Metabolic Changes in Ovarian Cancer最新文献

{"title":"Abstract A41: Ovarian cancer as an infectious disease. Targeting of mitochondrial activity to prevent and treat recurrent ovarian cancer","authors":"M. Bazzaro","doi":"10.1158/1557-3265.OVCA17-A41","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A41","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85804204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A20: Claudin-4 regulates ovarian tumor cell response to the microenvironment","authors":"D. Hicks, C. Breed, Patricia G. Webb, K. Neal, K. Behbakht, H. Baumgartner","doi":"10.1158/1557-3265.OVCA17-A20","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A20","url":null,"abstract":"Interaction of tumor cells with extracellular matrix proteins of the peritoneal lining plays a critical role in the unique metastatic process of ovarian cancer. Although peritoneal attachment is known to be a key step in the progression of ovarian cancer, the underlying molecular mechanisms driving adhesion and the downstream changes in cell behavior that lead to poor treatment outcomes are not well understood. The objective of this study was to investigate the potential role of the transmembrane protein claudin-4 in regulating ovarian tumor cell interaction with and response to extracellular matrix proteins. Adhesion, apoptosis (cleaved caspase-3), proliferation (DNA content), and scratch assays were performed with ovarian tumor cells (OVCAR3, PEO4) cultured on different proteins found in the extracellular matrix of the peritoneal mesothelium (type I collagen, type IV collagen, fibronectin, and laminin) or a nonphysiologic cell adhesive (Cell-Tak). Number of cells attached within one hour, percent cells positive for apoptosis at 24 hours post treatment, cell number over time, and percent wound closure at 8 hours was measured in response to claudin-4 disruption (DFYNP mimic peptide) or loss of claudin-4 expression (shRNA-mediated gene silencing). Immunofluorescence of phosphorylated focal adhesion kinase (pFAK) was performed to examine formation of focal adhesions in response to claudin-4 disruption or loss of expression. Proximity ligation assays, immunoprecipitation, and immunofluorescence were performed to examine interaction of claudin-4 with tubulin. Results from these studies showed that ovarian tumor cells preferentially attach to type I collagen compared to the other matrix proteins and that disruption of claudin-4 inhibited this attachment. Attachment to type I collagen made tumor cells more resistant to apoptosis, more proliferative, and more migratory compared to tumor cells cultured on the other matrix proteins. In the presence of type I collagen, disruption of claudin-4 restored tumor cell apoptotic response to paclitaxel, induced mitotic arrest, reduced proliferation rate, and inhibited migration. The size of pFAK-containing focal adhesions was significantly smaller and fewer adhesions were present in ovarian tumor cells cultured on type I collagen treated with the claudin-4 disrupting peptide or with loss of claudin-4 expression compared to cells that express high levels of claudin-4. Additionally, we observed a direct interaction of claudin-4 with both alpha and beta tubulin that was dependent on stage of cell cycle. In conclusion, we have demonstrated a novel role for claudin-4 in regulating ovarian tumor cell response to the tumor microenvironment to promote tumor survival and growth. These observations have important therapeutic implications for inhibiting the survival and deadly spread of ovarian tumors through blocking the biologic activity of claudin-4. Citation Format: Douglas A. Hicks, Christopher Breed, Patricia G. Webb, ","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"1 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91485198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A56: Development of a cloud-based machine learning system (CLOBNET) to predict platinum resistance in high-grade serous ovarian cancer","authors":"Veli-Matti Isoviita, Liina Salminen, Jimmy Azar, J. Hynninen, R. Lehtonen, Pia Röring, S. Grénman, A. Färkkilä, S. Hautaniemi","doi":"10.1158/1557-3265.ovca17-a56","DOIUrl":"https://doi.org/10.1158/1557-3265.ovca17-a56","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87018463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A37: Epigenetic modification of ovarian cancer immunogenicity","authors":"P. Spiliopoulou, J. Walton, Suzanne Dowson, Alexander W. D. Binks, O. Maddocks, P. Adams, I. McNeish","doi":"10.1158/1557-3265.ovca17-a37","DOIUrl":"https://doi.org/10.1158/1557-3265.ovca17-a37","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87021915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A45: Treatment patterns and outcomes among platinum-refractory/resistant ovarian cancer patients","authors":"R. Parikh, S. Kurosky, M. Udall, Jane Chang, J. Cappelleri, J. Doherty, J. Kaye","doi":"10.1158/1557-3265.OVCA17-A45","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A45","url":null,"abstract":"Background: Real-world evidence on current treatment patterns and outcomes is limited for patients with platinum-refractory/resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (PRROC). This study aimed to describe the treatment patterns and outcomes of patients with PRROC in the United States (US), the United Kingdom (UK), and Canada (CA). Methods: Physicians retrospectively reviewed medical records of females aged ≥18 years diagnosed with PRROC from January 2010 to June 2014. Follow-up data available through October 2016 were extracted. Patient characteristics, initial PRROC treatment regimens, and associated health care utilization were assessed descriptively; clinical outcomes were estimated using the Kaplan-Meier and Cox proportional-hazards methods. Results: Data were obtained on 392 US, 296 UK, and 82 CA patients. At initial diagnosis of epithelial ovarian, fallopian tube, or peritoneal cancer, 65.8% (US), 93.3% (UK), and 82.9% (CA) of patients had stage III/IV disease and 43.6% (US), 73.7% (UK), and 56.1% (CA) had high-grade tumors. Most patients were diagnosed with PRROC in 2013 or 2014 (US: 64.8%, UK: 72.3%, CA: 64.6%) and mean age at PRROC diagnosis was 57 years in the US and CA and 59 years in the UK. The proportion of patients with ECOG performance status (PS) ≤1 at PRROC diagnosis was 57.7% in the US, 80.1% in the UK, and 36.6% in CA. Most patients received systemic treatment after PRROC diagnosis (US 71.4%; UK 83.1%; CA 81.7%). Most of the patients received only one treatment line at the time of extraction (US: 64.3%, UK: 75.6%, CA: 70.2%). Bevacizumab ± chemotherapy (US 41.4%; UK 12.6%; CA 35.8%) and pegylated liposomal doxorubicin (PLD) monotherapy (US 18.6%; UK 50.0%; CA 34.3%) were the most common initial therapies. Common subsequent treatments varied between the countries, including topotecan, gemcitabine, PLD, paclitaxel. During initial treatment for PRROC, 80.7%, 59.8%, and 44.8% of patients had at least one office visit and 18.9%, 7.3%, and 19.4% of patients had at least one emergency department visit in the US, UK, and CA, respectively. Hospitalizations during initial treatment for PRROC were observed among 17.5% of patients in the US, 10.2% in the UK, and 14.9% in CA. Treatment toxicity was the most common reason for hospitalization (US 75.5%; UK 64.0%; CA 80.0%). Median progression-free survival (PFS; 95% confidence interval) was 6.4 (5.4-9.3), 8.0 (6.8-9.2), and 5.6 (4.9-6.2) months in the US, UK, and CA, respectively. The Cox proportional-hazards model showed that stage III/IV, high-grade tumors, and poorer PS were associated with shorter survival. Conclusions: Even though bevacizumab ± chemotherapy and PLD were the most common initial PRROC treatments in the three countries, relatively higher utilization of bevacizumab ± chemotherapy was observed in the US and CA than the UK, plausibly due to lack of bevacizumab reimbursement in the UK for the treatment of PRROC. Limited PFS and a high prevalence","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"79 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89539464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A29: Effects of lysophosphatidic acid on ovarian cancer metastatic dissemination","authors":"Y. Klymenko, Brandi Bos, L. Campbell, Elizabeth A. Loughran, Yueying Liu, Oleg Kim, K. Nephew, M. Stack","doi":"10.1158/1557-3265.OVCA17-A29","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A29","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81060743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A25: Tissue transglutaminase interacts with Frizzled 7 in ovarian cancer stem cells","authors":"S. Condello, L. Sima, C. Ivan, H. Cardenas, G. Schiltz, Rama K. Mishra, D. Matei","doi":"10.1158/1557-3265.OVCA17-A25","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A25","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88933764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A61: Ascites-derived and tissue-derived ovarian cancer cell primary 3D cultures aimed for personalized medicine","authors":"Y. Nanki, A. Hirasawa, H. Nomura, A. Okubo, Manabu