Exploring a multiparameter MRI-based radiomics approach to predict tumor proliferation status of serous ovarian carcinoma.

OBJECTIVES: To develop a multiparameter magnetic resonance imaging (MRI)-based radiomics approach that can accurately predict the tumor cell proliferation status of serous ovarian carcinoma (SOC). MATERIALS AND METHODS: A total of 134 patients with SOC who met the inclusion and exclusion criteria were retrospectively screened from institution A, spanning from January 2016 to March 2022. Additionally, an external validation set comprising 42 SOC patients from institution B was also included. The region of interest was determined by drawing each ovarian mass boundaries manually slice-by-slice on T2-weighted imaging fat-suppressed fast spin-echo (T2FSE) and T1 with contrast enhancement (T1CE) images using ITK-SNAP software. The handcrafted radiomic features were extracted, and then were selected using variance threshold algorithm, SelectKBest algorithm, and least absolute shrinkage and selection operator. The optimal radiomic scores and the clinical/radiological independent predictors were integrated as a combined model. RESULTS: Compared with the area under the curve (AUC) values of each radiomic signature of T2FSE and T1CE, respectively, the AUC value of the radiomic signature (T1CE-T2FSE) was the highest in the training set (0.999 vs. 0.965 and 0.860). The homogeneous solid component of the ovarian mass was considered the only independent predictor of tumor cell proliferation status among the clinical/radiological variables. The AUC of the radiomic-radiological model was 0.999. CONCLUSIONS: The radiomic-radiological model combining radiomic scores and the homogeneous solid component of the ovarian mass can accurately predict tumor cell proliferation status of SOC which has high repeatability and may enable more targeted and effective treatment strategies. CRITICAL RELEVANCE STATEMENT: The proposed radiomic-radiological model combining radiomic scores and the homogeneous solid component of the ovarian mass can predict tumor cell proliferation status of SOC which has high repeatability and may guide individualized treatment programs. KEY POINTS: • The radiomic-radiological nomogram may guide individualized treatment programs of SOC. • This radiomic-radiological nomogram showed a favorable prediction ability. • Homogeneous slightly higher signal intensity on T2FSE is vital for Ki-67.

LLGL2 Inhibits Ovarian Cancer Metastasis by Regulating Cytoskeleton Remodeling via ACTN1.

Epithelial ovarian cancer is the most lethal gynecological malignant tumor. Although debulking surgery, chemotherapy, and PARP inhibitors have greatly improved survival, the prognosis for patients with advanced EOC without HRD is still poor. LLGL2, as a cell polarity factor, is involved in maintaining cell polarity and asymmetric cell division. In the study of zebrafish development, LLGL2 regulated the proliferation and migration of epidermal cells and the formation of cortical F-actin. However, the role of LLGL2 in ovarian cancer has not been described. Our study found, through bioinformatics analysis, that low expression of LLGL2 was significantly associated with a more advanced stage and a higher grade of EOC and a poorer survival of patients. Functional experiments that involved LLGL2 overexpression and knockdown showed that LLGL2 inhibited the migration and invasion abilities of ovarian cancer cells in vitro, without affecting their proliferation. LLGL2-overexpressing mice had fewer metastatic implant foci than the controls in vivo. Mechanistically, immunoprecipitation combined with mass spectrometry analysis suggested that LLGL2 regulated cytoskeletal remodeling by interacting with ACTN1. LLGL2 altered the intracellular localization and function of ACTN1 without changing its protein and mRNA levels. Collectively, we uncovered that LLGL2 impaired actin filament aggregation into bundles by interacting with ACTN1, which led to cytoskeleton remodeling and inhibition of the invasion and metastasis of ovarian cancer cells.

Survival impact of bowel resection in patients with FIGO stage II-IV ovarian cancer.

