Implementing a nurse-led screening clinic for symptom distress with community-based referral for cancer survivors: A feasibility study.

INTRODUCTION: This prospective, single-arm, pragmatic implementation study evaluated the feasibility of a nurse-led symptom-screening program embedded in routine oncology post-treatment outpatient clinics by assessing (1) the acceptance rate for symptom distress screening (SDS), (2) the prevalence of SDS cases, (3) the acceptance rate for community-based psychosocial support services, and (4) the effect of referred psychosocial support services on reducing symptom distress. METHODS: Using the modified Edmonton Symptom Assessment System (ESAS-r), we screened patients who recently completed cancer treatment. Patients screening positive for moderate-to-severe symptom distress were referred to a nurse-led community-based symptom-management program involving stepped-care symptom/psychosocial management interventions using a pre-defined triage system. Reassessments were conducted at 3-months and 9-months thereafter. The primary outcomes included SDS acceptance rate, SDS case prevalence, intervention acceptance rate, and ESAS-r score change over time. RESULTS: Overall, 2988/3742(80%) eligible patients consented to SDS, with 970(32%) reporting ≥1 ESAS-r symptom as moderate-to-severe (caseness). All cases received psychoeducational material, 673/970(69%) accepted psychosocial support service referrals. Among 328 patients completing both reassessments, ESAS-r scores improved significantly over time (p < 0.0001); 101(30.8%) of patients remained ESAS cases throughout the study, 112(34.1%) recovered at 3-month post-baseline, an additional 72(22%) recovered at 9-month post-baseline, while 43(12.2%) had resumed ESAS caseness at 9-month post-baseline. CONCLUSION: Nurse-led SDS programs with well-structured referral pathways to community-based services and continued monitoring are feasible and acceptable in cancer patients and may help in reducing symptom distress. We intend next to develop optimal strategies for SDS implementation and referral within routine cancer care services.

Evaluation of an Isothermal Amplification HPV Assay on Self-Collected Vaginal Samples as Compared to Clinician-Collected Cervical Samples.

This study aimed to evaluate the concordance of HPV results between the SentisTM HPV assay (Sentis) (BGI Group, Shenzhen, China), an isothermal amplification-based HPV assay, on self-collected and clinician-collected samples and the agreement of Sentis on self-collected samples with the BD OnclarityTM HPV assay (Onclarity) (Becton, Dickinson, and Company, Franklin Lakes, New Jersey, USA), a PCR-based HPV assay, on clinician-collected samples. This was a prospective study of 104 women attending the colposcopy clinic for abnormal smears. After informed consent, participants self-collected vaginal samples before having clinician-collected cervical samples. Self-collected samples underwent HPV testing with Sentis (Self-Sentis HPV) and clinician-collected samples were tested with Sentis (Clinician-Sentis HPV) and Onclarity (Clinician-Onclarity), which was used as a reference standard. The concordance was assessed using Cohen's kappa. The prevalence of HPV and the acceptability of self-sampling were also evaluated. The concordance rate between Self-Sentis HPV and Clinician-Sentis HPV was 89.8% with a kappa of 0.769. The concordance rate between Self-Sentis HPV and Clinician-Onclarity was 84.4% with a kappa of 0.643. The prevalence of HPV was 26.0% on Clinician-Onclarity, 29.3% on Clinician-Sentis HPV, and 35.6% on Self-Sentis HPV. Overall, 65% of participants would undergo self-sampling again. This was attributed to mainly not feeling embarrassed (68%) and being convenient (58%). Our study showed a substantial agreement between Self-Sentis HPV with Clinician-Sentis HPV and Clinician-Onclarity. Self-sampling was also shown to be a generally well-accepted method of screening.

Patient-Initiated Follow-Up in Ovarian Cancer.

