Tumors Of Female Reproductive Organs Research Articles

ELK3 Targeting AEG1 Promotes Migration and Invasion of Ovarian Cancer Cells under Hypoxia.

Ovarian cancer (OC) is one of the most common tumors in female reproductive organs with a five-year survival rate of less than 45%. Metastasis is a crucial contributor to OC development. ETS transcription factor (ELK3), as a transcriptional factor, have been involved in multiple tumor development. However, its role in OC remains elusive. In this study, we observed high expression of ELK3 and AEG1 in human OC tissues. OVCAR-3 and SKOV3 cells were treated with hypoxia to mimic tumor microenvironment in vivo. We found that the expression of ELK3 was significantly increased in cells under hypoxia compared with normoxia. ELK3 knockdown inhibited cell migration and invasion abilities under hypoxia. Moreover, ELK3 knockdown decreased β-catenin expression and inhibited the activation of Wnt/β-catenin pathway in SKOV3 cells under hypoxia. Astrocyte-elevated gene-1 (AEG1) has been reported to promote OC progression. Our results showed that the mRNA level of AEG1 was decreased when ELK3 knockdown under hypoxia. Dural luciferase assay confirmed that ELK3 bound to gene AEG1 promoter (-2005-+15) and enhanced its transcriptional activity under hypoxia. Overexpression of AEG1 increased the migration and invasion abilities of SKOV3 cell with ELK3 knockdown. In the absence of ELK3, the activation of β-catenin was recovered by AEG1 overexpression. To sum up, we conclude that ELK3 promotes AEG1 expression by binding to its promoter. ELK3 could promote migration and invasion of OC cells by targeting AEG1, which provides a potential basis for therapeutic approaches to OC.

Automatic Detection and Segmentation of Ovarian Cancer Using a Multitask Model in Pelvic CT Images.

Ovarian cancer is one of the most common malignant tumours of female reproductive organs in the world. The pelvic CT scan is a common examination method used for the screening of ovarian cancer, which shows the advantages in safety, efficiency, and providing high-resolution images. Recently, deep learning applications in medical imaging attract more and more attention in the research field of tumour diagnostics. However, due to the limited number of relevant datasets and reliable deep learning models, it remains a challenging problem to detect ovarian tumours on CT images. In this work, we first collected CT images of 223 ovarian cancer patients in the Affiliated Hospital of Qingdao University. A new end-to-end network based on YOLOv5 is proposed, namely, YOLO-OCv2 (ovarian cancer). We improved the previous work YOLO-OC firstly, including balanced mosaic data enhancement and decoupled detection head. Then, based on the detection model, a multitask model is proposed, which can simultaneously complete the detection and segmentation tasks.

Эндометриоидная цистаденома – глубокий яичниковый эндометриоз

Among all endometriosis lesions of female reproductive organs, ovarian endometrioma is the most discussed nosology. Since 2014, ovarian endometrioid cysts have been classified as benign tumors (WHO Classification of Tumours of Female Reproductive Organs, 4th edition). In 2021, the 11th revision of the International Classification of Diseases (ICD-11) was amended, according to which the term “endometrioid ovarian cyst” (from 2018 to 2021 – heading GA18.3 Ovarian endometriotic cyst, section GA18 Acquired abnormalities of ovary) is no longer used, and the clinical and morphological signs of these cysts are presented in the heading GA10.B5 Deep ovarian endometriosis. In 2020, WHO updated the histological classification of female genital tumors (Female Genital Tumours WHO Classification of Tumours, 5th Edition), in which the section “endometrioid tumors” is presented only with endometrioid cystadenoma and endometrioid adenofibroma without mentioning the endometrioid cyst, but in accordance with the ICD-11, endometrioid cystadenoma is coded as “GA10.B5 Deep ovarian endometriosis”. Thus, on the one hand, ovarian endometrioma is a neoplastic process and requires appropriate approaches when choosing treatment tactics, on the other hand, cystectomy for endometrioma is accompanied by a pronounced loss of ovarian reserve. A possible consensus in this problem seems to be a minimally invasive method in the treatment of patients with ovarian endometriomas – ethanol sclerotherapy with cytological examination of the aspirate obtained from the neoplasm. The effectiveness of sclerotherapy largely depends on the choice of postoperative hormonal therapy. Today, dienogest is considered to be the most effective “anti-endometrioid” progestogen. However, there is an erroneous opinion that ethinylestradiol neutralizes the antiproliferative effect of dienogest and stimulates the growth of endometriosis. On the contrary, ethinylestradiol enhances the inhibitory effect of progestogen on the growth of ovarian endometrioma cells. Key words: endometrioid cystadenoma, ovarian endometrioma, deep ovarian endometriosis, sclerotherapy, dienogest

Prediction of Key Candidate Genes for Platinum Resistance in Ovarian Cancer.

