Anti-tumorigenic and Platinum-Sensitizing Effects of Apolipoprotein A1 and Apolipoprotein A1 Mimetic Peptides in Ovarian Cancer

Objective: Apolipoprotein A1 (ApoA1) is remarkably decreased in serum and ovarian tissues of ovarian cancer patients. ApoA1 and ApoA1 mimetic peptides can sequestrate pro-inflammatory phospholipids, some of which are known to activate a variety of oncogenic pathways. Besides, more intrinsic anti-tumorigenic properties, independent from interaction with lipids, have also been described for ApoA1. We aimed to disclose the effects of ApoA1 and a mimetic peptide on the malignant phenotype of ovarian cancer cells, particularly regarding cell viability, invasiveness and platinum sensitization. Methods: Cells viability was assessed by MTS assay. Extracellular matrix invasion was assessed by transwell and spheroid invasion assays. Western blotting was performed to evaluate the effect of test compounds on intracellular pathways. Sensitization assays were performed in vitro and in the biologically relevant in ovo chorioallantoic membrane model. Results: Both ApoA1 and the mimetic peptide, at a concentration of 100 μg/mL, were able to decrease the viability of SKOV3, CAOV3, and OVCAR3 cells (p 0.05). ApoA1 decreased SKOV3 cells invasiveness at 300 μg/mL after 72 and 96 h of exposure (p < 0.05), while the ApoA1 mimetic peptide prevented cell invasion at 50 and 100 μg/mL (p < 0.01). Treatment with 100 μg/mL of ApoA1 mimetic peptide decreased Akt phosphorylation in SKOV3 cells (p < 0.01). Accordingly, treatment with increasing concentrations of the peptide sensitized SKOV3, OVCAR3 and CAOV3 cells to cisplatin. This synergistic effect was observed both in vitro and in ovo. Conclusions: These results support the role of ApoA1 and ApoA1 mimetics as suppressors of ovarian tumorigenesis and as chemosensitising agents.publishersversionpublishe

Inactivating mutations and X-ray crystal structure of the tumor suppressor OPCML reveal cancer-associated functions

OPCML, a tumor suppressor gene, is frequently silenced epigenetically in ovarian and other cancers. Here we report, by analysis of databases of tumor sequences, the observation of OPCML somatic missense mutations from various tumor types and the impact of these mutations on OPCML function, by solving the X-ray crystal structure of this glycoprotein to 2.65 A resolution. OPCML consists of an extended arrangement of three immunoglobulin-like domains and homodimerizes via a network of contacts between membrane-distal domains. We report the generation of a panel of OPCML variants with representative clinical mutations and demonstrate clear phenotypic effects in vitro and in vivo including changes to anchorage-independent growth, interaction with activated cognate receptor tyrosine kinases, cellular migration, invasion in vitro and tumor growth in vivo. Our results suggest that clinically occurring somatic missense mutations in OPCML have the potential to contribute to tumorigenesis in a variety of cancers

Adiposity and cancer at major anatomical sites: umbrella review of the literature

Objective To evaluate the strength and validity of the evidence for the association between adiposity and risk of developing or dying from cancer. Design Umbrella review of systematic reviews and metaanalyses. Data sources PubMed, Embase, Cochrane Database of Systematic Reviews, and manual screening of retrieved references. Eligibility criteria Systematic reviews or meta-analyses of observational studies that evaluated the association between indices of adiposity and risk of developing or dying from cancer. Data synthesis Primary analysis focused on cohort studies exploring associations for continuous measures of adiposity. The evidence was graded into strong, highly suggestive, suggestive, or weak after applying criteria that included the statistical significance of the random effects summary estimate and of the largest study in a meta-analysis, the number of cancer cases, heterogeneity between studies, 95% prediction intervals, small study effects, excess significance bias, and sensitivity analysis with credibility ceilings. Results 204 meta-analyses investigated associations between seven indices of adiposity and developing or dying from 36 primary cancers and their subtypes. Of the 95 meta-analyses that included cohort studies and used a continuous scale to measure adiposity, only 12 (13%) associations for nine cancers were supported by strong evidence. An increase in body mass index was associated with a higher risk of developing oesophageal adenocarcinoma; colon and rectal cancer in men; biliary tract system and pancreatic cancer; endometrial cancer in premenopausal women; kidney cancer; and multiple myeloma. Weight gain and waist to hip circumference ratio were associated with higher risks of postmenopausal breast cancer in women who have never used hormone replacement therapy and endometrial cancer, respectively. The increase in the risk of developing cancer for every 5 kg/m2 increase in body mass index ranged from 9% (relative risk 1.09, 95% confidence interval 1.06 to 1.13) for rectal cancer among men to 56% (1.56, 1.34 to 1.81) for biliary tract system cancer. The risk of postmenopausal breast cancer among women who have never used HRT increased by 11% for each 5 kg of weight gain in adulthood (1.11, 1.09 to 1.13), and the risk of endometrial cancer increased by 21% for each 0.1 increase in waist to hip ratio (1.21, 1.13 to 1.29). Five additional associations were supported by strong evidence when categorical measures of adiposity were included: weight gain with colorectal cancer; body mass index with gallbladder, gastric cardia, and ovarian cancer; and multiple myeloma mortality. Conclusions Although the association of adiposity with cancer risk has been extensively studied, associations for only 11 cancers (oesophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney) were supported by strong evidence. Other associations could be genuine, but substantial uncertainty remains. Obesity is becoming one of the biggest problems in public health; evidence on the strength of the associated risks may allow finer selection of those at higher risk of cancer, who could be targeted for personalised prevention strategies