This study aimed to assess the feasibility of patient-initiated follow-up (PIFU) in combination with regular tumour marker monitoring as an alternative to conventional hospital follow-up for ovarian cancer survivors. Women who had recently completed treatment for ovarian cancer and had a raised pre-treatment tumour marker were recruited. Participants were allocated to PIFU (intervention group) or conventional hospital follow-up (control group) according to their own preference. Both groups had regular tumour marker monitoring. The change in fear of cancer recurrence (FCR) score as measured by the FCR inventory, and the supportive care need (SCN) scores as measured by the SCN survey at baseline and at 6 months between PIFU and hospital follow-up were compared. Out of 64 participants, 37 (58%) opted for hospital follow-up and 27 (42%) opted for PIFU. During the 6-month study period, there was no significant difference in the change of FCR between the two groups (p = 0.35). There was a significant decrease in the sexuality unmet needs score in the intervention group from baseline to 6-month FU (mean difference -8.7, 95% confidence interval -16.1 to -1.4, p = 0.02). PIFU with tumour marker monitoring is a feasible follow-up approach in ovarian cancer survivorship care. FCR and SCN were comparable between PIFU and conventional hospital follow-up.

Maximizing the cost-effectiveness of cervical screening in the context of routine HPV vaccination by optimizing screening strategies with respect to vaccine uptake: a modeling analysis.

BACKGROUND: Regarding primary and secondary cervical cancer prevention, the World Health Organization proposed the cervical cancer elimination strategy that requires countries to achieve 90% uptake of human papillomavirus (HPV) vaccines and 70% screening uptake. The optimal cervical screening strategy is likely different for unvaccinated and vaccinated cohorts upon national HPV immunization. However, health authorities typically only provide a one-size-fits-all recommendation for the general population. We aimed to evaluate the cost-effectiveness for determining the optimal screening strategies for vaccinated and unvaccinated cohorts. METHODS: We considered the women population in Hong Kong which has a unique HPV infection and cervical cancer epidemiology compared to other regions in China and Asia. We used mathematical models which comprise a deterministic age-structured compartmental dynamic component and a stochastic individual-based cohort component to evaluate the cost-effectiveness of screening strategies for cervical screening. Following the recommendations in local guidelines in Hong Kong, we considered strategies that involved cytology, HPV testing, or co-testing as primary cervical screening. We also explored the impacts of adopting alternative de-intensified strategies for vaccinated cohorts. The 3-year cytology screening was used as the base comparator while no screening was also considered for vaccinated cohorts. Women's lifetime life years, quality-adjusted life years, and costs of screening and treatment were estimated from the societal perspective based on the year 2022 and were discounted by 3% annually. Incremental cost-effectiveness ratios (ICERs) were compared to a willingness to pay (WTP) threshold of one gross domestic product per capita (US $47,792). Probabilistic and one-way sensitivity analyses were conducted. RESULTS: Among unvaccinated cohorts, the strategy that adds reflex HPV to triage mild cytology abnormality generated more life years saved than cytology-only screening and could be a cost-effective alternative. Among vaccinated cohorts, when vaccine uptake was 85% (based on the uptake in 2022), all guideline-based strategies (including the cytology-only screening) had ICERs above the WTP threshold when compared with no screening if the vaccine-induced protection duration was 20 years or longer. Under the same conditions, HPV testing with genotyping triage had ICERs (compared with no screening) below the WTP threshold if the routine screening interval was lengthened to 10 and 15 years or screening was initiated at ages 30 and 35 years. CONCLUSIONS: HPV testing is a cost-effective alternative to cytology for vaccinated cohorts, and the associated optimal screening frequency depends on vaccine uptake. Health authorities should optimize screening recommendations by accounting for population vaccine uptake.

Medical students' perception of the application of a virtual reality training model to acquire vaginal examination skills.

OBJECTIVE: To review the perception of and feedback from medical students on the application of a virtual reality (VR) model to acquire vaginal examination (VE) skills. METHODS: A specially designed VR training model on VE was developed with the aim of enhancing medical students' VE skills. Medical students attending the gynecology clinic were invited to try this VR training model. Their participation was voluntary and at the completion of their VR training, they were asked to complete an anonymous questionnaire to give their feedback and perception regarding this learning experience. RESULTS: Sixty-five sixth-year medical students completed the VR training and the feedback questionnaire: 55 (84.7%) of them reported that the training instructions were clear and 60 (92.4%) considered the training to the helpful in recalling the details of the tasks. It was also reported that VR technology could facilitate learning and interaction, and motivate learning in 80.1% and 66.2% of medical students, respectively. CONCLUSION: VR technology is a potential teaching modality for medical students to acquire VE skills. However, further evaluation is needed to determine whether this learning tool is effective in enhancing clinical competence.

Tumor-secreted exosomal miR-141 activates tumor-stroma interactions and controls premetastatic niche formation in ovarian cancer metastasis.

