Ovarian Metastasis Research Articles

ISG15 mediates the function of extracellular vesicles in promoting ovarian cancer progression and metastasis

AbstractThe interferon stimulated gene 15 (ISG15), a ubiquitin like protein and its conjugates have been implicated in various human malignancies. However, its role in ovarian cancer progression and metastasis is largely unknown. In high grade serous ovarian cancer (HGSOC), ascites is the major contributor to peritoneal metastasis. In this study, we identified significantly elevated ISG15 protein expression in HGSOC patient ascites, ascites derived primary ovarian cancer cells (POCCs), POCC small extracellular vesicles (sEVs) as well as metastatic tissue. Our results demonstrates that ISG15 increases exocytosis in ascites‐derived POCCs by decreasing the endosome‐lysosomal fusion, indicating a key role in sEV secretion. Further, knockdown (KD) of ISG15 resulted in a significant decrease in vesicles secretion from HGSOC cells and in vivo mouse models, leading to reduced HGSOC cell migration and invasion. Furthermore, our pre‐clinical mouse model studies revealed the influence of vesicular ISG15 on disease progression and metastasis. In addition, knockdown of ISG15 or using the ISG15 inhibitor, DAP5, in combination therapy with carboplatin showed to improve the platinum sensitivity in‐vitro and reduce tumour burden in‐vivo. We also found that ISG15 expression within sEV represents a promising prognostic marker for HGSOC patients. Our findings suggest that ISG15 is a potential therapeutic target for inhibiting progression and metastasis in HGSOC and that vesicular ISG15 expression could be a promising biomarker in the clinical management of ovarian cancer.Significance: High‐grade serous ovarian cancer (HGSOC) has high morbidity and mortality rates, but its progression and metastasis are still poorly understood, and there is an urgent need for early detection and targeted therapies. Our study presents novel findings that implicate ISG15‐mediated vesicular proteins in the advancement and spread of HGSOC. These results offer pre‐clinical evidence of potential new molecular targets, prognostic markers and therapeutic strategies for HGSOC that could ultimately enhance patient survival.

PARP1-stabilised FOXQ1 promotes ovarian cancer progression by activating the LAMB3/WNT/β-catenin signalling pathway.

Metastasis is an important factor that causes ovarian cancer (OC) to become the most lethal malignancy of the female reproductive system, but its molecular mechanism is not fully understood. In this study, through bioinformatics analysis, as well as analysis of tissue samples and clinicopathological characteristics and prognosis of patients in our centre, it was found that Forkhead box Q1 (FOXQ1) was correlated with metastasis and prognosis of OC. Through cell function experiments and animal experiments, the results show that FOXQ1 can promote the progression of ovarian cancer in vivo and in vitro. Through RNA-seq, chromatin immunoprecipitation sequencing (ChIP-seq), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), Western blotting (WB), quantitative real-time polymerase chain reaction (qRT‒PCR), immunohistochemistry (IHC), luciferase assay, and ChIP-PCR, it was demonstrated that FOXQ1 can mediate the WNT/β-catenin pathway by targeting the LAMB promoter region. Through coimmunoprecipitation (Co-IP), mass spectrometry (MS), ubiquitination experiments, and immunofluorescence (IF), the results showed that PARP1 could stabilise FOXQ1 expression via the E3 ubiquitin ligase Hsc70-interacting protein (CHIP). Finally, the whole mechanism pathway was verified by animal drug combination experiments and clinical specimen prognosis analysis. In summary, our results suggest that PARP1 can promote ovarian cancer progression through the LAMB3/WNT/β-catenin pathway by stabilising FOXQ1 expression.

Comparison of the clinical outcomes of patients with stage IA-IIA2 cervical adenocarcinoma and squamous cell carcinoma after radical hysterectomy: A propensity score-matched real-world analysis.

