD44- subsets exerted the opposite effects. CONCLUSION: Ascites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastatic and metabolic switch properties via PDK4-mediated STAT3/AKT/NF-κB/IL-8 signalling, suggesting PDK4 as a viable therapeutic molecular target for ovarian cancer management.
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Interleucina-8/genética , Recurrencia Local de Neoplasia/genética , Neoplasias Ováricas/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/genética , Factor de Transcripción STAT3/genética , Aldehído Deshidrogenasa/genética , Ascitis/metabolismo , Ascitis/patología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Receptores de Hialuranos/genética , FN-kappa B/genética , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Proteína Oncogénica v-akt/genética , Neoplasias Ováricas/patología , Receptores de Interleucina-8A/genética , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Gestational trophoblastic disease (GTD) is a heterogeneous group of diseases developed from trophoblasts. ASPP (Ankyrin-repeat, SH3-domain and proline-rich region containing protein) family proteins, ASPP1 and ASPP2, have been reported to be dysregulated in GTD. They modulate p53 activities and are responsible for multiple cellular processes. Nevertheless, the functional role of the ASPP family inhibitory member, iASPP, is not well characterized in GTD. METHODS: To study the functional role of iASPP in GTD, trophoblastic tissues from normal placentas, hydatidiform mole (HM) and choriocarcinoma were used for immunohistochemistry, whereas siRNAs were used to manipulate iASPP expression in choriocarcinoma cell lines and study the subsequent molecular changes. RESULTS: We demonstrated that iASPP was overexpressed in both HM and choriocarcinoma when compared to normal placenta. Progressive increase in iASPP expression from HM to choriocarcinoma suggests that iASPP may be related to the development of trophoblastic malignancy. High iASPP expression in HM was also significantly associated with a high expression of autophagy-related protein LC3. Interestingly, iASPP silencing retarded the growth of choriocarcinoma through senescence instead of induction of apoptosis. LC3 expression decreased once iASPP was knocked down, suggesting a downregulation on autophagy. This may be due to iASPP downregulation rendered decrease in Atg5 expression and concomitantly hindered autophagy in choriocarcinoma cells. Autophagy inhibition per se had no effect on the growth of choriocarcinoma cells but increased the susceptibility of choriocarcinoma cells to oxidative stress, implying a protective role of iASPP against oxidative stress through autophagy in choriocarcinoma. CONCLUSIONS: iASPP regulates growth and the cellular responses towards oxidative stress in choriocarcinoma cells. Its overexpression is advantageous to the pathogenesis of GTD. (266 words).
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Autofagia , Coriocarcinoma/metabolismo , Mola Hidatiforme/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Estrés Oxidativo , Proteínas Represoras/metabolismo , Adolescente , Adulto , Proteína 5 Relacionada con la Autofagia/metabolismo , Línea Celular Tumoral , Coriocarcinoma/patología , Femenino , Estudios de Seguimiento , Técnicas de Silenciamiento del Gen , Humanos , Mola Hidatiforme/patología , Péptidos y Proteínas de Señalización Intracelular/clasificación , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Persona de Mediana Edad , Placenta/citología , Placenta/metabolismo , Embarazo , Proteínas Represoras/clasificación , Proteínas Represoras/genética , Transfección , Proteína p53 Supresora de Tumor/metabolismo , Adulto JovenRESUMEN
A subpopulation of cells within tumors has been suggested to possess the ability to initiate tumorigenesis and contribute to resistance to cancer therapy. Identification and isolation of this subpopulation in cancer cells can be achieved by detecting specific cell-surface markers. In this study, flow cytometry analysis revealed an abundant CD71+ subpopulation in human papillomavirus (HPV)-positive cervical cancer cells, while limited CD71+ cells were detected in HPV-negative cervical cancer cells. Furthermore, ectopic expression of the HPV-E6 protein in HPV-negative C33A cells enriched the CD71+subpopulation. The CD71+ subpopulation isolated from the C33A cell line and an HPV-E6-overexpressing clone exhibited enhanced transforming ability, proliferation, and resistance to irradiation. In contrast, suppression of CD71 in HPV-positive SiHa cells and the HPV-E6-overexpressing stable clone inhibited spheroid formation and in vitro and in vivo tumorigenicity and sensitized cells to irradiation treatment. CRISPR/Cas9 knockout of CD71 in SiHa cells also produced similar inhibitory effects on tumorigenicity. Double knockout of CD71 and CD55 reversed the oncogenic properties of the HPV-E6-overexpressing clone. These findings suggest that the HPV-E6 protein enriches the subpopulation of CD71+cells in cervical cancer, which exhibit cancer stem-like cell properties and are resistant to irradiation treatment. Targeting the CD71+ subpopulation in cervical cancer cells with siRNAs or CRISPR/Cas9 may provide new insights for the development of novel therapeutic approaches for treating cervical cancer. IMPLICATIONS: We describe the enrichment of CD71+ population by HPV-E6 protein in cervical cancer cells that promotes cancer aggressiveness and resistance to irradiation treatment.