PurposeOvarian cancer is one of the common malignant tumors of female reproductive organs, which seriously threatens the life and health of women. Resistance to chemotherapeutic drugs for ovarian cancer is the root cause of recurrence in most patients. The purpose of this study is to determine the differentially expressed genes of platinum resistance in ovarian cancer, and to screen out molecular targets and diagnostic markers that could be used to treat ovarian cancer platinum resistance.MethodsWe downloaded 5 gene microarray datasets GSE58470, GSE45553, GSE41499, GSE33482, and GSE15372 from the Gene Expression Omnibus database, all of which are associated with ovarian cancer platinum resistance. Subsequently, the intersection of the statistically significant differentially expressed genes in 5 gene chips was taken, and relevant bioinformatics and clinical parameters were performed on the screened differential genes. qRT-PCR was utilized to examine the mRNA expression levels in ovarian cancer sensitive and cisplatin-resistant cells.ResultsThree differential genes, IFI27, JAG1, DNM3, may be closely related to platinum resistance of ovarian cancer, were screened by microarray datasets. According to the combined verification of bioinformatics, clinical case analyses and experiments, it was inferred that the increased expression of DNM3 was beneficial to patients with platinum resistance, but the high expression of IFI27 and JAG1 may lead to the risk of platinum resistance.ConclusionIFI27, JAG1 and DNM3 screened by relevant gene chips may serve as new biomarkers of platinum resistance in ovarian cancer.

Study on the clinical significance of TRPV2 and MMP2 expressions in ovarian cancer

Ovarian cancer was one of the most common malignant tumors in female reproductive organs. Moreover, epithelial ovarian cancer showed the highest mortality rate in gynecological tumors, posing serious threats to women’s li... | Find, read and cite all the research you need on Tech Science Press

High-Grade Serous Carcinoma of the Fallopian Tube

A woman presented with pelvic pain, increased abdominal girth, and gastrointestinal symptoms. A pelvic adnexal mass was identified by imaging and resected. Pathology diagnosed the mass as high-grade serous carcinoma (HGSC) of the fallopian tube.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Which gene is most commonly altered in high-grade serous carcinoma?a.KRASb.BRAFc.NRASd.TP53 Answer: d. TP53 Some form of TP53 gene alteration is found in nearly all HGSCs.1Kurman R.J. Shih I. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory.Am J Surg Pathol. 2010; 34: 433-443Crossref PubMed Scopus (1196) Google Scholar,2Kurman R.J. Carcangiu M.L. Herrington C.S. Young R.H. WHO Classification of Tumours of Female Reproductive Organs. IARC, Lyon, France2014Google Scholar In contrast, KRAS and BRAF mutations are more frequent in low-grade serous carcinoma (LGSC).1Kurman R.J. Shih I. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory.Am J Surg Pathol. 2010; 34: 433-443Crossref PubMed Scopus (1196) Google Scholar,2Kurman R.J. Carcangiu M.L. Herrington C.S. Young R.H. WHO Classification of Tumours of Female Reproductive Organs. IARC, Lyon, France2014Google Scholar Further, a significant percentage of HGSCs arise from intraepithelial carcinoma of the fallopian tube whereas LGSC commonly evolves from a continuum of ovarian neoplastic precursors including serous borderline tumor. Morphologically, HGSC often has an infiltrative mixture of papillae, glandular, and solid structures composed of cells with marked cytologic atypia, and frequent mitotic activity. LGSC also has destructive invasion, but the micropapillae have low-grade nuclear features and a lower frequency of mitotic activity.

Analysis of expression and prognosis of KLK7 in ovarian cancer.