BACKGROUND: Metastatic colonization is one of the critical steps in tumor metastasis. A pre-metastatic niche is required for metastatic colonization and is determined by tumor-stroma interactions, yet the mechanistic underpinnings remain incompletely understood. METHODS: PCR-based miRNome profiling, qPCR, immunofluorescent analyses evaluated the expression of exosomal miR-141 and cell-to-cell communication. LC-MS/MS proteomic profiling and Dual-Luciferase analyses identified YAP1 as the direct target of miR-141. Human cytokine profiling, ChIP, luciferase reporter assays, and subcellular fractionation analyses confirmed YAP1 in modulating GROα production. A series of in vitro tumorigenic assays, an ex vivo model and Yap1 stromal conditional knockout (cKO) mouse model demonstrated the roles of miR-141/YAP1/GROα/CXCR1/2 signaling cascade. RNAi, CRISPR/Cas9 and CRISPRi systems were used for gene silencing. Blood sera, OvCa tumor tissue samples, and tissue array were included for clinical correlations. RESULTS: Hsa-miR-141-3p (miR-141), an exosomal miRNA, is highly secreted by ovarian cancer cells and reprograms stromal fibroblasts into proinflammatory cancer-associated fibroblasts (CAFs), facilitating metastatic colonization. A mechanistic study showed that miR-141 targeted YAP1, a critical effector of the Hippo pathway, reducing the nuclear YAP1/TAZ ratio and enhancing GROα production from stromal fibroblasts. Stromal-specific knockout (cKO) of Yap1 in murine models shaped the GROα-enriched microenvironment, facilitating in vivo tumor colonization, but this effect was reversed after Cxcr1/2 depletion in OvCa cells. The YAP1/GROα correlation was demonstrated in clinical samples, highlighting the clinical relevance of this research and providing a potential therapeutic intervention for impeding premetastatic niche formation and metastatic progression of ovarian cancers. CONCLUSIONS: This study uncovers miR-141 as an OvCa-derived exosomal microRNA mediating the tumor-stroma interactions and the formation of tumor-promoting stromal niche through activating YAP1/GROα/CXCRs signaling cascade, providing new insight into therapy for OvCa patients with peritoneal metastases.

Outcome after loop electrosurgical excision procedure for cervical high-grade squamous intraepithelial lesion.

OBJECTIVE: The dilemma in treating cervical high-grade squamous intraepithelial lesion (HSIL) is how to achieve complete excision to minimize the risk of cervical cancer while sparing the anatomy of the cervix and its ability to function during pregnancy. The optimal management for positive margins after excisional treatment is still controversial. This study was conducted to determine the clinical and histologic predictors of residual/recurrent HSIL and assess the outcome of women with positive margin. MATERIALS AND METHODS: This retrospective cohort study included 386 women who had excisional treatment for HSIL during 1st January 2012 to 31st December 2015 in a university-affiliated hospital. RESULTS: Overall, 212 (54.9%) women had negative margins and 155 (40.2%) had positive margins. The cumulative rate of residual/recurrent HSIL at 2 and 5 years was 15.7% and 16.8% respectively in positive margins and 1.8% and 5.0% respectively in negative margins (p < 0.001). Of women who had residual/recurrent HSIL, significantly more women had positive margins compared to negative margins (74.1% vs 25.9%, p = 0.001). Positive margin was significantly associated with higher rate of subsequent abnormal cervical smear (48.2% vs 28.9%, p < 0.001), requiring further colposcopy (32.1% vs 14.4%, p < 0.001) and further treatment for SIL (7.5% vs 4.8%, p < 0.001) compared to negative margin. CONCLUSION: Most women (85%) with positive margin went without residual/recurrent HSIL, of which the option of close surveillance with cytology is reasonable. Repeat excision may be considered in selected women with positive margin, endocervical glandular involvement and those who are older or unable to comply with follow-up.

New Insights into Ferroptosis Initiating Therapies (FIT) by Targeting the Rewired Lipid Metabolism in Ovarian Cancer Peritoneal Metastases.