INTRODUCTION: To compare the effect of bowel resection vs stripping on the clinical outcomes of patients with FIGO II-IV ovarian cancer. METHODS: We retrospectively analyzed patients with FIGO II-IV ovarian cancer who suffered from bowel involvement and underwent cytoreductive surgery between January 2014 and March 2022. Patients' survival was compared by Kaplan-Meier survival analysis and Cox proportional hazards models. RESULTS: Four hundred and twelve patients were included. 48 patients underwent bowel resection (BR), and 364 patients underwent bowel tumor stripping (BTS). The BR group had longer operative duration, hospital stay, time to post-operative chemotherapy, and more intraoperative bleeding. The median PFS was 37 months (95% CI 12-62) in BTS compared to 25 months (95% CI 10-40) in BR among patients who achieved R0 resection (p = 0.590). Among those with R1 resection, the median PFS in BST was 23 months (95% CI 16-30) and that in BR was 15 months (95% CI 12-18, p = 0.136); moreover, a favorable median PFS was observed in BTS with residual bowel lesions (23 months, 95% CI 14-32), compared to BR (15 months, 95% CI 12-18, p = 0.144). Multivariate analysis indicated that FIGO stage, PCI, cytoreduction time and residual lesions were independent prognostic factors of PFS. CONCLUSION: For patients with FIGO stage II-IV ovarian cancer with bowel implicated, bowel resection is necessary to achieve complete removal to improve the survival. If complete resection was judged unfeasible, cautious decision of bowel resection is required. Neoadjuvant chemotherapy might reduce the ratio of bowel resection for some with mesenteric involvement.

Survival Outcomes of Patients with International Federation of Gynecology and Obstetrics Stage IV Ovarian Cancer: Cytoreduction Still Matters.

PURPOSE: There is still no consensus on the therapeutic strategies for patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV ovarian cancer (OC). We aim to outline the clinical characteristics and optimal therapeutic strategies of patients with FIGO stage IV OC. METHODS: This single center retrospective study analyzed the clinical features and survival of patients with FIGO stage IV OC that underwent cytoreduction or received at least one course of chemotherapy between January 2014 and December 2020. RESULTS: One hundred and twenty patients were included. Surgery, especially optimal cytoreduction without residual mass improved the overall survival of patients in surgery group (P = .047, HR .432, 95% CI .181-.987). Secondly, the completion of chemotherapy improved median overall survival of patients either with (53.0 months vs 25.0 months, P < .001, HR 7.015, 95% CI 1.372-35.881) or without cytoreduction (43.0 months vs 6.0 months, P = .006, HR 5.969, 95% CI 1.115-31.952). In patients with FIGO stage IVB, those with only extra-abdominal lymph node metastases had better survival. CONCLUSIONS: In patients with FIGO stage IV, complete resection of intra-abdominal tumor foci and completion of chemotherapy provided considerable survival benefits to patients with FIGO stage IV OC. Among patients with FIGO stage IVB, those with only extra-abdominal lymph node metastases had a better prognosis.

A prediction nomogram for suboptimal debulking surgery in patients with serous ovarian carcinoma based on MRI T1 dual-echo imaging and diffusion-weighted imaging.

BACKGROUND: Serous ovarian carcinoma (SOC) has the highest morbidity and mortality among ovarian carcinoma. Accurate identification of the probability of suboptimal debulking surgery (SDS) is critical. This study aimed to develop a preoperative prediction nomogram of SDS for patients with SOC. METHODS: A prediction model was established including 205 patients of SOC from institution A, and 45 patients from institution B were enrolled for external validation. Multivariate logistic regression was used to screen independent predictors and establish a nomogram to predict the occurrence of SDS. RESULTS: Multivariate logistic regression demonstrated that the CA-125 level (odds ratio [OR] 8.260, 95% confidence interval [CI] 2.003-43.372), relationship between the sigmoid colon/rectum and ovarian mass (OR 28.701, 95% CI 4.561-286.070), diaphragmatic metastasis (OR 12.369, 95% CI 1.675-274.063), and FIGO stage (OR 32.990, 95% CI 6.623-274.509) were independent predictors for SDS. The area under the curve, concordance index, and 95% CI of the nomogram constructed from the above four factors were 0.951, 0.934, and 0.919-0.982, respectively. The model showed a good fit by the Hosmer-Lemeshow test (training set, p = 0.2475; internal validation set, p = 0.2355; external validation set, p = 0.2707). The external validation proved the reliability of the prediction nomogram. The calibration curve was close to the ideal diagonal line. The decision curve analysis demonstrated a significantly better net benefit. The clinical impact curve indicated good effectiveness in clinical application. CONCLUSION: A prediction nomogram for SDS in patients with SOC provides gynecologists with an accurate and effective tool for appropriate management.