BackgroundOvarian cancer is one of the common malignant tumors in female reproductive organs. Kallikrein-related peptidase (KLK) 7 is a secreted serine peptidase that is related to different cancer. To investigate the expression and significance of KLK7 in ovarian cancer.Materials and methodsThe expression of KLK7 in human ovarian cancer was evaluated by Oncomine and Cancer Cell Line Encyclopedia database. Then the co-expression genes relevant to the KLK7 gene were analyzed by the Pearson correlation test. Finally, the impact of KLK7 on clinical prognosis was investigated in distinct subtypes of ovarian cancer patients by UALCAN database and Kaplan–Meier plotter database.ResultsIt was found that the expression of KLK7 was higher in ovarian cancer compared with other types of cancer, such as gastric cancer and pancreatic cancer. The expression of KLK7 was found to be increased in four various ovarian cancer data sets compared with the healthy tissues. In addition, upregulation of KLK7 expression was associated with age and cancer stage. Moreover, survival analysis revealed that higher KLK7 expression was negatively associated with progression-free survival.ConclusionKnowledge of the expression of KLK7 may be useful for better understanding the outcome in ovarian cancer patients.

Analysis of factors affecting the prognosis of patients with cervical intraepithelial neoplasia 2.

According to the 2014 World Health Organization Classification of Tumors of Female Reproductive Organs, patients with cervical intraepithelial neoplasia 2 (CIN2) have an equivocal diagnosis, but p16 is considered as the reference index for CIN2. Positive p16 expression in CIN2 is associated with high-grade squamous intraepithelial lesions (HSIL), whereas p16 negative lesions are low-grade squamous intraepithelial lesions. The purpose of the present study was to examine the clinical value of p16 and human papillomavirus (HPV) E6/E7 mRNA in the prognostication of patients with CIN2. From January 2013 to January 2016, 108 patients were diagnosed with CIN2 by biopsy and followed up at 6-month intervals at Peking University People's Hospital (Beijing, China). The expression of HPV E6/E7 mRNA was detected by in situ hybridization, while the expression of p16 and Ki-67 proteins was detected by immunohistochemistry. Of the 108 CIN2 cases, 20 progressed to HSIL/CIN3, 36 cases demonstrated persistence with CIN2 after the follow-up and 52 cases achieved regression (≤CIN1). Of the p16-positive 82 cases, 20 cases were detected to have progressed, whereas in the p16-negative group, no progression was observed. There were statistically significant differences among the p16-positive and negative groups (P<0.05). In the HPV E6/E7 mRNA-positive 69 cases, 18 cases were detected to have progressed, whereas in the HPV E6/E7 mRNA-negative 39 cases, progression was detected in only 2 cases. There were statistically significant differences among the HPV E6/E7 mRNA-positive and negative groups (P<0.05). The area under the receiver operating characteristics curve was plotted; the area under the curve for HPV E6/E7 mRNA was 0.745, that for p16 was 0.546 and that for Ki-67 was 0.501. The detection of HPV E6/E7 mRNA may provide important predictive information for the prognosis of CIN2, however p16 and Ki-67 proteins may provide little value.

Upregulated CXCL14 is associated with poor survival outcomes and promotes ovarian cancer cells proliferation.

Ovarian cancer is one of the common malignant tumours of female reproductive organs. Due to early diagnosis difficulties and lack of effective treatment in the late stage, ovarian cancer has the highest mortality rate in female reproductive system malignancies. Therefore, finding reliable early diagnosis indicators and new therapeutic targets for ovarian cancer is an urgent problem to be solved. Chemokine (C-X-C motif) ligand 14 (CXCL14) is a small cytokine belonging to the CXC chemokine family, which has been found to possess multi-effects in tumourigenesis and development. Here, we reported that CXCL14 was preferentially expressed in ovarian cancer. By analysing the TCGA database, we found that CXCL14 was highly expressed in advanced ovarian cancer patients and correlated with poor prognosis. In addition, the abnormal high CXCL14 levels were observed in serum and ovarian tissue of ovarian cancer patients by qRT-PCR and ELISA. In vitro and in vivo experiments both confirmed that overexpression of CXCL14 promoted the ovarian cancer cell proliferation. Moreover, transfection of CXCL14 increased the phosphorylation level of signal transducer and activator of transcription 3 (STAT3), and administration of STAT3 inhibitor III inhibited the tumour-promoting effects of CXCL14. Therefore, our study suggests that CXCL14 could be utilised as a novel adjunct biomarker for early diagnosis of ovarian cancer and provides new targets and ideas for the treatment of advanced ovarian cancer. SIGNIFICANCE PARAGRAPH: CXCL14 could be utilised as a novel adjunct biomarker for early diagnosis of ovarian cancer and provides new targets and ideas for the treatment of advanced ovarian cancer.