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Antígenos CD/genética , Antígenos CD/metabolismo , Proteínas Oncogénicas Virales/genética , Infecciones por Papillomavirus/patología , Tolerancia a Radiación , Receptores de Transferrina/genética , Receptores de Transferrina/metabolismo , Neoplasias del Cuello Uterino/virología , Animales , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de la radiación , Proteínas Oncogénicas Virales/metabolismo , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/radioterapia , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/radioterapiaRESUMEN
OBJECTIVES: To review the clinicopathologic features of five patients with epithelioid trophoblastic tumor (ETT). METHODS: Characteristics of patients diagnosed with ETT in 2000 to 2012 were reviewed. RESULTS: Among 190 patients with gestational trophoblastic neoplasia (GTN), two had pure ETT and three had mixed ETT and choriocarcinoma. The median age was 32.5 years. All the patients had localized disease in the uterus. One patient with pure ETT had a recurrence in the ureter 6 years after the initial treatment. Another patient with pure ETT had two full-term deliveries after fertility-sparing surgery. The three patients with mixed tumors had chemotherapy for GTN before their diseases were completely treated by hysterectomy. At a median follow-up of 102 months, all patients survived. CONCLUSIONS: ETT is indolent. Recurrence can happen, but the risk factors are not clear. When patients with GTN fail to respond to chemotherapy, the possibility of mixed GTN should be considered.
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Coriocarcinoma/diagnóstico , Enfermedad Trofoblástica Gestacional/diagnóstico , Neoplasias Uterinas/diagnóstico , Adulto , Coriocarcinoma/patología , Femenino , Enfermedad Trofoblástica Gestacional/patología , Humanos , Persona de Mediana Edad , Embarazo , Neoplasias Uterinas/patologíaRESUMEN
Hydatidiform mole (HM), an unusual pregnancy with pure or predominant paternal genetic contribution, is the most common form of gestational trophoblastic disease. Most HM regress after uterine evacuation but some will develop into persistent disease or even frank malignancy. Although p53 is highly expressed in HM, TP53 mutations have rarely been detected in previous studies. Here we screened for specific missense mutations on several TP53 hotspots in 49 HMs using a highly sensitive pyrosequencing approach and revealed the significant existence of such mutations in HM tissues. A particularly high frequency (â¼59% of the cases) of p53 inactivating mutation on exon 7 has been detected. Our identification of hitherto unreported TP53 mutations in HM suggests the presence of p53 mutants and reflects the advantages of using pyrosequencing for point mutation detection in clinical samples. Traditional sequencing method may have overlooked such mutations that only occur in a small population of trophoblasts.