Computed tomographic enterography (CTE) in evaluating bowel involvement in patients with ovarian cancer.

PURPOSE: To explore the utility of CTE in the evaluation of bowel invasion in patients with primary ovarian, fallopian tube, and peritoneal cancer. METHODS: This observational study included 73 patients who received CTE before operation between September 2019 and December 2021. Two radiologists reviewed CTE images, focusing on the sites and depth of bowel involvement. Based on the findings during surgical exploration, we evaluated the diagnostic power, like sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (+ LR), and negative likelihood ratio (- LR) of CTE. Additionally, the characteristic images of bowel involvement on CTE corresponding to surgical findings were shown in the study. RESULTS: The rate of macroscopic bowel invasion in this cohort was 49.31% (36/73), of which eight patients had small bowel involvement, 17 patients had colon involvement and 27 patients had sigmoid-rectum involvement. CTE detected bowel invasion in the small intestine with a sensitivity, specificity, PPV, NPV, and accuracy of 87.50%, 92.31%, 58.33%, 98.36%, 91.78%; for colon, the statistics were 58.82%, 96.43%, 83.33%, 88.52%, 87.67% and for sigmoid-rectum 62.96%, 82.61%, 68.00%, 79.17%, 75.34%, respectively. CONCLUSION: CTE appeared a preferable diagnostic power on the small bowel and colon invasion in patients with primary ovarian, fallopian tube, and peritoneal cancer.

Lymphadenectomy in Primary Fallopian Tube Cancer is Associated with Improved Survival.

BACKGROUND AND OBJECTIVES: Primary fallopian tube cancer (PFTC) shares the same diagnostic and management guidelines with epithelial ovarian cancer (EOC). The LION trail raised concerns regarding the role of systematic pelvic and para-aortic lymphadenectomy during debulking surgery. We aimed to evaluate the significance of lymphadenectomy in PFTC survival. METHODS: This retrospective study analyzed the clinical features and survival of patients with PFTC who underwent primary surgery in our center between January 2013 and October 2020. RESULTS: Sixty-one patients diagnosed with PFTC were included in the study. Twenty-five (41.0%, 25/61) were diagnosed with FIGO (International Federation of Gynecology and Obstetrics) stages I/II and 36 (59.0%, 36/61) were diagnosed with stage III/IV. Twenty-nine (47.5%, 29/61) underwent pelvic lymphadenectomy with or without para-aortic lymphadenectomy, among which 12 (41.4%, 12/29) had lymph node metastasis confirmed by postoperative pathology. The mean progression-free survival was 60.4 months in the lymphadenectomy group and 37.8 months in the no-lymphadenectomy group (p = 0.042, HR 0.374, 95% CI 0.145-0.966). CONCLUSIONS: PFTC is often diagnosed earlier and has a better prognosis than EOC. Most patients with PFTC would benefit from lymphadenectomy. However, the extent to which this association translates to a more diverse population needs to be further identified.

Predictive Value of Serum Cytokeratin 19 Level for the Feasibility of Conserving Ovaries in Endometrial Cancer.

