Metabolic reprogramming of the ovarian cancer microenvironment in the development of antiangiogenic resistance.

Antiangiogenic therapies, such as treatment with bevacizumab, display modest survival benefits in ovarian cancer (OC) patients. After a transient response, the upregulation of compensatory proangiogenic pathways and the adoption of alternative vascularization processes lead to the development of resistance. Considering the high mortality rate of OC, there is an urgent need to uncover the underlying mechanisms of antiangiogenic resistance for the development of novel and effective treatment strategies. Recent investigations have confirmed that metabolic reprogramming in the tumor microenvironment (TME) exerts an essential effect on tumor aggressiveness and angiogenesis. In this review, we provide an overview of the metabolic crosstalk between OC and the TME, highlighting the regulatory mechanisms underlying the development of antiangiogenic resistance. Metabolic interventions may interrupt this complex and dynamic interactive network, providing a promising therapeutic option to improve clinical outcome in OC patients.

The epigenetic factor CHD4 contributes to metastasis by regulating the EZH2/ß-catenin axis and acts as a therapeutic target in ovarian cancer.

BACKGROUND: The overall survival rate of patients with advanced ovarian cancer (OC) has remained static for several decades. Advanced ovarian cancer is known for its poor prognosis due to extensive metastasis. Epigenetic alterations contribute to tumour progression and therefore are of interest for potential therapeutic strategies. METHODS: Following our previous study, we identified that CHD4, a chromatin remodelling factor, plays a strong role in ovarian cancer cell metastasis. We investigated the clinical significance of CHD4 through TCGA and GEO database analyses and explored the effect of CHD4 expression modulation and romidepsin treatment on the biological behaviour of ovarian cancer through CCK-8 and transwell assays. Bioluminescence imaging of tumours in xenografted mice was applied to determine the therapeutic effect of romidepsin. GSEA and western blotting were used to screen the regulatory mechanism of CHD4. RESULTS: In ovarian cancer patient specimens, high CHD4 expression was associated with a poor prognosis. Loss of function of CHD4 in ovarian cancer cells induced suppression of migration and invasion. Mechanistically, CHD4 knockdown suppressed the expression of EZH2 and the nuclear accumulation of ß-catenin. CHD4 also suppressed the metastasis of ovarian cancer cells and prevented disease progression in a mouse model. To inhibit the functions of CHD4 that are mediated by histone deacetylase, we evaluated the effect of the HDAC1/2 selective inhibitor romidepsin. Our findings indicated that treatment with romidepsin suppressed the progression of metastases in vitro and in vivo. CONCLUSIONS: Collectively, our results uncovered an oncogenic function of CHD4 in ovarian cancer and provide a rationale for clinical trials of romidepsin in ovarian cancer patients.

Bevacizumab confers significant improvements in survival for ovarian cancer patients with low miR-25 expression and high miR-142 expression.

BACKGROUND: Lymphovascular space invasion (LVSI) is the first step of hematogenous metastasis. Exploration of the differential miRNA expression profiles between LVSI-positive and LVSI-negative ovarian cancer tissues may help to identify key miRNAs involved in the hematogenous metastasis of ovarian cancer. This study is aimed to identify microRNAs (miRNAs) that are differentially expressed between LVSI-positive and LVSI-negative ovarian cancer tissues, followed by exploring their association with bevacizumab response in ovarian cancer patients. METHODS: The Cancer Genome Altas (TGGA) dataset was used to identify the differentially expressed miRNAs between LVSI-positive and LVSI-negative ovarian cancer tissues. The prognostic value of the differentially expressed miRNAs was determined using GSE140082 dataset. RESULTS: We showed that miR-25 and miR-142 were differentially expressed between LVSI-positive and LVSI-negative ovarian cancer tumors. Kaplan-Meier analysis indicated that high miR-25 expression was associated with increased progression free survival (PFS) and extended overall survival (OS). Moreover, patients with low miR-25 expression benefited significantly from bevacizumab treatment in terms of PFS. A similar trend was observed in terms of OS though without reaching statistical significance. In contrast, no significant survival benefits from bevacizumab were observed in patients with high miR-25 expression in terms of PFS and OS. There was no significant correlation between miR-142 expression and PFS. In contrast, high miR-142 expression was associated with reduced OS. Moreover, patients with high miR-142 expression benefited significantly from bevacizumab treatment in terms of PFS and OS. However, bevacizumab treatment conferred no significant improvements in both PFS and OS in patients with low miR-142 expression. The nomogram for PFS indicated that miR-25 expression had a larger contribution to PFS than debulking status and bevacizumab treatment. And the nomogram for OS illustrated both miR-25 expression and miR-142 expression as sharing a larger contribution to OS than bevacizumab treatment and debulking status. CONCLUSION: In conclusion, miR-25 expression correlates with a better PFS and OS in ovarian cancer. Patients with low miR-25 expression and high miR-142 expression could benefit from bevacizumab treatment significantly.