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Mola Hidatiforme/genética , Mutación Puntual , Proteína p53 Supresora de Tumor/genética , Neoplasias Uterinas/genética , Análisis Mutacional de ADN , Femenino , Humanos , Mola Hidatiforme/metabolismo , Mola Hidatiforme/patología , Embarazo , Estudios Retrospectivos , Trofoblastos/metabolismo , Trofoblastos/patología , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologíaRESUMEN
Ovarian clear cell carcinoma (OCCC) is a type of epithelial ovarian cancer that is strongly associated with endometriosis, resistance against conventional chemotherapy and thus poorer prognosis. The expression of inhibitory member of the ASPP family proteins (iASPP) and Polo-like kinase (PLK)1 were significantly higher in OCCC compared to benign cystadenomas and endometriosis. Both protein expressions were found to correlate with chemoresistance in patients with OCCC while high iASPP expression alone was significantly associated with a poor patient survival. The growth of OCCC cell lines, OVTOKO and KK, were inhibited after iASPP silencing. Such effect was related to senescence triggering as evidenced by increased SA-ß-Gal staining and p21WAF1/Cip1 expression. Moreover, knockdown of iASPP induced PLK1 downregulation, whereas either genes' silencing sensitized the cells in response to cisplatin treatment. More prominent apoptosis was induced by cisplatin in OCCC cells after the knockdown of either iASPP or PLK1 as evidenced by the formation of more cleaved caspase 3. Heightened chemosensitivity to cisplatin after iASPP knockdown was further demonstrated in in vivo xenograft model. Additionally, both iASPP and PLK1 were shown to regulate autophagic flux as the induction of LC3B-II and LC3 puncta were much less in OCCC cells with either knockdown. Importantly, inhibition of autophagy also enhanced chemosensitivity to cisplatin in OCCC cells. These findings strongly imply that iASPP and PLK1 affect the chemoresistance of OCCC via the regulation of autophagy and apoptosis. Both iASPP and PLK1 can be potential therapeutic targets for treating OCCC in combination with conventional chemotherapy.
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Adenocarcinoma de Células Claras/patología , Autofagia , Proteínas de Ciclo Celular/metabolismo , Cisplatino/farmacología , Resistencia a Antineoplásicos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Ováricas/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Adenocarcinoma de Células Claras/tratamiento farmacológico , Adenocarcinoma de Células Claras/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proteínas de Ciclo Celular/genética , Proliferación Celular , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Pronóstico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Transducción de Señal , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasa Tipo Polo 1RESUMEN
Accumulating evidence indicates that the human papillomavirus (HPV) E6 protein plays a crucial role in the development of cervical cancer. Subpopulations of cells that reside within tumours are responsible for tumour resistance to cancer therapy and recurrence. However, the identity of such cells residing in cervical cancer and their relationship with the HPV-E6 protein have not been identified. Here, we isolated sphere-forming cells, which showed self-renewal ability, from primary cervical tumours. Gene expression profiling revealed that cluster of differentiation (CD) 55 was upregulated in primary cervical cancer sphere cells. Flow-cytometric analysis detected abundant CD55(+) populations among a panel of HPV-positive cervical cancer cell lines, whereas few CD55(+) cells were found in HPV-negative cervical cancer and normal cervical epithelial cell lines. The CD55(+) subpopulation isolated from the C33A cell line showed significant sphere-forming ability and enhanced tumourigenicity, cell migration, and radioresistance. In contrast, the suppression of CD55 in HPV-positive CaSki cells inhibited tumourigenicity both in vitro and in vivo, and sensitized cells to radiation treatment. In addition, ectopic expression of the HPV-E6 protein in HPV-negative cervical cancer cells dramatically enriched the CD55(+) subpopulation. CRISPR/Cas9 knockout of CD55 in an HPV-E6-overexpressing stable clone abolished the tumourigenic effects