Objective: To determine the predictive value of cytokeratin 19 (CK19) for evaluating the safety of ovarian preservation in patients with endometrial cancer (EC). Methods: Five hundred and seventeen EC patients hospitalized from November 2010 to June 2016 were reviewed retrospectively. Pre-operative tumor biomarkers including CA125, HE4, CK19, and CA19-9 were obtained. Predictive biomarkers associated with ovarian metastasis were selected using univariate and multivariate Logistic regression. The cut-off values were determined by receiver operating characteristic (ROC) curves. Kaplan-Meier method and Cox multivariate regression model was used to perform survival analysis. Results: Among clinical parameters and biomarkers included, age > 65, type II EC, CA125 ≥ 35 u/ml, CK19 > 3.3 ng/ml, and myometrial invasion ≥ 50% depth appeared as significant predictors of the risk of ovarian involvement in univariable logistic analysis. In multivariable analysis, CK19 > 3.3 ng/ml (OR = 11.541, 95%CI: 1.968-67.668, P = 0.007) and Type II EC (OR = 8.336, 95%CI: 1.456-47.722, P = 0.017) were independent risk predictors of ovarian metastasis in pre-menopausal women. In pre-menopausal women with Type I EC (n = 142), CK19 level could satisfactorily predict the risk of ovarian metastasis (AUC = 0.860, 95%CI: 0.792-0.912, P < 0.001), and when the cut-off point was set as 2.45 ng/ml, the negative predictive value and negative likelihood ratio were 99% and 0.19, with the maximum Youden index of 0.598. Conclusions: The present study advocates the necessity of incorporating serum CK19 measurement into the pre-operative evaluation of EC, especially as extension of current standard approach with ovarian preservation counseling.

Topical Application of Pseudomonas aeruginosa-Mannose Sensitive Hemagglutinin (PA-MSHA) for Refractory Lymphatic Leakage Following Lymphadenectomy in Patients with Gynecological Malignancies.

PURPOSE: To observe the feasibility and efficacy of Pseudomonas aeruginosa-mannose sensitive hemagglutinin (PA-MSHA) in refractory lymphatic leakage following lymphadenectomy among patients with gynecological cancers. PATIENTS AND METHODS: Ten cases with post-operative massive lymphatic leakage were collected, in which patients failed to respond to conservative treatment. Topical PA-MSHA injection of a single dose (2mL) was performed through drainage tube or transvaginal catheter into pelvic or peritoneal cavity. Drainage volumes and side effects were recorded. RESULTS: The incidence of refractory lymphatic leakage following pelvic and para-aortic lymphadenectomy was 2.44% (10/409). All ten patients (100%) had quick recovery and were discharged within 72 hours. Among them, one patient (10%) experienced fever and six patients (60%) experienced abdominal pain, one of which was moderate and relieved by routine analgesic treatment. During 11 (6-38) months of follow-up time, no long-term side effect was observed. CONCLUSION: Topical injection of PA-MSHA of a single dose appears a feasible and effective treatment for refractory post-operative lymphatic leakage.

Differential Impact of Systemic Lymphadenectomy Upon the Survival of Patients with Type I vs Type II Endometrial Cancer: A Retrospective Observational Cohort Study.

PURPOSE: To determine whether systemic lymphadenectomy exerts a similar effect on the survival of patients with either type I or type II endometrial cancer (EC). PATIENTS AND METHODS: In this retrospective study, 682 eligible patients diagnosed with EC were typed according to the pathological reports. The thoroughness of lymphadenectomy was evaluated by the lymph node number of which the cut-off value was determined by the receiver operator characteristic (ROC) curve and Youden index. The impact of thoroughness on the survival of both types was analyzed, respectively, by Kaplan Meier (K-M) method and further evaluated in subgroups with and without lymphatic metastasis. Independent prognostic factors of survival were selected by proportional hazard regression (Cox) model. RESULTS: The cut-off level of lymph node number was 20. The differential impact of the lymph node number removed on survival was noted when patients with different types were analyzed separately. Among type II EC, those with >20 lymph nodes removed presented better overall survival (OS) than those with ≤20 (p=0.002). The number of lymph nodes removed >20 was proved as an independent factor for improved OS in type II EC (HR=0.329,95% CI: 0.123-0.881, p=0.0027). In the subgroup of type II with >20 lymph nodes resected, similar 5-year OS rates were observed in those with or without identified positive node (90.9% vs 92.9%, p=0.965). Type I EC seemed unbeneficial from such a procedure. CONCLUSION: Systemic lymphadenectomy could enhance the OS of type II EC other than type I.