Analysis of Prediagnostic Metabolic Profiles of Endometrial Carcinoma Patients in the Obese Population

Abstract Endometrial carcinoma has been traditionally divided into type 1 and type 2 carcinomas. Excess estrogen is believed to be the pathologic mechanism of type 1 carcinoma. The WHO Classification of Tumors of Female Reproductive Organs lists obesity as a risk factor for type 1 endometrial carcinoma. On the contrary, type 2 carcinoma is generally not associated with estrogen or obesity. Endometrial endometrioid carcinoma is the most common type 1 carcinoma. Endometrial serous carcinoma is a typical type 2 carcinoma. In our community, with a high prevalence of obesity, we investigated whether serous carcinoma, a type 2 carcinoma, could also occur in the obese population, and whether there are identifiable metabolic differences between endometrioid carcinoma patients and serous carcinoma patients in the obese population prior to cancer diagnosis, which might provide clues to the different pathogenesis of the two types of carcinoma. Two cohorts of postmenopausal patients with serous carcinoma or endometrioid carcinoma between 2006 and 2016 were established. Then each cohort was subdivided into four categories based on patients’ average BMI (within 5 years before cancer diagnosis): nonobese (&lt;30), moderately obese (30-35), severely obese (35-40), and morbidly obese (&gt;40). Patients’ average triglycerides, HDL, blood pressures, and HbA1c levels (within 5 years before cancer diagnosis) were obtained. In total, 304 patients were in the endometrioid carcinoma cohort, while 135 patients were in the serous carcinoma cohort. In the morbidly obese category (BMI &gt;40), serous carcinoma patients had significantly lower triglycerides and HbA1c levels than endometrioid carcinoma patients while their BMIs were comparable. For HDL and systolic and diastolic blood pressures, no significant difference was observed between the two groups. In each of the other BMI categories, serous carcinoma patients also had lower triglycerides and HbA1c levels than endometrioid carcinoma patients. In the serous carcinoma patient cohort, there was a moderately negative correlation between average BMI and triglycerides/HbA1c levels, with a Pearson’s correlation coefficient of –0.25 for triglycerides level and –0.19 for HbA1c level. On the contrary, there was no correlation between average BMI and triglycerides/HbA1c levels in the endometrioid carcinoma patient cohort (Pearson’s coefficient close to 0). In summary, the serous carcinoma patients in the obese population lacked the metabolic profiles generally associated with high BMI. These findings show that there are identifiable prediagnostic metabolic differences between endometrioid carcinoma patients and serous carcinoma patients. The metabolic differences between the two groups in each BMI category suggest that BMI should be combined with metabolic markers, rather than used alone, in the evaluation of risk factors for endometrial carcinoma. Future epidemiologic and experimental studies focusing on the association between metabolic syndrome and endometrial carcinoma should separate different histologic subtypes of endometrial carcinoma in the study design due to their distinct metabolic profiles.

Hormonal therapy in uterine sarcomas.

Uterine sarcomas (USs) are a group of rare but aggressive uterine malignancies, accounting for only 1% of the malignant tumors of female reproductive organs. Due to the high rate of recurrence and metastasis, the prognosis of USs is poor. Given the high mortality rate and limited clinical benefit of surgery and adjuvant chemoradiotherapy, hormonal therapy has shown good prospects in recent years. Hormonal agents include progestins, aromatase inhibitors (AIs), and gonadotropin‐releasing hormone analogue (GnRH‐a). According to the literature, hormonal therapy has been confirmed effective for recurrent, metastatic or unresectable low‐grade endometrial stromal sarcoma (LGESS) and hormone receptor positive (ER+/PR+) uterine leiomyosarcoma (uLMS) with favorable tolerance and compliance. Besides, hormonal therapy can also be used in patients with early‐staged disease who desire to preserve fertility. However, due to the rarity of USs, the rationale of hormonal therapy is generally extrapolated from data of hormone‐sensitive breast cancer, and present studies of hormonal therapy in USs were almost limited to case reports and small‐sized retrospective studies. Therefore, further systematic researches and standardized clinical trials are needed to establish the optimal hormonal therapy regimen of USs. Herein, we reviewed the existing studies related to the hormonal therapy in USs in order to provide reference for clinical management in specific settings.