Itoh, T. Akahane, T. Chiyoda, F. Kataoka, E. Tominaga, D. Aoki","doi":"10.1158/1557-3265.OVCA17-A61","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A61","url":null,"abstract":"Objective: Ovarian cancer is a poor-prognosis gynecologic disease with over 220,000 diagnoses each year worldwide and a 5-year survival rate less than 40%. In this study, we present a method for isolation and characterization of ovarian cancer cells from patient-derived ascites and tissue samples by using three-dimensional (3D) cell culture. Materials and Methods: Ascites and tissue samples were obtained from primary ovarian, peritoneal, and fallopian tube cancer patients intraoperatively. Samples were isolated and cultured within 6 hours after collection. After isolation, cells were resuspended in Matrigel and were placed at the center of each well. Optimized medium is added to each well. NanoCulture Plate LH96 (Low-Binding, MH pattern, 96-wells, Medical and Biological Laboratories Co., Ltd., Japan) were used for 3D cell culture. Plates were incubated at 37°C. The cultures were examined for metabolically active cells by ATP assay and medium changed on days 0, 1, 4, 7, 10, and 14. Results: We successfully obtained ascites-derived primary cell cultures within 1-7 days from 100% (3/31) of the ascites samples and 62% (5/8) from tissue-derived primary cell cultures. Spheroids-like structures were formed in 30% (1/3) of ascites samples and 50% (4/8) of tissue samples. The tumorigenicity and invasiveness of the cells were demonstrated using new 3D spheroid model cultured in vitro by NanoCulture Plate LH96. Conclusion: Primary ascites and tissue culture of ovarian cancer cells can successfully be cultured by 3D cell culture plates. We may apply this method for drug sensitivity testing; therefore, 3D cell culture has a potential to evaluate the sensitivity of candidate chemotherapeutic drug for individual patients. Citation Format: Yoshiko Nanki, Akira Hirasawa, Hiroyuki Nomura, Aki Okubo, Manabu Itoh, Tomoko Akahane, Tatsuyuki Chiyoda, Fumio Kataoka, Eiichiro Tominaga, Daisuke Aoki. Ascites-derived and tissue-derived ovarian cancer cell primary 3D cultures aimed for personalized medicine. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A61.","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"295 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79227247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A32: Single-cell RNA-seq analysis of primary tumor and corresponding metastatic lesion in high-grade serous ovarian cancer","authors":"A. Shih, A. Menzin, J. Whyte, J. Lovecchio, A. Liew, H. Khalili, K. Onel, P. Gregersen, Annette Lee","doi":"10.1158/1557-3265.OVCA17-A32","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A32","url":null,"abstract":"Ovarian cancer is highly curable when diagnosed early as localized disease. Most women come to medical attention, however, with metastatic disease. For these women, cure rates are quite low; only 30% of patients with late-stage high-grade serous ovarian cancer (HGSOC) will live more than 5 years. Although initially sensitive to platinum-based chemotherapy, in most cases, drug resistance develops and a progressive disease course ensues. Therefore, in order to improve prognosis and overall survival, there is an urgent need to understand the basis of drug resistance and to identify new therapeutic targets. Previous studies have stressed the significant role that tumor heterogeneity and microenvironment have in clinical outcome. It is our goal to understand the genomics of metastatic lesions as compared to primary lesions, to identify the genetic drivers of metastasis and drug resistance, which we can then functionally investigate in order to develop novel therapies. Corresponding primary and metastatic tumor tissue samples from women with HGSOC were analyzed by single-cell RNA-seq. Isolated cells from each paired tissue sample were processed for next-gen sequencing using the BioRad droplet digital SEQ Single Cell Isolator and the Illumina SureCell Whole Transcriptome Analysis 3’ library prep kit, Normalization of expression, clustering of cells and gene expression markers defining each cluster was done by using the Seurat package in R. To identify specific tumor cell subsets in intra- and inter-patient analyses, a graph-based clustering using the principal components of the most variable expressed genes and T-distributed stochastic neighbor embedding (tSNE) analyses was performed. Overall, we have found that while there is considerable heterogeneity among primary tumor cells from different patients, the expression profiles of metastatic lesions from different patients are remarkably