To compare the pathological findings and survival outcomes of patients with 2009 FIGO stage IA-IIA2 cervical cancer between groups with adenocarcinoma (ADC) and squamous cell carcinoma (SCC) using the Chinese Cervical Cancer Clinical (FOUR-C) study database. Patients from 2004 to 2018 with cervical ADC and SCC who underwent radical hysterectomy were identified through the FOUR-C database. Propensity score matching (PSM) was conducted to balance baseline clinicopathological characteristics. The Kaplan-Meier method and Cox regression analysis were used to evaluate the prognostic effect of ADC on the 5-year overall survival (OS). We identified 1611 (9.8%) patients with ADC and 14 894 (90.2%) patients with SCC. Compared with SCC, ADC was significantly associated with an increased risk of death (odds ratio [OR] 1.40, 95% CI 1.12-1.74) and disease progression (OR 1.34, 95% CI 1.14-1.57). ADC had a greater propensity for lymph node metastasis, uterine corpus invasion, perineural invasion, and ovarian metastases than SCC (P < 0.05). After 1:2 PSM, significant differences were still observed between these two histology subtypes (OS: OR 1.43, 95% CI 1.10-1.86; DFS: OR 1.45, 95% CI 1.19-1.76). The subgroup analysis further showed a worse prognosis for patients with ADC than for patients with SCC among patients with any of the high- or intermediate- risk factors (OR 1.60, 95% CI 1.21-2.12), but no significant differences were observed for the patients with no risk factors (OR 0.71, 95% CI 0.32-1.58). ADC is an independent prognostic factor for shorter survival in surgically treated patients with cervical cancer presenting intermediate- or high-risk factors but does not affect survival outcomes in patients without any risk factors.

M6A methylation-mediated regulation of LncRNA MEG3 suppresses ovarian cancer progression through miR-885-5p and the VASH1 pathway

BackgroundOvarian cancer poses a serious threat to women's health. Due to the difficulty of early detection, most patients are diagnosed with advanced-stage disease or peritoneal metastasis. We found that LncRNA MEG3 is a novel tumor suppressor, but its role in tumor occurrence and development is still unclear.MethodsWe investigated the expression level of MEG3 in pan-cancer through bioinformatics analysis, especially in gynecological tumors. Function assays were used to detect the effect of MEG3 on the malignant phenotype of ovarian cancer. RIP, RNA pull-down, MeRIP-qPCR, actinomycin D test were carried out to explore the m6A methylation-mediated regulation on MEG3. Luciferase reporter gene assay, PCR and Western blot were implemented to reveal the potential mechanism of MEG3. We further confirmed the influence of MEG3 on tumor growth in vivo by orthotopic xenograft models and IHC assay.ResultsIn this study, we discovered that MEG3 was downregulated in various cancers, with the most apparent downregulation in ovarian cancer. MEG3 inhibited the proliferation, migration, and invasion of ovarian cancer cells. Overexpression of MEG3 suppressed the degradation of VASH1 by negatively regulating miR-885-5p, inhibiting the ovarian cancer malignant phenotype. Furthermore, we demonstrated that MEG3 was regulated at the posttranscriptional level. YTHDF2 facilitated MEG3 decay by recognizing METTL3‑mediated m6A modification. Compared with those injected with vector control cells, mice injected with MEG3 knockdown cells showed larger tumor volumes and faster growth rates.ConclusionWe demonstrated that MEG3 is influenced by METTL3/YTHDF2 methylation and restrains ovarian cancer proliferation and metastasis by binding miR-885-5p to increase VASH1 expression. MEG3 is expected to become a therapeutic target for ovarian cancer.

Visualization of tumor-associated neutrophils in malignant ascites of ovarian cancer with aptamer-decorated AIE probes