Ovarian cancer is one of the most lethal gynecological cancers worldwide. The poor prognosis of this malignancy is substantially attributed to the inadequate symptomatic biomarkers for early diagnosis and effective remedies to cure the disease against chemoresistance and metastasis. Ovarian cancer metastasis is often relatively passive, and the single clusters of ovarian cancer cells detached from the primary ovarian tumor are transcoelomic spread by the peritoneal fluid throughout the peritoneum cavity and omentum. Our earlier studies revealed that lipid-enriched ascitic/omental microenvironment enforced metastatic ovarian cancer cells to undertake metabolic reprogramming and utilize free fatty acids as the main energy source for tumor progression and aggression. Intriguingly, cell susceptibility to ferroptosis has been tightly correlated with the dysregulated fatty acid metabolism (FAM), and enhanced iron uptake as the prominent features of ferroptosis are attributed to the strengthened lipid peroxidation and aberrant iron accumulation, suggesting that ferroptosis induction is a targetable vulnerability to prevent cancer metastasis. Therefore, the standpoints about tackling altered FAM in combination with ferroptosis initiation as a dual-targeted therapy against advanced ovarian cancer were highlighted herein. Furthermore, a discussion on the prospect and challenge of inducing ferroptosis as an innovative therapeutic approach for reversing remedial resistance in cancer interventions was included. It is hoped this proof-of-concept review will indicate appropriate directions for speeding up the translational application of ferroptosis-inducing compounds (FINs) to improve the efficacy of ovarian cancer treatment.

Molecular Biomarkers for the Early Detection of Ovarian Cancer.

Ovarian cancer is the deadliest gynecological cancer, leading to over 152,000 deaths each year. A late diagnosis is the primary factor causing a poor prognosis of ovarian cancer and often occurs due to a lack of specific symptoms and effective biomarkers for an early detection. Currently, cancer antigen 125 (CA125) is the most widely used biomarker for ovarian cancer detection, but this approach is limited by a low specificity. In recent years, multimarker panels have been developed by combining molecular biomarkers such as human epididymis secretory protein 4 (HE4), ultrasound results, or menopausal status to improve the diagnostic efficacy. The risk of ovarian malignancy algorithm (ROMA), the risk of malignancy index (RMI), and OVA1 assays have also been clinically used with improved sensitivity and specificity. Ongoing investigations into novel biomarkers such as autoantibodies, ctDNAs, miRNAs, and DNA methylation signatures continue to aim to provide earlier detection methods for ovarian cancer. This paper reviews recent advancements in molecular biomarkers for the early detection of ovarian cancer.

A patient with relapsed high-grade serous ovarian carcinoma with somatic RAD51C mutations treated with PARPi monotherapy: a case report.

We report our experience in the management of a relapsed ovarian cancer patient with somatic RAD51C mutation, treated with olaparib monotherapy. The patient was diagnosed with stage 4 high-grade serous ovarian carcinoma and was treated with neoadjuvant chemotherapy, cytoreductive surgery, and postoperative chemotherapy. After a second cancer recurrence, she underwent FoundationOne CDx testing following disease progression on multiple lines of chemotherapy. Based on the FoundationOne CDx results, olaparib monotherapy was started. After 13 months of therapy, all lesions responded to the treatment, and she achieved complete response as demonstrated by normalization of the levels of CA125 and positron emission tomography-computed tomography (PET-CT). We plan to continue olaparib monotherapy until disease progression.

Clinical performance of the Roche Cobas 4800 HPV test for primary cervical cancer screening in a Chinese population.

High-risk human papillomavirus (HR-HPV) testing has become an increasing important strategy in primary cervical cancer screening in recent years. It warrants the evaluation of molecular-based HPV tests for accuracy and efficacy of screening. The performance of Roche Cobas 4800 HPV test was validated and compared with Digene Hybrid Capture 2 (HC2) high-risk HPV DNA test for primary screening in a large Chinese screening cohort. Of 6345 women screened, overall agreement between Cobas and HC2 was 92.23% (95% CI: 91.57-92.89). The inter-assay agreement was correlated with the severity of underlying biology, with an increasing concordance found in samples with more severe abnormalities. Most of the discordant samples had the test signal strength closer to the test limits of the detection than concordant samples, reflecting a low viral load and infection of a cluster of low-risk HPV in these samples. The Cobas test demonstrated significantly higher specificity in identifying CIN2+/CIN3+ cases than HC2 test (66.46% vs 43.67% and 65.42% vs 42.86%, p<0.001), with comparable sensitivity in clinical evaluation. Increased specificity of Cobas test would accent women having the highest risk of developing CIN2+, with the potential to reduce unnecessary colposcopy referral in a screening population.