Ovarian seromucinous tumor: A case series of WHO newly introduced entity

Introduction: Ovarian epithelial tumors account for the majority of female ovarian neoplasms but seromucinous tumors are rare and not adequately described in the literature. The recent World Health Organization (WHO) 2014 classification of tumors of female reproductive organs introduced this new category of ovarian neoplasm as “seromucinous tumors. Materials and Method: Sectioning of tissue followed by staining and immunohistochemistry. Results: Four of our cases which were diagnosed as cystic lesion clinically and radiologically , on histopathological examination two of them reported as seromucinous cystadenoma and rest two as seromucinous borderline tumors (SMBT). One of the case of SMBT also showed microinvasion along with focal areas of intraepithelial carcinoma high grade and clear cell component. Conclusion: Proper histopathological diagnosis is very important for better treatment and to reduce the use of aggressive therapies.

MOLECULAR-GENETIC MODELS FOR PROGNOSIS OF DEVELOPMENT OF TUMORS OF REPRODUCTIVE SYSTEM IN WOMEN WITH FAMILY HISTORY OF CANCER

To develop a prognostic molecular genetic model for assessing the risk of development of benign and malignant tumors of female reproductive organs (FRO) in patients from cancer-affected families. The work presents the data on a comprehensive clinical examination of 210women (90patients with FRO cancer with aggregation of tumor pathology in families, 65patients with benign pathology of FRO from cancer-affected families, 55women- control group of healthy women without family history of cancer). Clinical genealogical analysis, morphological examination of tumors and molecular genetic studies of genomic DNA from peripheral blood and tumors were carried out. It was established that in the families of patients with benign and malignant pathology of FRO, malignant tumors associated with Lynch II syndrome are observed. Based on the analysis of detected ESR-1, CYP2D6*4and mutations in BRCA1/2genes in cancer patients and in patients with benign pathology, molecular genetic models have been developed to assess the individual risk of development of benign and malignant tumors of FRO. It has been established that these molecular genetic models and combinations of gene mutations and gene polymorphisms (SNP) by the intergene interaction that was analyzed, were found to be reliable in assessing the risk of benign and malignant pathology of the mammary gland and ovary. The model, which included the polymorphic variants of the T397C(ESR1)/CYP2D6*4genes was of the best predictive accuracy for the evaluation of the risk of benign tumors of the FRO (71.68%) and the highest reliability (p < 0.001). At the same time, all identified models of intergene interaction in the development of malignant pathology of FRO were reliable, prognostically significant with high reproduction and almost identical accuracy (65.00-68.23%). The obtained results indicate a high informativeness of such molecular genetic indices as the polymorphism of ESR1and CYP2D6*4genes and mutations in BRCA1/2genes to assess the risk of benign or malignant tumors of FRO in families of patients with family history of cancer.

Mitotically active cellular fibroma of the ovary: a rare case and review of literature

AbstractMitotically active cellular fibroma (MACF) is a category of fibromatous tumours of the ovary described in the WHO classification of tumours of female reproductive organs. The case of a 54-year-old female who presented with lower limb swelling due to deep vein thrombosis (DVT) is reported. On examination, she had a 5 x 8 cm fixed pelvic mass. She underwent optimal cytoreductive surgery. Grossly the tumour, which was found to occupy the left pelvic space, was hard and irregular in shape and was adherent to the surrounding structures. Histopathology revealed collagen-producing spindle cells showing mitotic activity of 6–8/10 HPF with minimal nuclear atypia and Ki 67 labelling index of 10%. A final diagnosis of MACF was made. In view of sparse evidence regarding its management and due to residual tumour (< 1 cm), she received adjuvant radiotherapy. She has remained disease free over a period of two years.