Clinical value of bioelectrical properties of cancerous tissue in advanced epithelial ovarian cancer patients

Currently, there are no valid pre-operatively established biomarkers or algorithms that can accurately predict surgical and clinical outcome for patients with advanced epithelial ovarian cancer (EOC). In this study, we suggest that profiling of tumour parameters such as bioelectrical-potential and metabolites, detectable by electronic sensors, could facilitate the future development of devices to better monitor disease and predict surgical and treatment outcomes. Biopotential was recorded, using a potentiometric measurement system, in ex vivo paired non-cancerous and cancerous omental tissues from advanced stage EOC (n = 36), and lysates collected for metabolite measurement by microdialysis. Consistently different biopotential values were detected in cancerous tissue versus non-cancerous tissue across all cases (p < 0.001). High tumour biopotential levels correlated with advanced tumour stage (p = 0.048) and tumour load, and negatively correlated with stroma. Within our EOC cohort and specifically the high-grade serous subtype, low biopotential levels associated with poorer progression-free survival (p = 0.0179, p = 0.0143 respectively). Changes in biopotential levels significantly correlated with common apoptosis related pathways. Lactate and glucose levels measured in paired tissues showed significantly higher lactate/glucose ratio in tissues with low biopotential (p < 0.01, n = 12). Our study proposes the feasibility of biopotential and metabolite monitoring as a biomarker modality profiling EOC to predict surgical and clinical outcomes

The RNA binding protein Larp1 regulates cell division, apoptosis and cell migration.

The RNA binding protein Larp1 was originally shown to be involved in spermatogenesis, embryogenesis and cell-cycle progression in Drosophila. Our data show that mammalian Larp1 is found in a complex with poly A binding protein and eukaryote initiation factor 4E and is associated with 60S and 80S ribosomal subunits. A reduction in Larp1 expression by siRNA inhibits global protein synthesis rates and results in mitotic arrest and delayed cell migration. Consistent with these data we show that Larp1 protein is present at the leading edge of migrating cells and interacts directly with cytoskeletal components. Taken together, these data suggest a role for Larp1 in facilitating the synthesis of proteins required for cellular remodelling and migration

Anti-tumorigenic and Platinum-Sensitizing Effects of Apolipoprotein A1 and Apolipoprotein A1 Mimetic Peptides in Ovarian Cancer

Objective: Apolipoprotein A1 (ApoA1) is remarkably decreased in serum and ovarian tissues of ovarian cancer patients. ApoA1 and ApoA1 mimetic peptides can sequestrate pro-inflammatory phospholipids, some of which are known to activate a variety of oncogenic pathways. Besides, more intrinsic anti-tumorigenic properties, independent from interaction with lipids, have also been described for ApoA1. We aimed to disclose the effects of ApoA1 and a mimetic peptide on the malignant phenotype of ovarian cancer cells, particularly regarding cell viability, invasiveness and platinum sensitization.Methods: Cells viability was assessed by MTS assay. Extracellular matrix invasion was assessed by transwell and spheroid invasion assays. Western blotting was performed to evaluate the effect of test compounds on intracellular pathways. Sensitization assays were performed in vitro and in the biologically relevant in ovo chorioallantoic membrane model.Results: Both ApoA1 and the mimetic peptide, at a concentration of 100 μg/mL, were able to decrease the viability of SKOV3, CAOV3, and OVCAR3 cells (p &lt; 0.05). The peptide at this concentration was not able to affect the viability of immortalized non-neoplastic ovarian cells (p &gt; 0.05). ApoA1 decreased SKOV3 cells invasiveness at 300 μg/mL after 72 and 96 h of exposure (p &lt; 0.05), while the ApoA1 mimetic peptide prevented cell invasion at 50 and 100 μg/mL (p &lt; 0.01). Treatment with 100 μg/mL of ApoA1 mimetic peptide decreased Akt phosphorylation in SKOV3 cells (p &lt; 0.01). Accordingly, treatment with increasing concentrations of the peptide sensitized SKOV3, OVCAR3 and CAOV3 cells to cisplatin. This synergistic effect was observed both in vitro and in ovo.Conclusions: These results support the role of ApoA1 and ApoA1 mimetics as suppressors of ovarian tumorigenesis and as chemo-sensitising agents