Orchestrated Action of AMPK Activation and Combined VEGF/PD-1 Blockade with Lipid Metabolic Tunning as Multi-Target Therapeutics against Ovarian Cancers.

Ovarian cancer is one of the most lethal gynecological malignancies worldwide, and chemoresistance is a critical obstacle in the clinical management of the disease. Recent studies have suggested that exploiting cancer cell metabolism by applying AMP-activated protein kinase (AMPK)-activating agents and distinctive adjuvant targeted therapies can be a plausible alternative approach in cancer treatment. Therefore, the perspectives about the combination of AMPK activators together with VEGF/PD-1 blockade as a dual-targeted therapy against ovarian cancer were discussed herein. Additionally, ferroptosis, a non-apoptotic regulated cell death triggered by the availability of redox-active iron, have been proposed to be governed by multiple layers of metabolic signalings and can be synergized with immunotherapies. To this end, ferroptosis initiating therapies (FITs) and metabolic rewiring and immunotherapeutic approaches may have substantial clinical potential in combating ovarian cancer development and progression. It is hoped that the viewpoints deliberated in this review would accelerate the translation of remedial concepts into clinical trials and improve the effectiveness of ovarian cancer treatment.

A Selective ß-Catenin-Metadherin/CEACAM1-CCL3 Axis Mediates Metastatic Heterogeneity upon Tumor-Macrophage Interaction.

Tumor heterogeneity plays a key role in cancer relapse and metastasis, however, the distinct cellular behaviors and kinetics of interactions among different cancer cell subclones and the tumor microenvironment are poorly understood. By profiling an isogenic model that resembles spontaneous human ovarian cancer metastasis with an highly metastatic (HM) and non-metastatic (NM) tumor cell pair, one finds an upregulation of Wnt/ß-catenin signaling uniquely in HM. Using humanized immunocompetent mice, one shows for the first time that activated ß-catenin acts nonautonomously to modulate the immune microenvironment by enhancing infiltrating tumor-associated macrophages (TAM) at the metastatic site. Single-cell time-lapse microscopy further reveals that upon contact with macrophages, a significant subset of HM, but not NM, becomes polyploid, a phenotype pivotal for tumor aggressiveness and therapy resistance. Moreover, HM, but not NM, polarizes macrophages to a TAM phenotype. Mechanistically, ß-catenin upregulates cancer cell surface metadherin, which communicates through CEACAM1 expressed on macrophages to produce CCL3. Tumor xenografts in humanized mice and clinical patient samples both corroborate the relevance of enhanced metastasis, TAM activation, and polyploidy in vivo. The results thus suggest that targeting the ß-catenin-metadherin/CEACAM1-CCL3 positive feedback cascade holds great therapeutic potential to disrupt polyploidization of the cancer subclones that drive metastasis.

Human Papillomavirus Self-Sampling for Primary Cervical Cancer Screening in Under-Screened Women in Hong Kong during the COVID-19 Pandemic.

The aim of this study was to assess the effectiveness of HPV self-sampling for cervical cancer screening and the best means of service delivery, with a specific focus on under-screened women, particularly during the COVID-19 pandemic. Using three arms of service delivery (social media, school outreach and underserved outreach), we recruited under-screened women aged 30-65 years from two population groups: the general public and specific underserved communities, from whom self-sampled specimens and optional clinician-sampled cervical specimens were obtained for HPV testing. A total of 521 self-sampling kits were distributed, of which 321 were returned, giving an overall uptake rate of 61.6%. The response rate was higher in the face-to-face underserved outreach (65.5%) compared to social media (22.8%) and school outreach (18.2%). The concordance for HPV detection between self-sampled and clinician-sampled specimens was 90.2% [95% confidence interval (CI) 85.1-93.8%; Cohen's kappa 0.59 (95% CI 0.42-0.75)]. Overall, 89.2% of women were willing to have self-sampling again. In conclusion, HPV self-sampling is an effective method for cervical cancer screening and can be considered as an option, particularly in women who are reluctant or unable to attend regular screening. Various service deliveries could be considered to increase participation in cervical cancer screening.

Diagnostic Performance of Risk of Malignancy Algorithm (ROMA), Risk of Malignancy Index (RMI) and Expert Ultrasound Assessment in a Pelvic Mass Classified as Inconclusive by International Ovarian Tumour Analysis (IOTA) Simple Rules.