Neoadjuvant chemotherapy followed by interval debulking surgery is a recommended treatment for advanced-stage ovarian cancer (OC) patients to avoid bowel and spleen resection. Pre-operative chemotherapy requires ascites from OC patients for cytopathological examinations based on hematoxylin & eosin staining to detect tumor cells, whose low ratio make them difficult to be detected in ascites. Sensitive detection of tumor-related immunocytes (TRI) in ascites is not only indicative of underlying malignant ascites, but also could predict chemoresistance and poor overall survival of OC patients. The antibodies can only recognize immunocytes but cannot distinguish TRI. Herein, we identified an aptamer99 (Apt-99) using a fluorescence-activated cell sorting-based aptamer selection strategy, which could target tumor-related neutrophils (TRNs) with high binding affinity. In contrast, FAM-labeled Apt-99 couldn’t distinguish the neutrophils in the smears of other patients’ derived ascites or peritoneal lavages, such as metastatic ovarian cancer from colon carcinoma and myomas of the uterus. LC-MS/MS analysis, and the molecular docking experiments demonstrated that the target molecule of Apt-99 were S100A8&A9 heterodimers. Moreover, Apt-99-labeled aggregation-induced emission dots were facilely prepared and used for specifically visualizing the TRNs in the ascites smears. The findings indicated the diagnostic potential of Apt-99 and the possibility of further clinical trials.

Clinicopathological features and clinical outcomes in individuals with Krukenberg tumors of colorectal origin.

191 Background: Krukenberg tumors (KT) are metastases to the ovary generally originating from a gastrointestinal primary such as colorectal carcinoma. The prognosis is poor with KT, and clinicopathological features associated with clinical outcomes have not been extensively studied. The study aimed to investigate the associations of clinicopathological features with outcomes in patients with KT of colorectal carcinoma (CRC) origin. Methods: This retrospective study utilized medical records and patient registries to identify 160 patients with a confirmed histopathological diagnosis of KT at Stanford University Medical Center between 2000 and 2020. Data collection included demographics, historical, clinicopathological, treatment and outcome variables. The primary tumor type was (N, %): CRC (101, 63.1%); gastric (24, 15%), breast (13, 8.1%); small bowel (10, 6.2%), other (12, 7.5%). Statistical analysis was performed using Chi-squared, Mann-Whitney U, and log-rank Kaplan-Meier analysis. Results: Analysis of the CRC cohort subdivided by location of the primary, N: 45 vs. 56, right colon (R) vs. left colon (L) revealed no significant difference in median age at diagnosis of KT, race/ethnicity, oligometastatic disease, histopathological differentiation or ovarian tumor volume. Patients with R vs L sided CRC primaries had a higher proportion of synchronous presentation at the time of KT diagnosis (75.6% vs 41.1%, R vs L, p&lt;0.001). Time to progression was not different, but overall survival (OS) was shorter in R CRC (767 vs. 1246 days, R vs. L, p &lt;0.01). By Kaplan-Meier analysis, patients with R CRC had a shorter OS (log-rank p=0.016). In the subgroup with unilateral KT, R sided CRC primaries involved the R ovary (85%) whereas L-sided CRC primaries involved the L ovary (70%) ( χ2, p&lt;0.002). Patient with bilateral (B) versus unilateral (U) had a larger ovarian tumor volume (2,073cm3 vs. 307 cm3, p&lt;0.01) but no difference in oligometastatic disease, chronicity, time to progression or overall survival. There was no statistical difference (p=0.93) between the association of bilateral KT inter-ovarian tumor size and CRC Laterality within individual patients. Conclusions: In this study, KT tumors predominantly originate from CRC. The clinical features of R versus L CRC, such as chronicity and OS are conveyed prognostically in patients with KT. Individuals with L CRC exhibited a better overall prognosis compared to those with R CRC. In patients with unilateral KT metastasis to ipsilateral ovary is significantly associated with location of CRC and is suggestive of a retrograde lymphatic or transcoelomic route of metastatic spread. Further studies are needed to confirm these findings and to elucidate ovarian organ tropism mediators that facilitate development and growth in metastatic ovarian cancer.

Phase II clinical study evaluating the efficacy and safety of disitamab vedotin combined with sintilimab and S-1 in the conversion treatment of HER2-overexpression unresectable gastric cancer.