Glutamine-fructose-6-phosphate transaminase 2 (GFPT2) promotes the EMT of serous ovarian cancer by activating the hexosamine biosynthetic pathway to increase the nuclear location of ß-catenin.

The hexosamine biosynthetic pathway (HBP), a branch of glucose metabolism, provides a substrate for glycosylation modification, which has a wide-ranging effect on cellular functions. Glutamine-fructose-6-phosphate transaminase 2 (GFPT2) has been reported to regulate the HBP as the first and rate-limiting enzyme. Given the inverse association between GFPT2 expression and survival of patients with serous ovarian cancer (SOC) observed in The Cancer Genome Atlas (TCGA) database, we attempted to investigate the role of GFPT2 and its related mechanisms in SOC. The results showed that GFPT2 was over-expressed in SOC tissues, and positive correlations with advanced stage (FIGO III/IV), suboptimal removal rate and poor survival were observed in 90 SOC patients. Cell migration and invasion were also inhibited in GFPT2 knockdown SKOV3 and HEY cells. The levels of O-linked ß-N-acetylglucosamine (O-GlcNAc) and intranuclear ß-catenin were evaluated and the observed increase in O-GlcNAcylation induced by GFPT2 may contribute to epithelial-mesenchymal transition (EMT). These data provide novel insights into the function of GFPT2 and O-GlcNAcylation in the EMT and thus the invasiveness SOC.

WHSC1 acts as a prognostic indicator and functions as an oncogene in cervical cancer.

Purpose: Wolf-Hirschhorn syndrome candidate 1 (WHSC1) is an epigenetic modifier, considered to play a driving role in oncogenesis. However, very little is known about the roles of WHSC1 and its prognostic impacts in cervical cancer. This study aimed to investigate the role of WHSC1 in the prognosis of cervical cancer and explore the effect of WHSC1 on proliferation, migration, and invasion of cervical cancer cells and angiogenesis in human umbilical vein endothelial cells (HUVECs). Methods: We evaluated the expression levels of WHSC1 in cervical cancer samples and relevant cell lines by immunohistochemistry, real-time quantitative PCR, and Western blot. In vitro, Cell Counting Kit-8 and transwell assays were used to investigate the viability and migration of C33A cells, and a tube formation assay was used to study the effect of WHSC1 on angiogenesis in HUVECs. Results: WHSC1 was overexpressed in cervical cancer tissues and cells, and correlated with the FIGO stage and differentiation. WHSC1 knockdown inhibited proliferation, suppressed migration and invasion in endothelial nitric oxide synthase (eNOS)-overexpressing C33A cells, and inhibited angiogenesis in HUVECs. Conclusion: WHSC1 may be a poor prognostic indicator of cervical cancer and a potential novel therapeutic target for the same. WHSC1 may participate in the regulation of cervical cancer progression through the eNOS signaling pathway.

ALPL regulates the aggressive potential of high grade serous ovarian cancer cells via a non-canonical WNT pathway.