The accurate prediction of malignancy for a pelvic mass detected on ultrasound allows for appropriate referral to specialised care. IOTA simple rules are one of the best methods but are inconclusive in 25% of cases, where subjective assessment by an expert sonographer is recommended but may not always be available. In the present paper, we evaluate the methods for assessing the nature of a pelvic mass, including IOTA with subjective assessment by expert ultrasound, RMI and ROMA. In particular, we investigate whether ROMA can replace expert ultrasound when IOTA is inconclusive. This prospective study involves one cancer centre and three general units. Women scheduled for an operation for a pelvic mass underwent a pelvic ultrasound pre-operatively. The final histology was obtained from the operative sample. The sensitivity, specificity and accuracy for each method were compared with the McNemar test. Of the 690 women included in the study, 171 (25%) had an inconclusive IOTA. In this group, expert ultrasound was more sensitive in diagnosing a malignant mass compared to ROMA (81% vs. 63%, p = 0.009) with no significant difference in the specificity or accuracy. All assessment methods involving IOTA had similar accuracies and were more accurate than RMI or ROMA alone. In conclusion, when IOTA was inconclusive, assessment by expert ultrasound was more sensitive than ROMA, with similar specificity.

PFKFB3 Regulates Chemoresistance, Metastasis and Stemness via IAP Proteins and the NF-κB Signaling Pathway in Ovarian Cancer.

Glycolysis has been reported to be critical for cancer stem cells (CSCs), which are associated with tumor chemoresistance, metastasis and recurrence. Thus, selectively targeting glycolytic enzymes may be a potential therapy for ovarian cancer. 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), the main source of fructose-2,6-bisphosphate, controls the first committed step in glycolysis. We investigate the clinical significance and roles of PFKFB3 in ovarian cancer using in vitro and in vivo experiments. We demonstrate that PFKFB3 is widely overexpressed in ovarian cancer and correlates with advanced stage/grade and poor outcomes. Significant up-regulation of PFKFB3 was found in ascites and metastatic foci, as well as CSC-enriched tumorspheres and ALDH+CD44+ cells. 3PO, a PFKFB3 inhibitor, reduced lactate level and sensitized A2780CP cells to cisplatin treatment, along with the modulation of inhibitors of apoptosis proteins (c-IAP1, c-IAP2 and survivin) and an immune modulator CD70. Blockade of PFKFB3 by siRNA approach in the CSC-enriched subset led to decreases in glycolysis and CSC properties, and activation of the NF-κB cascade. PFK158, another potent inhibitor of PFKFB3, impaired the stemness of ALDH+CD44+ cells in vitro and in vivo, whereas ectopic expression of PFKFB3 had the opposite results. Overall, PFKFB3 was found to mediate metabolic reprogramming, chemoresistance, metastasis and stemness in ovarian cancer, possibly via the modulation of inhibitors of apoptosis proteins and the NF-κB signaling pathway; thus, suggesting that PFKFB3 may be a potential therapeutic target for ovarian cancer.

Aberrant Cholesterol Metabolism in Ovarian Cancer: Identification of Novel Therapeutic Targets.

Cholesterol is an essential substance in mammalian cells, and cholesterol metabolism plays crucial roles in multiple biological functions. Dysregulated cholesterol metabolism is a metabolic hallmark in several cancers, beyond the Warburg effect. Reprogrammed cholesterol metabolism has been reported to enhance tumorigenesis, metastasis and chemoresistance in multiple cancer types, including ovarian cancer. Ovarian cancer is one of the most aggressive malignancies worldwide. Alterations in metabolic pathways are characteristic features of ovarian cancer; however, the specific role of cholesterol metabolism remains to be established. In this report, we provide an overview of the key proteins involved in cholesterol metabolism in ovarian cancer, including the rate-limiting enzymes in cholesterol biosynthesis, and the proteins involved in cholesterol uptake, storage and trafficking. Also, we review the roles of cholesterol and its derivatives in ovarian cancer and the tumor microenvironment, and discuss promising related therapeutic targets for ovarian cancer.

Epigenetic Silencing of miR-33b Promotes Peritoneal Metastases of Ovarian Cancer by Modulating the TAK1/FASN/CPT1A/NF-κB Axis.