DNA methylation-based profiling reveals distinct clusters with survival heterogeneity in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) is the most common type of epigenetically heterogeneous ovarian cancer. Methylation typing has previously been used in many tumour types but not in HGSOC. Methylation typing in HGSOC may promote the development of personalized care. The present study used DNA methylation data from The Cancer Genome Atlas database and identified four unique methylation subtypes of HGSOC. With the poorest prognosis and high frequency of residual tumours, cluster 4 featured hypermethylation of a panel of genes, which indicates that demethylation agents may be tested in this group and that neoadjuvant chemotherapy may be used to reduce the possibility of residual lesions. Cluster 1 and cluster 2 were significantly associated with metastasis genes and metabolic disorders, respectively. Two feature CpG sites, cg24673765 and cg25574024, were obtained through Cox proportional hazards model analysis of the CpG sites. Based on the methylation level of the two CpG sites, the samples were classified into high- and low-risk groups to identify the prognostic information. Similar results were obtained in the validation set. Taken together, these results explain the epigenetic heterogeneity of HGSOC and provide guidance to clinicians for the prognosis of HGSOC based on DNA methylation sites.

Patients with low nicotinamide N-methyltransferase expression benefit significantly from bevacizumab treatment in ovarian cancer.

BACKGROUND: The role of nicotinamide N-methyltransferase (NNMT) in ovarian cancer is still elusive. Our aim is to explore the expression of NNMT in ovarian cancer and to assess its association with patient prognosis and treatment response. METHODS: We first analyzed the differential expression of NNMT among fallopian tube epithelium, primary ovarian cancers, metastatic ovarian cancers, and recurrent ovarian cancers using Gene Expression Ominus (GEO) database (GSE10971, GSE30587, GSE44104 and TCGA datasets). Then, we assessed the association of NNMT expression with clinical and molecular parameters using CSIOVDB database and GSE28739 dataset. Next, we evaluate the association of NNMT expression with the prognosis of ovarian cancer patients in both GSE9891 dataset and TCGA dataset. Finally, GSE140082 dataset was used to explore the association of NNMT expression with bevacizumab response. RESULTS: NNMT expression was significantly elevated in lymphovascular space invasion (LVSI)-positive ovarian cancers compared with that in LVSI-negative ovarian cancers (TCGA dataset, P < 0.05), Moreover, increased expression of NNMT was associated with increased tumor stage, grade, and mesenchymal molecular subtype (CSIOVDB database). Survival analysis indicated that increased expression of NNMT was associated with a reduced OS in both GSE9891 dataset (HR: 2.28, 95%CI: 1.51-3.43, Log-rank P < 0.001) and TCGA dataset (HR: 1.55, 95%CI: 1.02-2.36, Log-rank P = 0.039). Multivariate analysis further confirmed the negative impact of NNMT expression on OS in ovarian cancer patients in those two datasets. Furthermore, the NNMT-related nomogram showed that NNMT shared a larger contribution to OS, compared with debulking status. More interestingly, bevacizumab conferred significant improvements in OS for patients with low NNMT expression (HR: 0.56, 95%CI: 0.31-0.99, Log-rank P = 0.049). In contrast, patients with high NNMT expression didn't benefit from bevacizumab treatment significantly (HR: 0.85, 95%CI: 0.48-1.49, Log-rank P = 0.561). NNMT expression was positively correlated with the expression of genes, LDHA and PGAM1, involved in Warburg effect. CONCLUSIONS: In conclusion, NNMT expression is associated with the aggressive behavior of ovarian cancer, correlates with a poor prognosis, and is predictive of sensitivity to bevacizumab treatment.