Exploring the clonal evolution of CD133/aldehyde-dehydrogenase-1 (ALDH1)-positive cancer stem-like cells from primary to recurrent high-grade serous ovarian cancer (HGSOC). A study of the Ovarian Cancer Therapy–Innovative Models Prolong Survival (OCTIPS) Consortium

Background High-grade serous ovarian cancer (HGSOC) causes 80% of all ovarian cancer (OC) deaths. In this setting, the role of cancer stem-like cells (CSCs) is still unclear. In particular, the evolution of CSC biomarkers from primary (pOC) to recurrent (rOC) HGSOCs is unknown. Aim of this study was to investigate changes in CD133 and aldehyde dehydrogenase-1 (ALDH1) CSC biomarker expression in pOC and rOC HGSOCs. Methods Two-hundred and twenty-four pOC and rOC intrapatient paired tissue samples derived from 112 HGSOC patients were evaluated for CD133 and ALDH1 expression using immunohistochemistry (IHC); pOCs and rOCs were compared for CD133 and/or ALDH1 levels. Expression profiles were also correlated with patients' clinicopathological and survival data. Results Some 49.1% of the patient population (55/112) and 37.5% (42/112) pOCs were CD133+ and ALDH1+ respectively. CD133+ and ALDH1+ samples were detected in 33.9% (38/112) and 36.6% (41/112) rOCs. CD133/ALDH1 coexpression was observed in 23.2% (26/112) and 15.2% (17/112) of pOCs and rOCs respectively. Pairwise analysis showed a significant shift of CD133 staining from higher (pOCs) to lower expression levels (rOCs) (p < 0.0001). Furthermore, all CD133 + pOC patients were International Federation of Gynaecology and Obstetrics (FIGO)-stage III/IV (p < 0.0001) and had significantly worse progression-free interval (PFI) (p = 0.04) and overall survival (OS) (p = 0.02). On multivariate analysis, CD133/ALDH1 coexpression in pOCs was identified as independent prognostic factor for PFI (HR: 1.64; 95% CI: 1.03–2.60; p = 0.036) and OS (HR: 1.71; 95% CI: 1.01–2.88; p = 0.045). Analysis on 52 pts patients with known somatic BRCA status revealed that BRCA mutations did not influence CSC biomarker expression. Conclusions The study showed that CD133/ALDH1 expression impacts HGSOC patients' survival and first suggests that CSCs might undergo phenotypic change during the disease course similarly to non stem-like cancer cells, providing also a first evidence that there is no correlation between CSCs and BRCA status

Impact of BRCA Mutation Status on Tumor Dissemination Pattern, Surgical Outcome and Patient Survival in Primary and Recurrent High-Grade Serous Ovarian Cancer:A Multicenter Retrospective Study by the Ovarian Cancer Therapy-Innovative Models Prolong Survival (OCTIPS) Consortium

Background: This study seeks to evaluate the impact of breast cancer (BRCA) gene status on tumor dissemination pattern, surgical outcome and survival in a multicenter cohort of paired primary ovarian cancer (pOC) and recurrent ovarian cancer (rOC). Patients and Methods: Medical records and follow-up data from 190 patients were gathered retrospectively. All patients had surgery at pOC and at least one further rOC surgery at four European high-volume centers. Patients were divided into one cohort with confirmed mutation for BRCA1 and/or BRCA2 (BRCAmut) and a second cohort with BRCA wild type or unknown (BRCAwt). Patterns of tumor presentation, surgical outcome and survival data were analyzed between the two groups. Results: Patients with BRCAmut disease were on average 4 years younger and had significantly more tumor involvement upon diagnosis. Patients with BRCAmut disease showed higher debulking rates at all stages. Multivariate analysis showed that only patient age had significant predictive value for complete tumor resection in pOC. At rOC, however, only BRCAmut status significantly correlated with optimal debulking. Patients with BRCAmut disease showed significantly prolonged overall survival (OS) by 24.3 months. Progression-free survival (PFS) was prolonged in the BRCAmut group at all stages as well, reaching statistical significance during recurrence. Conclusions: Patients with BRCAmut disease showed a more aggressive course of disease with earlier onset and more extensive tumor dissemination at pOC. However, surgical outcome and OS were significantly better in patients with BRCAmut disease compared with patients with BRCAwt disease. We therefore propose to consider BRCAmut status in regard to patient selection for cytoreductive surgery, especially in rOC