of the HPV-E6 protein. Taken together, our data suggest that HPV-E6 protein expression enriches the CD55(+) population, which contributes to tumourigenicity and radioresistance in cervical cancer cells. Targeting CD55 via CRISPR/Cas9 may represent a novel avenue for developing new strategies and effective therapies for the treatment of cervical cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Antígenos CD55/metabolismo , Proteínas Oncogénicas Virales/metabolismo , Papillomaviridae/metabolismo , Infecciones por Papillomavirus/virología , Proteínas Represoras/metabolismo , Neoplasias del Cuello Uterino/virología , Animales , Antígenos CD55/genética , Proteína 9 Asociada a CRISPR/genética , Proteína 9 Asociada a CRISPR/metabolismo , Sistemas CRISPR-Cas , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Autorrenovación de las Células , Femenino , Edición Génica/métodos , Terapia Genética/métodos , Interacciones Huésped-Patógeno , Humanos , Ratones Desnudos , Proteínas Oncogénicas Virales/genética , Papillomaviridae/genética , Infecciones por Papillomavirus/diagnóstico , Tolerancia a Radiación , Proteínas Represoras/genética , Transducción de Señal , Células Tumorales Cultivadas , Regulación hacia Arriba , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/terapia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To review the clinical and pathological characteristics of patients with placental site trophoblastic tumor (PS TT) managed in a tertiary referral center in Hong Kong. STUDY DESIGN: Patients with a diagnosis of PSTT from 1995 to 2012 were identified from a computer database. Clinical and patho- logical data were obtained from medical records and the electronic database. RESULTS: Ten patients with PSTT were identified. Only 4 patients (40%) had disease confined to the uterus at presentation (Stage I). The most common site of metastasis was the lung. Four patients had pretreatment serum hCG levels <1,000 IU/L, and all of them had disease 'confined to the uterus. Of the 4 patients with Stage I disease 3 had hysterectomy only and 1 had both hysterectomy and chemotherapy. All 4 patients achieved complete remission; although 1 of them had a recurrence successfully treated with che- motherapy. For patients with Stage III/IV disease most of them had both hysterectomy and chemotherapy. Only 1 patient (20%) was alive without evidence of disease. CONCLUSION: Patients with Stage I disease have excellent prognosis after hysterectomy, and adjuvant treatment is not recommended. A low pretreatment serum hCG level (<1,000 IU/L) was a good predictor of early stage disease. The prognosis for patients with metastatic disease was poor despite surgery and com- bination chemotherapy.
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Histerectomía , Centros de Atención Terciaria , Tumor Trofoblástico Localizado en la Placenta , Femenino , Enfermedad Trofoblástica Gestacional , Hong Kong , Humanos , Recurrencia Local de Neoplasia , Embarazo , Tumor Trofoblástico Localizado en la Placenta/cirugía , Neoplasias UterinasRESUMEN
BACKGROUND: The occurrence of tubal ectopic pregnancy (tEP) is related to the inflammation of the oviduct. Recently, Adrenomedullin (ADM) was found highly expression in human oviduct. The current study is to investigate whether ADM have a modulatory action on inflammatory cytokines and chemokines in oviductal tissue from women with tubal ectopic pregnancy (tEP). METHODS: Oviductal isthmus samples were collected from women with tEP undergoing salpingectomy, and women undergoing hysterectomy for benign gynaecological conditions. The mRNA and protein levels of inflammatory cytokines/chemokines were assayed by PCR (n = 6 for tEP, n = 5 for controls) and protein microarray methods (n = 5 for both tEP and controls) respectively. RESULTS: Some of the inflammatory cytokines/chemokines were upregulated by ADM in oviducts from tEP patients at both mRNA and protein levels. Incubation of oviduct from tEP patients with ADM for 24 h down-regulated some of these cytokines/chemokines. CONCLUSION: Our results suggest an additional mechanism whereby ADM insufficiency may increase the susceptibility to tEP through diminished anti-inflammatory activity. The actual impact of the relationship between ADM and inflammatory process on tubal implantation needs further exploration.