similar, and are distinct from the primary lesions. As one example, by single-cell RNA-seq paired analysis of HGSOC primary tumor and corresponding metastatic lesions from 2 patients (primary fallopian and primary ovarian), we identified several cell clusters based on gene expression of common cellular markers. Further analysis identified significant expression of CD24, EPCAM, and KRT18 in epithelial cells of primary tumors while elevated CD44 expression was found in the T and B cell clusters of the metastatic lesions. Published studies have suggested elevated CD44 as a prognostic marker of poor overall survival. Whether elevated CD44 expression influences survival in our patients remains to be determined since clinical response data are not yet available. Additional analysis of gene expression profiles in other cell clusters is in progress. Our ability to study patient-derived primary tumor and corresponding metastatic lesions using high-throughput single-cell analysis represents an unprecedented unique opportunity to study ovarian cancer without a priori knowledge of t","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73779939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A23: Neuropilin-1 expression on regulatory T cells in ovarian cancer","authors":"A. Cillo, T. Bruno, F. Modugno, R. Edwards, D. Vignali","doi":"10.1158/1557-3265.OVCA17-A23","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A23","url":null,"abstract":"Introduction: Regulatory T cells (Treg) are a subpopulation of CD4+ T cells that suppress autoimmune responses, but also prevent clearance of tumors and chronic viral infections. In ovarian cancer, a higher frequency of tumor-infiltrating Treg is associated with poor prognosis, but insights into the mechanisms governing the survival and suppressive activity of Treg in this context are limited. Our group has recently described a signaling axis through neurophilin-1 (NRP1) on Treg in murine models of cancer that promotes the survival and suppressive function of Treg. Genetic knockout of NRP1 on murine Treg leads to reduced tumor growth and increased survival, underscoring the importance of NRP1+ Treg in suppressing antitumor immunity. Given the importance of NRP1+ Treg in murine cancer models, we sought to explore the expression pattern of NRP1 on tumor-infiltrating Treg from patients with ovarian cancer. Materials and Methods: Ovarian tumors were obtained through the health sciences tissue bank at the University of Pittsburgh, and ovarian ascites fluid was obtained through Magee Women’s Research Institute. Peripheral blood was obtained from healthy donors through the Red Cross. Peripheral blood mononuclear cells (PBMC) were isolated by density gradient centrifugation, and tumor-infiltrating lymphocytes were isolated by first mechanically disrupting the tumor, followed by treatment for 15 minutes at 37°C with 50 ug/mL Liberase DL. For flow cytometric analysis of Treg, cells from blood and tumors were first stained for surface markers, followed by live/dead discrimination, fixation and permeabilization, and staining for intracellular markers. Cells were analyzed on an LSR Fortessa at the Hillman Cancer Center Flow Core. For functional assays, Treg were selected from ascites fluid and assayed for their ability to suppressive naive CD8+ T cells ex vivo. Wilcoxon rank sum tests were used to assess differences between groups, and a two-sided alpha less than 5% was considered significant. Results: A total of 12 healthy donors and 20 ovarian cancer patients were studied. Intracellular and surface NRP1 expression was assessed by flow cytometry on CD4+CD25+FOXP3+ Treg from healthy donor peripheral blood and tumor-infiltrating lymphocytes from either ovarian cancer tumors or ascites fluid from patients with ovarian cancer. Intracellular NRP1 was expressed on a median of 1.8% (interquartile range [IQR]: 0.69% to 4.8%) of Treg from healthy donors compared with a median of 66% (IQR: 28% to 90%; p Conclusions and Future Directions: Both intracellular and surface NRP1 are expressed more frequently on tumor-infiltrating Treg and Treg from ascites fluid compared to Treg from healthy donor peripheral blood. Although the number of patients currently included in this study is small, there was also evidence that intracellular NRP1 expression on Treg was higher on malignant compared with benign tissue. Additionally, Treg from ascites fluid were capable of suppressing CD","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"97 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89915502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}