The ALPL gene is linked to hypophosphatasia, a rare genetic disease. Owing to the inverse relationships between ALPL expression and both the International Federation of Gynecology and Obstetrics (FIGO) stages and histological grades assigned to patients with serous ovarian cancer (SOC), this study was designed to explore the role and possible mechanisms of ALPL in cell motility of high grade SOC (HGSOC). The effects of ALPL overexpression on migration and invasion were detected in HGSOC cell lines SKOV3 and HEY. Gene ontology analysis for differential genes with ALPL overexpression identified several biological processes, including EMT, correlated with cell motility. Genes potentially implicated in EMT and associated with ALPL were screened using The Cancer Genome Atlas (TCGA) database. The WNT receptor Frizzled2 (FZD2) was identified and its role in HGSOC cell motility and survival was investigated. It was found that forced expression of ALPL could inhibit migration, invasion, and EMT in HGSOC cells. It also reduced the expression of FZD2 and its ligand WNT5A, accompanied by suppressed expression of their downstream target phosphorylated-STAT3 (pSTAT3). These effects were initiated via the FZD2 knockdown using siRNA and reversed by recombinant WNT5A protein. The relationship between FZD2 expression and poor HGSOC patient survival was also investigated. This data supports that ALPL might restrict the function of WNT5A-FZD2-STAT3 axis, a non-canonical WNT pathway for promoting EMT progression, which results in attenuated migration and invasion in HGSOC cells and improves survival in patients with SOC.

Multifactorial impact on the outcome of interval debulking surgery in patients with advanced epithelial ovarian or peritoneal cancers.

OBJECTIVE: To evaluate the impact of multiple clinical features upon the outcome of interval cytoreductive surgery and thus upon the survival in patients with advanced ovarian cancer and primary peritoneal carcinoma. METHODS: A retrospective analysis of patients receiving NACT followed by IDS between 2009 and 2017. Patients were analyzed according to the pre-NACT CA125, pre-IDS CA125, pre-IDS CA125 decline, patients' pre-IDS BMI, multisite bowel involvement and different working years of surgeons, for their influence upon the IDS outcome (e.g. optimal vs suboptimal) and the survival. RESULTS: After interval debulking surgery following 1-6 cycles of NACT, all patients analyzed were identified as optimal (n = 113) and suboptimal (n = 47) based on patients' record. The PFS/OS were 21/68 months and 9/26 months in optimal and suboptimal groups, respectively (p = .000, p = .000). Although differential levels of pre-IDS CA125, pre-IDS CA125 decline, bowel involvement and surgeons' working years were found to be significantly different between the two groups, surgeons' working years and multisite bowel invasion were the independent factors for IDS outcome, and the latter one was also highly related to survival. CONCLUSIONS: Following NACT, the rate of optimal IDS might be improved for patients without multisite bowel involvement. For those with bowel involvement, management strategy made by well-experienced surgeons might be a key factor for the outcome of IDS.

Identifying genes as potential prognostic indicators in patients with serous ovarian cancer resistant to carboplatin using integrated bioinformatics analysis.

Serous ovarian cancer (SOC) accounts for >50% of all epithelial ovarian cancers. However, patients with SOC present with various degrees of response to platinum­based chemotherapy and, thus, their survival may differ. The present study aimed to identify the candidate genes involved in the carcinogenesis and drug resistance of SOC by analyzing the microarray datasets GDS1381 and GDS3592. GDS1381 and GDS3592 were downloaded from the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/gds/). A total of 219 differentially expressed genes (DEGs) were identified. Potential genes that may predict the response to carboplatin and, thus, the prognosis of SOC were analyzed. The enriched functions and pathways of DEGs included extracellular region, extracellular space and extracellular exosome, among others. Upon screening the upregulated and downregulated genes on the connectivity map, 10 small­molecule drugs were identified that may be helpful in improving drug sensitivity in patients with ovarian cancer. A total of 30 hub genes were screened for further analysis after constructing the protein­to­protein interaction network. Through survival analysis, comparison of genes across numerous analyses, and immunohistochemistry, GNAI1, non­structural maintenance of chromosomes (non­SMC) condensin I complex subunit H (NCAPH), matrix metallopeptidase 9 (MMP9), aurora kinase A (AURKA) and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) were identified as the key molecules that may be involved in the carcinogenesis and carboplatin resistance of SOC. In conclusion, GNAI1, NCAPH, MMP9, AURKA and EZH2 should be examined in further studies for the possibility of their participation in the carcinogenesis and carboplatin response of SOC.