TPS428 Background: Gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA) is the fifth commonest cancer and the fourth leading cause of cancer deaths worldwide. In about 30% to 40% of patients with advanced gastric cancer have lost the opportunity for radical surgery at the first diagnosis, and the overall 5-year survival rate is less than 50%. In recent years, conversion therapy has shown great promise. Disitamab vedotin is an antibody-drug conjugate comprising a novel HER2-directed monoclonal antibody, In previous study C008, RC48 showed a good safety profile and promising activity towards GC, and showed equivalent efficacy for HER2 IHC 2+ or HER2 IHC 3+ tumors. Methods: This study is a single-arm, phase II trial carry out at 16 academic hospitals in China, and will evaluate DV combined with Sintilimab and S-1 in patients with HER2-expressing unresectable gastric cancer. Eligible patients are at ≥ 18 to ≤ 75 years old; histologically confirmed, unresectable stage IV GC or GEJA; Single initial unresectable factor. For example, peritoneal metastasis (P1), Intraperitoneal free cancer cells positive (CY1), Paraaortic lymph node metastasis, liver metastasis (≤ 3 lesions, and ≤ 5 cm for a single lesion), ovarian metastasis; and documented histologically confirmed HER2 IHC 3+ or 2+; ECOG 0-1; at least one unresectable, measurable tumor lesion according to the RECIST version 1.1; adaptable function of the heart, liver, and kidney. 30 patients will be enrolled in this trial and receive Disitamab Vedotin(2.5mg/kg, IV, Q3W), Sintilimab (200 mg, IV, Q3W) and S-1 (twice daily on D1-14 are given at a dose calculate according to the body surface area and repeated every 3 weeks), until patients assessed by MDT to meet the criteria for surgical resection undergo gastrectomy. And the patients with peritoneal dissemination will combine with intraperitoneal administration of paclitaxel (60mg / m2, Q3W). The primary endpoint is R0 resection rate, Secondary endpoints include cORR, OS, RFS and safety. Seven patients have been enrolled in this study. Clinical trial information: NCT05627414 .

Tumor-derived small extracellular vesicles facilitate omental metastasis of ovarian cancer by triggering activation of mesenchymal stem cells

BackgroundOmental metastasis is the major cause of ovarian cancer recurrence and shortens patient survival, which can be largely attributed to the dynamic evolution of the fertile metastatic microenvironment driven by cancer cells. Previously, we found that adipose-derived mesenchymal stem cells (ADSCs) undergoing a phenotype shift toward cancer-associated fibroblasts (CAFs) participated in the orchestrated omental premetastatic niche for ovarian cancer. Here, we aim to elucidate the underlying mechanisms.MethodsSmall extracellular vesicles were isolated from ovarian cancer cell lines (ES-2 and its highly metastatic subline, ES-2-HM) and patient ascites using ultracentrifugation. Functional experiments, including Transwell and EdU assays, and molecular detection, including Western blot, immunofluorescence, and RT–qPCR, were performed to investigate the activation of ADSCs in vitro. High-throughput transcriptional sequencing and functional assays were employed to identify the crucial functional molecules inducing CAF-like activation of ADSCs and the downstream effector of miR-320a. The impact of extracellular vesicles and miR-320a-activated ADSCs on tumor growth and metastasis was assessed in subcutaneous and orthotopic ovarian cancer xenograft mouse models. The expression of miR-320a in human samples was evaluated using in situ hybridization staining.ResultsPrimary human ADSCs cocultured with small extracellular vesicles, especially those derived from ES-2-HM, exhibited boosted migration, invasion, and proliferation capacities and elevated α-SMA and FAP levels. Tumor-derived small extracellular vesicles increased α-SMA-positive stromal cells, fostered omental metastasis, and shortened the survival of mice harboring orthotopic ovarian cancer xenografts. miR-320a was abundant in highly metastatic cell-derived extracellular vesicles, evoked dramatic CAF-like transition of ADSCs, targeted the 3′-untranslated region of integrin subunit alpha 7 and attenuated its expression. miR-320a overexpression in ovarian cancer was associated with omental metastasis and shorter survival. miR-320a-activated ADSCs facilitated tumor cell growth and omental metastasis. Depletion of integrin alpha 7 triggered CAF-like activation of ADSCs in vitro.8TP37CR9mn1qNp5Xi3wswYVideo ConclusionsmiR-320a in small extracellular vesicles secreted by tumor cells targets integrin subunit alpha 7 in ADSCs and drives CAF-like activation, which in turn facilitates omental metastasis of ovarian cancer.Graphical