Peritoneal metastases are frequently found in high-grade serous carcinoma (HGSOC) patients and are commonly associated with a poor prognosis. The tumor microenvironment (TME) is a complex milieu that plays a critical role in epigenetic alterations driving tumor development and metastatic progression. However, the impact of epigenetic alterations on metastatic ovarian cancer cells in the harsh peritoneal microenvironment remains incompletely understood. Here, we identified that miR-33b is frequently silenced by promoter hypermethylation in HGSOC cells derived from metastatic omental tumor tissues. Enforced expression of miR-33b abrogates the oncogenic properties of ovarian cancer cells cocultured in omental conditioned medium (OCM), which mimics the ascites microenvironment, and in vivo tumor growth. Of note, restoration of miR-33b inhibited OCM-upregulated de novo lipogenesis and fatty acid ß-oxidation in ovarian cancer cells, indicating that miR-33b may play a novel tumor suppressor role in the lipid-mediated oncogenic properties of metastatic ovarian cancer cells found in the omentum. Mechanistic studies demonstrated that miR-33b directly targets transforming growth factor beta-activated kinase 1 (TAK1), thereby suppressing the activities of fatty acid synthase (FASN) and carnitine palmitoyltransferase 1A (CPT1A) in modulating lipid metabolic activities and simultaneously inhibiting the phosphorylation of NF-κB signaling to govern the oncogenic behaviors of ovarian cancer cells. Thus, our data suggest that a lipid-rich microenvironment may cause epigenetic silencing of miR-33b, which negatively modulates ovarian cancer peritoneal metastases, at least in part, by suppressing TAK1/FASN/CPT1A/NF-κB signaling.

The Stress-Inducible BCL2A1 Is Required for Ovarian Cancer Metastatic Progression in the Peritoneal Microenvironment.

Emerging evidence indicates that hypoxia plays a critical role in governing the transcoelomic metastasis of ovarian cancer. Hence, targeting hypoxia may be a promising approach to prevent the metastasis of ovarian cancer. Here, we report that BCL2A1, a BCL2 family member, acts as a hypoxia-inducible gene for promoting tumor progression in ovarian cancer peritoneal metastases. We demonstrated that BCL2A1 was induced not only by hypoxia but also other physiological stresses through NF-κB signaling and then was gradually reduced by the ubiquitin-proteasome pathway in ascites-derived ovarian cancer cells. The upregulated BCL2A1 was frequently found in advanced metastatic ovarian cancer cells, suggesting its clinical relevance in ovarian cancer metastatic progression. Functionally, BCL2A1 enhanced the foci formation ability of ovarian cancer cells in a stress-conditioned medium, colony formation in an ex vivo omental tumor model, and tumor dissemination in vivo. Under stress conditions, BCL2A1 accumulated and colocalized with mitochondria to suppress intrinsic cell apoptosis by interacting with the BH3-only subfamily BCL2 members HRK/BAD/BID in ovarian cancer cells. These findings indicate that BCL2A1 is an early response factor that maintains the survival of ovarian cancer cells in the harsh tumor microenvironment.

Germline PALB2 Mutation in High-Risk Chinese Breast and/or Ovarian Cancer Patients.

The prevalence of the PALB2 mutation in breast cancer varies across different ethnic groups; hence, it is of intense interest to evaluate the cancer risk and clinical association of the PALB2 mutation in Chinese breast and/or ovarian cancer patients. We performed sequencing with a 6-gene test panel (BRCA1, BRCA2, TP53, PTEN, PALB2, and CDH1) to identify the prevalence of the PALB2 germline mutation among 2631 patients with breast and/or ovarian cancer. In this cohort, 39 mutations were identified with 24 types of mutation variants, where the majority of the mutations were frame-shift mutations and resulted in early termination. We also identified seven novel PALB2 mutations. Most of the PALB2 mutation carriers had breast cancer (36, 92.3%) and were more likely to have family history of breast cancer (19, 48.7%). The majority of the breast tumors were invasive ductal carcinoma (NOS type) (34, 81.0%) and hormonal positive (ER: 32, 84.2%; PR: 23, 60.5%). Pathogenic mutations of PALB2 were found in 39 probands with a mutation frequency of 1.6% and 1% in breast cancer and ovarian cancer patients, respectively. PALB2 mutation carriers were more likely have hormonal positive tumors and were likely to have familial aggregation of breast cancer.