Serum CA125 levels predict outcome of interval debulking surgery after neoadjuvant chemotherapy in patients with advanced ovarian cancer.

OBJECTIVE: To evaluate the correlation between the changes of serum CA125 level and the outcome of interval debulking surgery (IDS) after neoadjuvant chemotherapy (NACT) in patients with advanced epithelial ovarian cancer (EOC). METHODS: A retrospective review for 62 patients with FIGO stage III or IV EOC treated with NACT-IDS was conducted. Demographic data, clinical characters, pathological features and prognosis were collected. Continuous variables were evaluated by Student's t-test or Mann-Whitney U test. Categorical variables were evaluated by chi square test or Fisher's exact test as appropriate for category size. Standard univariate analyses and multivariable analysis with logistic regression were performed to identify independent predictor of optimal IDS. Kaplan-Meier method was used to analyze the prognosis. RESULTS: No statistical difference was found on serum CA125 levels between suboptimal (n = 34)IDS and optimal (n = 28) IDS either before NACT (median levels: 1552.2 U/mL and 1715.5 U/mL, p = 0.453) or before IDS (median levels: 27.25 U/mL and 26.4 U/mL, p = 0.713). Those with optimal IDS achieved longer progression free survival (PFS) and overall survival (OS) than those with suboptimal IDS (median PFS: 22 and 13.5 months, p < 0.001; median OS: 33.5 and 21 months, p = 0.005). Eighteen of 31 patients (58.1%) with serum CA125 declines ≥0.95828 achieved optimal IDS compared to 10 of the 31 patients (32.3%) with serum CA125 declines <0.95828 (p = 0.041). Standard univariate analyses and multivariable analysis showed that serum CA125 declines ≥0.95828 could be an independent predictor of optimal IDS. CONCLUSION: Patients who underwent optimal IDS have better prognosis compare to suboptimal IDS. The changes of serum CA125 after neoadjuvant chemotherapy might predict optimal interval debulking surgery in patients with advanced epithelial ovarian cancer.

DACT1 Overexpression in type I ovarian cancer inhibits malignant expansion and cis-platinum resistance by modulating canonical Wnt signalling and autophagy.

Type I epithelial ovarian cancer (EOC) is primarily resistant to platinum-based chemotherapies and needs novel therapeutics. Given the aberrant Wnt activation in type I EOC and the involvement of Dapper1 Antagonist of Catenin-1 (DACT1) in Wnt signalling, the role of DACT1 in tumourigenesis of type I EOC was evaluated. Firstly, all tested EOC cell lines and primary EOC tissues, especially type I EOC, were observed to have significantly lower DACT1 expression than normal controls. Next, 3AO cells, which arise from a patient with primary mucinous EOC and express low endogenous levels of DACT1, were transfected with a lentivirus carrying full-length DACT1 (3AO-DACT1), grew slower and formed smaller tumours in nude mice compared to 3AO-NC. Furthermore, 3AO-DACT1 had lower levels of key mediators of canonical Wnt signalling, Dvl2 and ß-catenin, GSK-3ß with phosphorylated Ser9, and the Wnt/ß-catenin target genes, with significantly lower nuclear ß-catenin levels. Additionally, 3AO-DACT which contained higher levels of lipidated LC3 (LC3-II) and Beclin1, but lower levels of p62/SQSTM1, were more sensitive to cis-platinum. And chloroquine partially rescued its cis-platinum resistance. We identified DACT1 as a negative regulator in type I EOC, protecting against malignant expansion by inhibiting canonical Wnt signalling and cis-platinum resistance by regulating autophagy.

Sulfiredoxin May Promote Cervical Cancer Metastasis via Wnt/ß-Catenin Signaling Pathway.