MARCH5-mediated downregulation of ACC2 promotes fatty acid oxidation and tumor progression in ovarian cancer

Lipid metabolic reprogramming has been recognized as a hallmark of human cancer. Acetyl-CoA Carboxylases (ACCs) are key rate-limiting enzymes involved in fatty acid metabolism regulation by catalyzing the carboxylation of acetyl-CoA to malonyl-CoA. Previously, most studies focused on the role of ACC1 in fatty acid metabolism in cancer, while the function of ACC2 remains largely uncharacterized in human cancers, especially in ovarian cancer (OC). Here, we show that ACC2 was significantly downregulated in cancerous tissue of OC, and the downregulation of ACC2 is closely associated with lager tumor size, metastases and worse prognosis in OC patients. Downregulation of ACC2 promoted proliferation and metastasis of OC both in vitro and in vivo by enhancing FAO. Notably, mitochondria-associated ubiquitin ligase (MARCH5) was identified to interact with and downregulate ACC2 by ubiquitination and degradation in OC. Moreover, ACC2 downregulation-enhanced FAO contributed to the progression of OC promoted by MARCH5. In conclusion, our findings demonstrate that MARCH5-mediated downregulation of ACC2 promotes FAO and tumorigenesis in OC, suggesting MARCH5-ACC2 axis as a potent candidate for the treatment and prevention of OC.

Abstract A018: GRB2 acts at reversed forks in the BRCA2-RAD51-MRE11 axis: a therapeutic target and enabling predictive biomarker for PARP inhibitor-immunotherapy combination

Abstract Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adaptor for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS–STING pathway to trigger pro-inflammatory cytokine production. Moreover, in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment reduced tumor burden and enabled high survival consistent with immune suppression of cancer growth. Collective findings unveil GRB2 function and mechanism for fork protection in the BRCA2-RAD51-MRE11 axis and suggest GRB2 as a potential therapeutic target and an enabling predictive biomarker for patient selection for PARPi and immunotherapy combination. Citation Format: John A. Tainer, Katharina Schlacher, Bin Wang, Guang Peng, Zamal Ahmed. GRB2 acts at reversed forks in the BRCA2-RAD51-MRE11 axis: a therapeutic target and enabling predictive biomarker for PARP inhibitor-immunotherapy combination [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A018.

Effect of different treatment modalities on ovarian cancer patients with liver metastases: A retrospective cohort study based on SEER.

To examine the trends in morbidity and mortality among ovarian cancer patients with liver metastases, and investigate the impact of different treatments on both overall survival (OS) and cancer-specific survival (CSS). 2,925 ovarian cancer patients with liver metastases from Surveillance, Epidemiology, and End Results 2010-2019 were included. The primary endpoint was considered as OS and CSS. We conducted trend analysis of the incidence, OS and CSS rates of liver metastases in ovarian cancer. Univariate and multivariate COX proportional risk models were used to investigate the association between different treatment methods and OS, and univariate and multivariate competing risk models were employed to evaluate the impact of treatment methods on CSS. At the end of follow-up, 689 patients remained alive. The OS and CSS rates were 76.44% and 72.99% for all patients, respectively. There was a significant decreasing trend in the incidence [average annual percent change (AAPC) = -2.3, 95% confidence interval (CI): -3.9, -0.7], all-cause mortality (AAPC = -12.8, 95% CI: -15.6, -9.9) and specific mortality (AAPC = -13.0, 95% CI: -16.1, -9.8) rate of liver metastases in ovarian cancer. After adjusting all confounding factor, only receiving surgery was associated with OS [hazard ratio (HR) = 0.39, 95%CI: 0.31-0.48]/CSS (HR = 0.37, 95%CI: 0.30-0.47). Chemotherapy was found to be protective factor for OS (HR = 0.33, 95%CI: 0.30-0.37)/CSS (HR = 0.44, 95%CI: 0.39-0.50) of ovarian cancer patients, while not receiving surgery remained a risk factor. Additionally, the result of subgroup analyses also showed that only receiving surgery and chemotherapy still were significant protective factor of OS and CSS for patients without other distant metastases, with distant metastases to the bone, lung, brain or other organs, with bone metastasis, and with lung metastasis. Our research has elucidated a downward trend in morbidity and mortality rates among patients with liver metastases originating from ovarian cancer. Only receiving surgery and chemotherapy as therapies methods confer survival benefits to patients.