Stromal POSTN induced by TGF-ß1 facilitates the migration and invasion of ovarian cancer.

OBJECTIVE: Periostin (POSTN) overexpression observed in various cancer types is correlated with metastasis and tumor progression. However, its effect on the crosstalk between ovarian cancer cells and cancer-associated fibroblasts (CAFs) remains elusive. This study aims to ascertain the role of CAF-derived POSTN in the ovarian cancer microenvironment. METHODS: POSTN expression in high-grade serous ovarian cancer (HGSC) was detected through immunochemistry. Transwell assay was conducted to determine cell migration and invasion. POSTN was knocked down or overexpressed using lentiviral vectors. The potential downstream effects of POSTN were explored and verified by RNA sequencing and western blotting, respectively. In vitro metastatic capability of ovarian cancer cells regulated by POSTN was determined by indirect co-culture. RESULTS: POSTN was highly enriched in HGSC stromal components, particularly in fibroblasts, while its overexpression was correlated with reduced overall survival (OS). CAF-derived POSTN functioned as a ligand for integrin αvß3, fueling the migration and invasion of ovarian cancer cells by activating the PI3K/Akt pathway and inducing the epithelial-mesenchymal transition (EMT). Additionally, the pro-metastatic properties and the activation of fibroblasts induced by TGF-ß1 partly relied on POSTN. CONCLUSIONS: Stromal-derived POSTN drives the remodeling of the pro-metastatic microenvironment, which might be as a potential therapeutic target in patients with ovarian cancer.

The prognostic value of ITGA and ITGB superfamily members in patients with high grade serous ovarian cancer.

BACKGROUND: Deregulation of integrins signaling had been documented to participate in multiple fundamental biological processes, and the aberrant expression of integrin family members were linked to the prognosis of various cancers. However, the role of integrins in predicting progression and prognosis of ovarian cancer patients are still largely elusive. This study is aimed to explore the prognostic values of ITGA and ITGB superfamily members in high grade serous ovarian cancers (HGSOC). METHODS: GSE26712 dataset was used to determine the differential expression of ITGA and ITGB superfamily member between HGSOC and normal counterparts. The Cancer Genome Altas (TGGA) and GSE9891 datasets were used to determine the prognostic values of ITGA and ITGB superfamily members in HGSOC, followed by the development of nomograms predictive of recurrence free survival (RFS) and overall survival (OS). RESULTS: ITGA6 and ITGB5 expression were significantly downregulated in HGSOC compared with that in normal counterparts. In contrast, ITGA2, ITGA5, ITGA7, ITGA8, ITGA9, ITGA10, ITGB3, ITGB4, ITGB6, and ITGB8 were all significantly upregulated in HGSOC compared with that in normal counterparts. Both univariable and multivariable analysis indicated that ITGB1 was associated with extended RFS. The ITGB1-related nomogram indicated that ITGB1 had the largest contribution to RFS, followed by FIGO stage and debulking status. The C-index for predicting RFS was 0.55 (95% CI 0.50-0.59) in TCGA dataset (training dataset) and 0.65 (95% CI 0.59-0.72) in GSE9891 dataset (validation dataset), respectively. Regarding OS, ITGB8 was associated with reduced survival suggested by both univariable and multivariable analysis. ITGA7 appeared to be associated with improved survival though without reaching statistical significance. The ITGA7/ITGB8-based nomogram showed that age at initial diagnosis had the largest contribution to OS, followed by ITGB8 and ITGA7 expression. The C-index for predicting OS was 0.65 (95% CI 0.60-0.69) in TCGA dataset (training dataset) and 0.59 (95% CI 0.51-0.66) in GSE9891 dataset (validation dataset), respectively. CONCLUSION: In conclusion, ITGB1, ITGA7 and ITGB8 added prognostic value to the traditional clinical risk factors used to assess the clinical outcomes of HGSOC.