Components of tissue fibrinolytic system as markers for processes in tumors of female reproductive organs.

e17032 Background: Components of tissue fibrinolytic system are now considered as important agents providing progressive tumor growth. The purpose of the study was to analyze fibrinolytic system components in uterine and breast tumors. Methods: We studied tumor samples in breast cancer (BC, n=24), nodular type of fibrocystic breast disease (FBD, n-15) and uterine myoma (UM, n=14) and in synchronous BC and UM (n=12). Intact breast tissues (IBT, n=16) and intact myometrium (IM, n=14) were used as the control. Activity of plasmin (P), total content and activity of uPA-Ag and uPA-act, tPA-Ag and tPA-act were determined by ELISA; plasminogen (PG) concentration was measured by spectrophotometry (ACTICHROME PLG, USA). Results: uPA-Ag in solitary BC was 6.5 times higher and uPA-act – 4.5 times higher than in IBT. Concentration of tPA-Ag in 75% of BC patients exceeded the value in IBT by 2.1 times, and tPA-act in 87.5% – by 1.5 times. tPA-Ag and tPA-act in FBD tissues were similar to IBT values, while uPA-Ag and uPA-act were increased by 2.2 times each. uPA-Ag in BC in BC+UM exceeded the norm by 10.6 times, uPA-act – by 5.5 times; tPA-Ag in 75% of samples was 3.8 times higher than in IBT, and tPA-act – 2.7 times higher. uPA-Ag and uPA-act levels in UM in BC+UM were similar to IM values, while tPA-Ag and tPA-act exceeded the norm by 1.8 and 1.5 times, respectively. Both uPA and tPA levels and activity in solitary UM did not differ significantly from IM. Conclusions: The results show an active conversion of plasminogen into plasmin in both solitary and synchronous BC and in synchronous UM. Components of tissue fibrinolytic system can be considered as reliable markers for processes in solitary and synchronous tumors of female reproductive organs.

Sex hormones as regulators of levels of growth factors in tissues of multiple primary tumors of female reproductive organs.

e23180 Background: Sex hormones are known to be able to influence the synthesis of growth factors in breast and uterine tumors; however, their relationship in multiple primary tumors is poorly studied. The purpose of the study was to analyze correlations between sex steroids and growth factors in tissues of solitary and synchronous breast cancer and uterine myoma. Methods: Levels of estrogens (E1, E2, E3), 2OHE1 and 16α-OHE1, Р4, VEGА and EGF were measured by ELISA in tissues of breast cancer (BC, n = 37), uterine myoma (n = 27) and in synchronous BC and uterine myoma (n = 36). Results: Strong positive correlations were observed in synchronous BC and uterine myoma: E3 with VEGF (r1= 83, r2= 79; p1,2&lt; 0.05) and EGF (r1= 78, r2= 82; p1,2&lt; 0.05), Е1 with VEGF ( r1= 81, r2= 77; p1,2&lt; 0.05) and EGF (r1= 76, r2= 80; p1,2&lt; 0.05), 16-OHE1 with VEGF and EGF (r1= 80, r2= 77; p1,2&lt; 0.05 and r1= 79 r2= 80; p1,2&lt; 0.05). We found strong negative correlations of Е3 and VEGF (r1= 80, r2= 77; p1,2&lt; 0.05) and EGF (r1= 79 r2= 80; p1,2&lt; 0.05), Р4 and VEGF (r1= - 81, r2= -79; p1,2&lt; 0.05) and EGF (r1= - 77, r2= -80; p1,2&lt; 0.05). Solitary breast tumors showed moderate positive correlations of E2 and E1 with VEGF (r1= 56, r2= 63; p1,2&lt; 0.05) and EGF (r1= 61, r2= 65; p1,2&lt; 0.05) and a moderate negative correlation between VEGF and EGF and Р4 (r1= - 61, r2= -59; p1,2&lt; 0,05). A strong negative correlation of EGF with Е1 and 16-OHE1 (r1= -79, r2= -76; р1,2&lt; 0.05) was registered in uterine myoma. Conclusions: Tissues of synchronous primary breast tumors and uterine myoma had similar correlations between levels of growth factors and sex hormones. Solitary breast tumors and uterine myoma showed correlations typical of the tumor type. Thus, expression of growth factors in multiple primary tumors, but not in solitary ones, is subject to a clearly determined regulatory role of sex steroids and their metabolites.