Ovarian Metastasis from Human Papillomavirus-associated Usual-type Endocervical Adenocarcinoma: Clinicopathological Characteristics for Distinguishing from Primary Ovarian Mucinous or Endometrioid Tumor.

Distinguishing ovarian metastasis of usual-type endocervical adenocarcinoma (UEA) from primary ovarian tumors is often challenging because of several overlapping features. This study aimed to investigate the clinicopathological characteristics and outcomes of patients with metastatic ovarian UEA. Clinicopathological information was collected from eight patients with metastatic ovarian UEA. Immunostaining was also performed. Most patients presented with adnexal masses that were suspected to be primary ovarian tumors. All examined cases showed block p16 positivity in paired primary and metastatic tumors. Five patients who completed post-operative chemotherapy or concurrent chemoradiotherapy (CCRT) did not experience recurrence. In contrast, one patient who refused further treatment after the first CCRT cycle experienced ovarian and peritoneal metastases. One patient with isolated ovarian metastasis left untreated and developed peritoneal metastasis during follow-up. Patients with UEA who received proper management for ovarian metastases showed favorable outcomes. Given that ovarian metastatic UEA can mimic primary ovarian borderline tumor or carcinoma of the mucinous or endometrioid type, pathologists should be aware of this unusual but distinctive morphology to avoid misdiagnosis and inappropriate treatment.

FSH induces EMT in ovarian cancer via ALKBH5-regulated Snail m6A demethylation.

Background: The therapeutic benefits of targeting follicle-stimulating hormone (FSH) receptor in treatment of ovarian cancer are significant, whereas the role of FSH in ovarian cancer progresses and the underlying mechanism remains to be developed. Methods: Tissue microarray of human ovarian cancer, tumor xenograft mouse model, and in vitro cell culture were used to investigate the role of FSH in ovarian carcinogenesis. siRNA, lentivirus and inhibitors were used to trigger the inactivation of genes, and plasmids were used to increase transcription of genes. Specifically, pathological characteristic was assessed by histology and immunohistochemistry (IHC), while signaling pathway was studied using western blot, quantitative RT-PCR, and immunofluorescence. Results: Histology and IHC of human normal ovarian and tumor tissue confirmed the association between FSH and Snail in ovarian cancer metastasis. Moreover, in epithelial ovarian cancer cells and xenograft mice, FSH was showed to promote epithelial mesenchymal transition (EMT) progress and metastasis of ovarian cancer via prolonging the half-life of Snail mRNA in a N6-methyladenine methylation (m6A) dependent manner, which was mechanistically through the CREB/ALKBH5 signaling pathway. Conclusions: These findings indicated that FSH induces EMT progression and ovarian cancer metastasis via CREB/ALKBH5/Snail pathway. Thus, this study provided new insight into the therapeutic strategy of ovarian cancer patients with high level of FSH.

Selectively targeting BCL6 using a small molecule inhibitor is a potential therapeutic strategy for ovarian cancer.

Ovarian cancer is one of the tumors with the highest fatality rate among gynecological tumors. The current 5-year survival rate of ovarian cancer is <35%. Therefore, more novel alternative strategies and drugs are needed to treat ovarian cancer. The transcription factor B-cell lymphoma 6 (BCL6) is critically associated with poor prognosis and cisplatin resistance in ovarian cancer treatment. Therefore, BCL6 may be an attractive therapeutic target for ovarian cancer. However, the role of targeting BCL6 in ovarian cancer remains elusive. Here, we developed a novel BCL6 small molecule inhibitor, WK369, which exhibits excellent anti-ovarian cancer bioactivity, induces cell cycle arrest and causes apoptosis. WK369 effectively inhibits the growth and metastasis of ovarian cancer without obvious toxicity in vitro and in vivo. meanwhile, WK369 can prolong the survival of ovarian cancer-bearing mice. It is worth noting that WK369 also has significant anti-tumor effects on cisplatin-resistant ovarian cancer cell lines. Mechanistic studies have shown that WK369 can directly bind to the BCL6-BTB domain and block the interaction between BCL6 and SMRT, leading to the reactivation of p53, ATR and CDKN1A. BCL6-AKT, BCL6-MEK/ERK crosstalk is suppressed. As a first attempt, our study demonstrates that targeting BCL6 may be an effective approach to treat ovarian cancer and that WK369 has the potential to be used as a candidate therapeutic agent for ovarian cancer.