SNAI2 3'untranslated region promotes the invasion of ovarian cancer cells by inducing MARCKS expression.

Objective: Recently, accumulating evidence has indicated that the 3' untranslated regions (3'UTRs) of protein coding genes play critical roles in the progression of various cancers, including ovarian cancer. This study is aimed to identify the potential role of SNAI2-3'UTR in ovarain cancer progression. Study Design: First, we tried to explore the clinical significance of SNAI2 in ovarian cancer using TCGA and GSE26712 dataset. Then, gain-of-function studies were performed to establish the role of SNAI2-3'UTR in invasion and migration of ovarian cancer cells. Finally, efforts were made to identify the downstream targets of SNAI2-3'UTR. Results: Our data indicated that the expression of SNAI2 was significantly correlated with FIGO stage (P=0.015) and lymphatic invasion status (P=0.004), whereas not with age(P>0.05) and histological grade(P>0.05). Patients with higher SNAI2 expression had a shorter overall survival (OS) in both TCGA dataset (P=0.039, HR=1.54(1.02-2.33)) and GSE26712 dataset (P=0.0017, HR=1.77(1.24-2.54)). Functional studies revealed that SNAI2-3'UTR promoted the invasion of both OVCA433 and SKOV-3 cells without significantly affecting their migratory abilities. MARCKS, which was also involved in the invasion of ovarian cancer cells, was identified as a potential downstream target of SNAI2-3'UTR. SNAI2-3'UTR may function as a ceRNA to upregulate MARCKS expression in ovarian cancer. Conclusion: In conclusion, our study demonstrated that SNAI2-3'UTR cloud promote the invasion of ovarian cancer cells by upregulating MARCKS expression, which proposed a new mechanism by which SNAI2 contributed to progression of ovarian cancer.

Development and validation of SIRT3-related nomogram predictive of overall survival in patients with serous ovarian cancer.

OBJECTIVE: Our aim is to analyzed the expression pattern of sirtuin(SIRT) superfamily and evaluated their prognostic values in serous ovarian cancer patients. METHODS: We first analyzed the differential expression of SIRT members among fallopian tube epithelium (FTE), primary serous ovarian cancers/tubal cancers (PSOCs/PSTCs), and omental metastases using GSE10971 and GSE30587 datasets. The prognostic values of SIRT members were evaluated using TCGA and GSE9891 dataset. RESULTS: SIRT3 and SIRT5 expression were significantly decreased and increased in PSOCs/PSTCs compared with that in normal counterparts, respectively. SIRT6 and SIRT7 were overexpressed in ometal metastases compared with corresponding primary counterparts. With respect to recurrence free survival, however, SIRT7 overexpression was correlated with better prognosis. A similar trend was observed by multivariable analysis. Regarding overall survival (OS), increased expression of SIRT3, SIRT5, and SIRT7 were associated with better survival by univariable analysis. Subsequent multivariable analysis showed that SIRT3 remained an independent favorable prognostic factor for OS. The SIRT3-related nomogram illustrated age at initial diagnosis as sharing the largest contribution to OS, followed by SIRT3 expression and FIGO stage. The C-index for OS prediction was 0.65 (95%CI, 0.61-0.69) in training cohort (TCGA dataset) and 0.65 (95%CI, 0.59-0.71) in validation cohort (GSE9891 dataset), respectively. The calibration plots showed optimal agreement between the prediction by SIRT3-related nomogram and actual observation for 1-, 3-, and 5-year OS probability. CONCLUSION: In conclusion, SIRT3 was an independent favorable prognostic factor for OS in serous ovarian cancer, and added prognostic value to the traditional clinicopathological factors used to evaluate patients' prognosis.