Prognostic Value of ADAMTS Proteases and Their Substrates in Epithelial Ovarian Cancer

Background: ADAMTS are metalloproteases with disintegrin and thrombospondin motifs. They are secreted proteases playing a role in biological processes such as inflammation, angiogenesis, and urogenital development. ADAMTS have specific substrates, such as the proteoglycans (PG) versican, aggrecan, and brevican. Despite data indicating a role of ADAMTS in tumor invasion and metastases, effects played by these molecules in cancer progression are still controversial. In ovarian cancer, the importance of ADAMTS gene mutations was recently described and related to chemotherapy outcome. Objective: To analyze protein levels of ADAMTS-1, -4, and -5, and TIMP-3 in human ovarian cancer classified as benign, borderline, or malignant. We also assessed the expression of the ADAMTS substrates aggrecan, brevican, and versican in these neoplasms. Correlations between overall survival and protein expression were performed. Methods: Tumors were classified according to the WHO Classification of Tumors of Female Reproductive Organs. Protein and PG expression was studied by immunohistochemistry. Differences in labeling were analyzed by percent measurements of stained areas. Results: ADAMTS-1, ADAMTS-5, and its tissue inhibitor TIMP-3 are increased in borderline and malignant tumors compared to benign neoplasms. Aggrecan and versican levels were increased in malignant subtypes compared to benign ovarian cancer. Higher ADAMTS-1, TIMP-3, and versican expression was associated with a shorter overall survival. Conclusions: Comparison of protease, TIMP-3, and substrate expression showed that in malignant tumors all ADAMTS and TIMP-3 expression levels were significantly raised compared to the substrates studied.

Transcriptional network in ovarian cancer cell line SKOV3 treated with Pinellia pedatisecta Schott extract.

Ovarian cancer is the most lethal disease among the malignant tumors of female reproductive organs. Few successful therapeutic options exist for patients with ovarian cancer. The common therapeutic methods are surgical operation, chemotherapy, radiotherapy, and combination of these treatments. In recent years, studies have indicated that Pinellia pedatisecta Schott (PPS), a traditional Chinese medicine, could inhibit tumor growth. In this study, we demonstrated that PPS extract could induce apoptosis in SKOV3 cells in a dose- and time-dependent manner. We further conducted transcriptome sequencing on PPS extract-treated SKOV3 cells along with controls, and identified 1,754 transcripts whose expression differs at least 3-fold over the controls. These differentially expressed transcripts include the apoptosis-related genes such as the caspase family members, and were significantly enriched in steroid biosynthesis in the KEGG pathway database compared with the transcriptome background. Most of the differentially expressed transcripts from this pathway were upregulated in PPS extract-treated cell line, indicating that PPS extract-induced apoptosis was accompanied by increased steroid biosynthesis (e.g. zymosterol). These results suggest that PPS extract could be a new cytostatic therapeutic agent for ovarian cancer.

The terminology of pre-invasive cervical lesions in the UK cervical screening programme.

The terminology of non-invasive epithelial abnormalities associated with an elevated risk of having or developing invasive cervical carcinoma (pre-invasive lesions) has been modified frequently over time as understanding of the underlying biology, and approaches to disease management, have changed. The arguments are now converging on the conclusion that the most appropriate terminology for cervical squamous intraepithelial abnormalities should be two-tier rather than three-tier. Given the findings of the Lower Anogenital Squamous Terminology (LAST) project in the USA, which have recently been endorsed by the World Health Organisation classification of tumours of female reproductive organs, the recommended terms are low-grade and high-grade squamous intraepithelial lesion (SIL), with the option of including the relevant cervical intraepithelial neoplasia (CIN) grade in parentheses. Although, at first sight, this appears to represent only a small change, there is a fundamental conceptual difference between the systems. The CIN system requires, first, the identification of a CIN lesion and, second, the determination of its grade on a continuum, with subsequent division into three grades. The SIL system is based on the existence of two different forms of human papillomavirus (HPV) infection, with productive infection leading to low-grade SIL and transforming infection leading to high-grade SIL.