Long noncoding RNA H19 in ovarian biology and placenta development.

As the first long noncoding RNA to be discovered, H19 has gained substantial attention as a key regulator of several biological processes and its roles in female reproductive biology are gradually getting revealed. Herein, we have summarized the current evidence regarding H19 expression pattern and involvement in the developmental and pathological processes associated with the ovary and the placenta. The findings indicate that within the ovaries, H19 is expressed in the antral and cystic atretic follicles as well as in the corpora lutea but absent in the primordial, primary, and secondary follicles. Its normal expression promotes the maturation of antral follicles and prevents their premature selection for the ovulatory journey while its aberrant induction promotes polycystic ovary syndrome development and ovarian cancer metastasis. In the placenta, H19 is highly expressed in the cytotrophoblasts and extravillous trophoblasts but weakly expressed in the syncytiotrophoblast layer and potentially controls trophoblast cell fate decisions during placenta development. Abnormal expression of H19 is observed in the placental villi of pregnancies affected by pre-eclampsia and fetal growth restriction. Therefore, dysregulated H19 is a candidate biomarker and therapeutic target for the mitigation of ovarian and placenta-associated diseases.

Clinicopathological features, treatment patterns, and survival outcomes among Syrian patients with advanced breast cancer.

Advanced breast cancer (ABC) is a heterogeneous disease with varied prognoses, that is affected by many clinicopathological features. This study aimed to investigate the clinicopathological characteristics, first-line treatment (FLx), and prognostic impact of these features on survival among Syrian patients with ABC. This retrospective cohort study included patients with ABC. The association of clinicopathological factors with survival was assessed using Kaplan-Meier curves and the log-rank test, as well as the Cox proportional hazards regression model to calculate the hazard ratio (HaR). A total of 423 patients with ABC were included in the study, with a median age (range) of 47 years (23-82). 83% of metastases were metachronous. Most patients (91.8%) received chemotherapy as the FLx. The median progression-free survival (PFS) and overall survival (OS) of all the patients were 7 and 16 months, respectively. The median PFS was associated with four factors, which were time of metastasis (adjusted HaR=1.861, 95% CI 1.420-2.438, P<0.0001), performance status (PS) (adjusted HaR=1.456, 95% CI 1.049-2.021, P=0.025), ovarian metastasis (adjusted HaR=7.907, 95% CI 1.049-59.576, P=0.045), and FLx (adjusted HaR=2.536, 95% CI 1.581-4.068, P<0.0001). Similarly, the OS was associated with three factors, including hormone receptors (HRs) status (adjusted HaR=1.124, 95% CI 1.009-1.252, P=0.034), time of metastasis (adjusted HaR=2.099, 95% CI 1.588-2.775, P<0.0001), and PS (adjusted HaR=1.787, 95% CI 1.429-2.233, P<0.0001). In the HR-positive/human epidermal growth receptor 2 (HER2)-negative group, endocrine therapy was significantly associated with longer PFS compared with chemotherapy (15 vs 7 months, adjusted HaR=2.699, 95% CI 1.417-5.143, P=0.003). Furthermore, there was no difference in OS between the two treatment modalities (P=0.855). ABC survival varies depending on the location of metastases. Good PS and synchronous stage 4 disease were independent prognostic factors for longer PFS and OS. In the HR-positive/HER2-negative group, PFS for endocrine therapy was significantly longer than chemotherapy, with no differences in OS. This study confirms that endocrine therapy is preferred as an FLx for ABC in the HR-positive/HER2-negative group.