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Adrenomedulina/farmacología , Quimiocinas/metabolismo , Citocinas/metabolismo , Trompas Uterinas/efectos de los fármacos , Embarazo Tubario/metabolismo , Adulto , Trompas Uterinas/metabolismo , Femenino , Humanos , Persona de Mediana Edad , EmbarazoRESUMEN
The objective of this study was to identify the tumor characteristics associated with mismatch repair deficiency in young patients with endometrial carcinoma. Young patients (45 yr old or younger) with endometrial carcinoma treated by hysterectomy in our institution between July 2001 and June 2009 were identified. The clinical and pathologic data were obtained by review of clinical records. Among the 122 cases identified, paraffin sections were available in 67 cases for immunohistochemical staining and frozen tissue available in 62 cases for microsatellite instability (MSI) analysis. Both paraffin sections and frozen tissue were available in 36 cases. Among the 67 cases with immunohistochemical staining, 22 (32.8%) showed loss of expression of at least 1 mismatch repair protein. Defective MLH1 or MSH2 expression was associated with poor prognostic factors, including a higher incidence of pelvic lymph nodes metastasis (P=0.018) and higher stage (P=0.022) for MLH1, and an increased risk of lymphovascular permeation (P=0.015) for MSH2. On the contrary, defective MSH6 protein expression was associated with a lower incidence of high-grade tumors (P=0.04). Among the 62 cases with MSI analysis, 12 (19.4%) tumors were classified as microsatellite-high (MSI-H), whereas 2 (3.2%) were classified as microsatellite-low (MSI-L). There was no difference in the pathologic characteristics between MSI-stable and MSI-H tumor. We concluded that defective mismatch repair expression is important in young patients with endometrial carcinoma, with MSH6 protein being most commonly affected. The phenotype resulting from defective MSH6 expression was different from that caused by MLH1 or MSH2 loss.
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Neoplasias Encefálicas/genética , Neoplasias Colorrectales/genética , Neoplasias Endometriales/genética , Síndromes Neoplásicos Hereditarios/genética , Proteínas Adaptadoras Transductoras de Señales/análisis , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Neoplasias Encefálicas/patología , Neoplasias Colorrectales/patología , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/genética , Neoplasias Endometriales/patología , Neoplasias Endometriales/cirugía , Femenino , Expresión Génica , Humanos , Histerectomía , Inmunohistoquímica , Metástasis Linfática , Inestabilidad de Microsatélites , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/análisis , Proteína 2 Homóloga a MutS/genética , Estadificación de Neoplasias , Síndromes Neoplásicos Hereditarios/patología , Proteínas Nucleares/análisis , Proteínas Nucleares/genética , Pelvis , PronósticoRESUMEN
OBJECTIVE: To study adrenomedullin (ADM) expression and its relation to ciliary beat frequency (CBF) in the nasal mucociliated epithelium in tubal ectopic pregnancy (tEP). DESIGN: Experimental study. SETTING: University teaching hospital. PATIENT(S): Women with tEP and normal intrauterine pregnancy matched for age and gestational age were recruited. Healthy nonpregnant women were also recruited as nonpregnant controls. INTERVENTION(S): Nasal epithelial brushing. MAIN OUTCOME MEASURE(S): Adrenomedullin expression in nasal epithelium (measured by real-time reverse transcription-polymerase chain reaction, plasma ADM concentration (measured by ELISA), and CBF (measured by photometric method). RESULT(S): We have demonstrated a similar decrease in ADM expression and CBF in the nasal mucociliated epithelium, as well as in plasma ADM concentration, in women with tEP compared with normal pregnant women. Adrenomedullin up-regulates nasal CBF via the ADM receptor, as in the oviduct. There is significant correlation between nasal and oviductal CBF. CONCLUSION(S): Nasal epithelium ADM and CBF, as well as plasma ADM, are possible predictors of women at risk of tEP.