Pten in mouse vagina.

It is well known that the phosphatase and tensin homolog deleted from chromosome 10 (Pten) is a tumor suppressor and is indispensable for epithelial cell homeostasis to prevent tumor formation. Mutations in Pten are frequently found both in sporadic and hereditary cancers, and mice with Pten deletion and/or loss-of-function mutations are highly susceptible to tumor induction by aberrant phosphatidylinositol 3-kinase (PI3K)/Akt pathway activation [1, 2]. The female reproductive tract (FRT) consists of the sites for reproduction and is of significant concern for women's health and disease, notably tumorigenesis. Despite the importance of this organ system, the molecular and cellular mechanisms that regulate cell proliferation and differentiation of these organs are not yet fully understood. Obviously, estrogen plays a central role in female reproductive organ biology. In the FRT, estrogen stimulation increases the organ weight, and promotes cell proliferation and differentiation, whereas estrogen withdrawal induces rapid involution, resulting in atrophy. These specific and reversible effects of estrogen are important in maintaining homeostasis and are required for normal health and reproduction. It is currently thought that excess estrogen stimulation plays a role in the etiology of hyperplasia and/or tumors in female reproductive organs. Therefore, homeostasis of FRT should be separately regulated according to the presence or absence of estrogen in order to prevent ectopic and excess cell proliferation, respectively. The mouse vagina exhibits a unique feature in response to estrogens and provides an intriguing model for analyzing stratified and squamous differentiation in the epithelium, because it undergoes characteristic changes from non-keratinized to a fully keratinized epithelium depending on the levels of endogenous estrogen during the estrous cycle. In addition, the mouse model allows a manipulation of estrogen levels by ovariectomy (OVX) and exogenous estrogen treatment. The vaginae of OVX mice show atrophied epithelia of 2-3 cell layers, whereas estrogen administration rapidly induces epithelial cell proliferation in the basal layer. The suprabasal cells are no longer mitogenic but differentiate while moving up through the epithelium. Finally, apical cells exhibit keratinization. The fully stratified and keratinized vaginal epithelium resembles the typical stratified and keratinized epidermis found in the skin and other organs. Pten has a pivotal role in maintaining stratified squamous epithelia, because conditional knockout (CKO) of Pten in the epithelium leads to hyperplasia, hyperkeratosis and tumor formation in squamous tissues (e.g., squamous cell carcinomas; SCC) [3]. In our current study [4], we utilized vaginal epithelium-specific conditional Pten knockout mice to elucidate the role of Pten in the vagina. PI3K/Akt signaling is a downstream and essential mediator for estrogen-induced events in FRT [5, 6]. We thus hypothesized that Akt activation by Pten mutation results in the phenocopy of estrogen-stimulated status and/or squamous epithelial hyperplasia even in the absence of estrogen. Pten CKO OVX mice, however, did not show such a simple phenotype, but exhibited epithelial hyperplasia in the suprabasal cells with increased cell mass and mucin production. No stratified epithelial cell markers, such as CK1 and filaggrin, were expressed. By contrast, estrogen administration to Pten CKO OVX mice induced stratification and keratinized differentiation in the vaginal epithelium as in the control mice. One of the most intriguing findings is that Pten is exclusively expressed in the suprabasal cells in the absence of estrogens, whereas estrogen administration induced Pten expression in the basal cells. Pten thus has dual roles in the vaginal epithelium, depending on the presence or absence of estrogen. In the absence of estrogen, Pten inhibits ectopic cell proliferation and abnormal mucin production in the suprabasal cells. In the presence of estrogen, Pten functions in the basal cells to prevent excessive basal cell proliferation as in the case of other squamous tissues. The current result that Pten regulates homeostasis of the vagina in different ways is quite unique and provides new insights into how Pten functions in tissue homeostasis. Primary vaginal cancer is rare, accounting for only 1-3% of gynecological malignancies, but SCC is the most common invasive malignancy of the cervix, vagina and vulva [7]. Our findings shed light on the underlying mechanisms of cancer biology associated with the Pten/PI3K/Akt signaling pathway and its crosstalk to estrogen.