Reclassify High-Grade Serous Ovarian Cancer Patients Into Different Molecular Subtypes With Discrepancy Prognoses and Therapeutic Responses Based on Cancer-Associated Fibroblast-Enriched Prognostic Genes.

Cancer-associated fibroblasts (CAFs) play critical roles in the metastasis and therapeutic response of high-grade serous ovarian cancer (HGSC). Our study intended to select HGSC patients with unfavorable prognoses and therapeutic responses based on CAF-enriched prognostic genes. The bulk RNA and single-cell RNA sequencing (scRNA-seq) data of tumor tissues were collected from the TCGA and GEO databases. The infiltrated levels of immune and stromal cells were estimated by multiple immune deconvolution algorithms and verified through immunohistochemical analysis. The univariate Cox regression analyses were used to identify prognostic genes. Gene Set Enrichment Analysis (GSEA) was conducted to annotate enriched gene sets. The Genomics of Drug Sensitivity in Cancer (GDSC) database was used to explore potential alternative drugs. We found the infiltered levels of CAFs were remarkedly elevated in advanced and metastatic HGSC tissues and identified hundreds of genes specifically enriched in CAFs. Then we selected 6 CAF-enriched prognostic genes based on which HGSC patients were reclassified into 2 subclusters with discrepancy prognoses. Further analysis revealed that the HGSC patients in cluster-2 tended to undergo poor responses to traditional chemotherapy and immunotherapy. Subsequently, we selected 24 novel potential therapeutic drugs for cluster-2 HGSC patients. Moreover, we discovered a positive correlation of infiltrated levels between CAFs and monocytes/macrophages in HGSC tissues. Collectively, our study successfully reclassified HGSC patients into 2 different subgroups that have discrepancy prognoses and responses to current therapeutic methods.

The Impact of Mitochondria in Ovarian Cancer Cell Metabolism, Proliferation, and Metastasis.

Mitochondrial dysfunctions are significantly implicated in cancer initiation, progression, and metastasis, which have been shown for several cancers including ovarian cancer.An increase in mitochondrial dysfunction is also associated with drug resistance along with cancer progression, which in part is related to its specific microenvironment that is characterized by ascites, low glucose levels, and hypoxia that causes ovarian cancer cells to switch to mitochondrial respiration to enable their survival. Peritoneal ascitic fluid accumulation is a specific feature of ovarian cancer, and it is a major cause of its metastatic spread that also presents challenges for effective treatment. Among the treatment difficulties for ovarian cancer is the mutation rate and frequency of mtDNA in ovarian cancer tissue that can affect the efficiency of chemotherapeutic drugs. The varied and multiple mutations of different types enable metabolic reprogramming, cancer cell proliferation, and drug resistance.New specific information on mechanisms underlying several of the mitochondrial dysfunctions has led to proposing various mitochondrial determinants as targets for ovarian cancer therapy, which include targeting specific mitochondrial proteins and phosphoproteins as well as reactive oxygen species (ROS) that accumulate abnormally in cancer cells. Because of the genetically and histologically heterogeneous nature of the disease, combination therapy approaches will be necessary to combat the disease and achieve progress in effective treatment of ovarian cancer. This chapter will address (1) mitochondrial vulnerabilities underlying dysfunction and disease; (2) mitochondrial dysfunction in ovarian cancer; (3) present treatment difficulties for ovarian cancer and new potential treatment strategies to target ovarian cancer mitochondrial metabolism; and (4) biobehavioral factors influencing ovarian cancer development.

Epithelial ovarian cancer and brain metastases: might the BRCA status, PARP inhibitor administration, and surgical treatment impact the survival?

ObjectiveTo evaluate disease characteristics and survival according to BRCA status, administration of poly-(ADP-ribose) polymerase inhibitors (PARPi), and surgery in patients with ovarian cancer and brain metastases.MethodsThis is a monocentric retrospective...

Peritoneal, ovarian and liver metastasis of a previously resected pancreatic glucagonoma: a case report

Peritoneal, ovarian and liver metastasis of a previously resected pancreatic glucagonoma: a case report