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Adrenomedulina/genética , Cilios/fisiología , Mucosa Nasal/fisiología , Embarazo Tubario , Adrenomedulina/sangre , Adrenomedulina/metabolismo , Adulto , Estudios de Casos y Controles , Regulación hacia Abajo/genética , Trompas Uterinas/metabolismo , Trompas Uterinas/fisiología , Femenino , Humanos , Persona de Mediana Edad , Mucosa Nasal/citología , Mucosa Nasal/metabolismo , Embarazo , Embarazo Tubario/sangre , Embarazo Tubario/diagnóstico , Embarazo Tubario/genética , Embarazo Tubario/fisiopatología , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Increasing evidence has suggested that hepatocellular carcinoma (HCC) might originate from a distinct subpopulation called cancer stem cells (CSCs), which are responsible for the limited efficacy of conventional therapies. We have previously demonstrated that granulin-epithelin precursor (GEP), a pluripotent growth factor, is upregulated in HCC but not in the adjacent non-tumor, and that GEP is a potential therapeutic target for HCC. Here, we characterized its expression pattern and stem cell properties in fetal and cancerous livers. METHODS: Protein expression of GEP in fetal and adult livers was examined in human and mouse models by immunohistochemical staining and flow cytometry. Liver cancer cell lines, isolated based on their GEP and/or ATP-dependent binding cassette (ABC) drug transporter ABCB5 expression, were evaluated for hepatic CSC properties in terms of colony formation, chemoresistance and tumorigenicity. RESULTS: We demonstrated that GEP was a hepatic oncofetal protein that expressed in the fetal livers, but not in the normal adult livers. Importantly, GEP+ fetal liver cells co-expressed the embryonic stem (ES) cell-related signaling molecules including ß-catenin, Oct4, Nanog, Sox2 and DLK1, and also hepatic CSC-markers CD133, EpCAM and ABCB5. Phenotypic characterization in HCC clinical specimens and cell lines revealed that GEP+ cancer cells co-expressed these stem cell markers similarly as the GEP+ fetal liver cells. Furthermore, GEP was shown to regulate the expression of ES cell-related signaling molecules ß-catenin, Oct4, Nanog, and Sox2. Isolated GEP(high) cancer cells showed enhanced colony formation ability and chemoresistance when compared with the GEP(low) counterparts. Co-expression of GEP and ABCB5 better defined the CSC populations with enhanced tumorigenic ability in immunocompromised mice. CONCLUSIONS: Our findings demonstrate that GEP is a hepatic oncofetal protein regulating ES cell-related signaling molecules. Co-expression of GEP and ABCB5 further enriches a subpopulation with enhanced CSC properties. The current data provide new insight into the therapeutic strategy.
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Antígenos de Neoplasias/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Separación Celular , Transformación Celular Neoplásica , Resistencia a Antineoplásicos , Granulinas , Humanos , Hígado/metabolismo , Hígado/patología , Ratones , Fenotipo , Progranulinas , Ensayo de Tumor de Célula MadreRESUMEN
BACKGROUND: Persistent high-risk type Human papillomavirus (HPV) infection is recognized as a necessary cause of cervical cancer. This study aimed to compare the HPV prevalence and risk factors between women residing in Hong Kong (HK) and Guangzhou (GZ) region of China. METHODOLOGY/PRINCIPAL FINDINGS: A total of 1,570 and 1,369 women were recruited from HK and GZ, respectively. The cytology samples were collected and tested for HPV infection. The overall and type-specific HPV prevalence and the potential risk factors for acquisition of HPV infection were studied. Women with normal cytology in the GZ cohort had significantly higher HPV prevalence (10%) than those in the HK cohort (6.2%, p<0.001). The patterns of the age-specific HPV prevalence were also different between the two cohorts. In the HK cohort, women at the age of 20-29 years old had the highest prevalence and a second peak was observed in the age of ≥ 60 years old. In the GZ cohort, the highest HPV prevalence was also observed in 20-29 years old but declined as the age increased and a second peak was not seen. HPV16 and HPV52 were the most common high-risk types found in the HK and GZ cohorts, respectively. Age was the most consistently observed independent risk factor for HPV infection in the HK, while the number of sexual partners had association in the GZ cohort. CONCLUSIONS/SIGNIFICANCE: Our study provides the current status and the epidemiological characteristics of HPV prevalence in Southern Chinese women. The results strongly suggested that population education and the effective cervical cancer screening would be vital in the prevention of cervical cancer.