Chemotherapy for gestational trophoblastic neoplasia patients with a FIGO score of 12 or greater: A multistudy analysis.

OBJECTIVE: To enable a comparison of reported chemotherapy regimens in gestational trophoblastic neoplasia (GTN) patients with a International Federation of Gynecology and Obstetrics (FIGO) score ≥12. STUDY DESIGN: Studies reporting cases of GTN with a FIGO score ≥12 were collected and screened for eligibility. A total of 17 studies encompassing 256 patients were included in final analysis. RESULTS: In the first-line setting, etoposide-methotrexate-dactinomycin alternating with cyclophosphamide-vincristine (EMA/CO), etoposide-platinum alternating with EMA (EP/EMA), and floxuridine-dactinomycin-etoposide-vincristine (FAEV) were the three most commonly used regimens. The complete response (CR) rate was 55.2% for EMA/CO, 60.0% for EP/EMA, and 63.1% for FAEV. There was no significant difference in CR rate among EMA/CO, EP/EMA and FAEV in the first-line setting. While limited by low number, the CR rate was 66.67% for methotrexate-bleomycin -etoposide (MBE), and 25% for vincristine-dactinomycin-cyclophosphamide (VAC). Of the patients who failed initial therapy, EMA/CO, EP/EMA, and paclitaxel- cisplatin alternating with paclitaxel-etoposide (TP/TE) were the three most commonly used salvage regimens. The CR rate was 39.7% for EMA/CO, 35.0% for EP/EMA, and 11.8% for TP/TE. While limited by low number, MBE was used in 5 patients and yielded a 80% CR rate. Of the fatal cases, 21 (61.8%) patients had brain metastases, and 41.2% (14/34) of the deaths were early deaths. CONCLUSION: EMA/CO, EP/EMA, and FAEV yielded comparable CR rates in GTN patients with a FIGO score ≥12 in the first-line setting.

Gene signature characteristic of elevated stromal infiltration and activation is associated with increased risk of hematogenous and lymphatic metastasis in serous ovarian cancer.

BACKGROUND: The clinical significance of hematogenous and lymphatic metastasis in ovarian cancer has been increasingly addressed, as it plays an imperative role in the formation of both intraperitoneal and distant metastases. Our objective is to identify the key molecules and biological processes potentially related to this relatively novel metastatic route in serous ovarian cancer. METHODS: Since lymphovascular space invasion (LVSI) is considered as the first step of hematogenous and lymphatic dissemination, we developed a gene signature mainly based on the transcriptome profiles with available information on LVSI status in the Cancer Genome Atlas (TCGA) dataset. We then explored the underlying biological rationale and prognostic value of the identified gene signature using multiple public databases. RESULTS: We observe that primary tumors with increased risk of hematogenous and lymphatic metastasis highly express a panel of genes, namely POSTN, LUM, THBS2, COL3A1, COL5A1, COL5A2, FAP1 and FBN1. The identified geneset is characterized by enhanced deposition of extracellular matrix and extensive stromal activation. Mechanistically, both the recruitment and the activation of stromal cells, especially fibroblasts, are closely associated with lymphovascular metastasis. Survival analysis further reveals that the elevated expression of the identified genes correlates to cancer progression and poor prognosis in patients with serous ovarian cancer. CONCLUSIONS: Our findings indicate that tumor stroma supports the hematogenous and lymphatic spread of ovarian cancer, increasing tumor invasiveness and ultimately resulting in worse survival. Thus stroma-targeted therapies may improve the clinical outcomes in combination with cytoreductive surgery and chemotherapy.