The abnormal elevation of sulfiredoxin (Srx/SRXN1)-an antioxidant enzyme whose main function is to protect against oxidative stress-has been shown to be closely correlated with the progression of several types of cancer, including human cervical cancer. However, the molecular mechanism by which Srx promotes tumor progression, especially cancer metastasis in cervical cancer, has not been elucidated. Here, we show that Srx expression gradually increases during the progression of human cervical cancer and its expression level is closely correlated with lymph node metastasis. Our study also reveals a significant positive correlation between the expression of Srx and ß-catenin in cervical cancer tissues. Loss-of-function studies demonstrate that Srx knockdown using a lentiviral vector-mediated specific shRNA decreases the migration and invasion capacity in HeLa (human papilloma virus 18 type cervical cancer cell line) and SiHa SiHa (cervical squamous cancer cell line). Notably, the exact opposite effects were observed in gain-of-function experiments in C-33A cells. Mechanistically, downregulation or upregulation of Srx leads to an altered expression of proteins associated with the Wnt/ß-catenin signaling pathway. Furthermore, blockage of the Wnt/ß-catenin signaling pathway contributed to attenuated Srx expression and resulted in significant inhibition of cell migration and invasion in cervical cancer cell lines. Combined, Srx might be an oncoprotein in cervical cancer, playing critical roles in activating the Wnt/ß-catenin signaling pathway; it may therefore be a therapeutic target for cervical cancer.

[Expressions of Ras and Sos1 in epithelial ovarian cancer tissues and their clinical significance].

OBJECTIVE: To detect the expressions of Ras and Sos1 proteins in human epithelial ovarian cancer (EOC) tissues and explore their correlation with the clinicopathological features of the patients. METHODS: The expressions of Ras and Sos1 proteins were detected immunohistochemically in 62 EOC tissues, 5 borderline ovarian cancer tissues, 15 benign epithelial ovarian neoplasm tissues, and 18 normal ovarian tissues. RESULTS: The EOC tissues showed significantly higher expression levels of both Ras and Sos1 than the other tissues tested (P<0.05). In EOC tissues, Ras and Sos1 proteins were expressed mostly on the cell membrane and in the cytoplasm. The expression level of Ras was correlated with pathological types of the tumor (P<0.05) and was the highest in serous cystadenomcarcinoma; Sos1 expression did not show significant correlation with the clinicopathological indexes of the patients. High expressions of both Ras and Sos1 proteins were associated with shorter progression-free survival of the patients, but this association was not statistically significant. CONCLUSIONS: Ras and Sos1 protein may participate in in the occurrence and development of EOC. The tissue-specific variation of Ras expression can lend support to a specific diagnosis of ovarian serous adenocarcinoma. The association of Ras and Sos1 protein expression with the tumor-free survival time of the patients awaits further investigation with a larger sample size.

The C3G/Rap1 pathway promotes secretion of MMP-2 and MMP-9 and is involved in serous ovarian cancer metastasis.

Complete resection is pivotal to improve survival to epithelial ovarian cancer (EOC). Crk SH3-domain-binding guanine nucleotide-releasing factor (C3G) is involved in multiple signaling pathways and it has opposite roles in different cancers. The present study aimed to identify C3G expression in ovarian tissue samples from patients with EOC and to explore its association with tumor grade. Eighty-seven archival paraffin-embedded, formalin-fixed, ovarian cancer tissues with serous histology were stained for C3G by immunohistochemistry. To evaluate the contribution of C3G to Rap1 activity, 36 patients with serous ovarian cancer (SOC) were investigated. Additionally, C3G was knocked down in SKOV3 and HEY cells. C3G regulated Rap1 activity and high Rap1 activity was correlated with poor differentiation, advanced FIGO stage, and unsuccessful cytoreductive surgery of SOC. Knockdown of C3G suppressed cell invasion, intravasation and extravasation, and reduced Rap1 activity and secretion of matrix metalloproteinase (MMP)-2 and MMP-9. C3G-mediated activation of Rap1 could direct the tumor pattern of human SOC by promoting the secretion of MMP-2 and MMP-9. These results suggest that C3G is involved in the metastatic spread of EOC.