Pub Date : 2018-08-01DOI: 10.1158/1557-3265.OVCA17-A28
H. Kenny, Madhu Lal, M. Shen, Betul Kara, Chun-Yi Chiang, K. Watters, Peter C. Hart, M. Ferrer, E. Lengyel
{"title":"Abstract A28: Beta-escin inhibits ovarian cancer metastasis by targeting the tumor microenvironment","authors":"H. Kenny, Madhu Lal, M. Shen, Betul Kara, Chun-Yi Chiang, K. Watters, Peter C. Hart, M. Ferrer, E. Lengyel","doi":"10.1158/1557-3265.OVCA17-A28","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A28","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74116975","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}
Pub Date : 2018-08-01DOI: 10.1158/1557-3265.OVCA17-A57
P. Roering, Piia Mikkonen, S. Potdar, K. Wennerberg, J. Hynninen, S. Grénman, A. Auranen, O. Carpén, Katja Kaipio
{"title":"Abstract A57: Drug sensitivity and resistance testing (DSRT) of clinically important compounds on primary ovarian cancer cell lines","authors":"P. Roering, Piia Mikkonen, S. Potdar, K. Wennerberg, J. Hynninen, S. Grénman, A. Auranen, O. Carpén, Katja Kaipio","doi":"10.1158/1557-3265.OVCA17-A57","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A57","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81625273","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}
Pub Date : 2018-08-01DOI: 10.1158/1557-3265.OVCA17-A51
Pingping Fang, Jill A. Madden, Lisa Neums, J. Chien
{"title":"Abstract A51: FOXM1 inhibition by thiostrepton synergizes with olaparib by attenuating adaptive response in ovarian cancer cells","authors":"Pingping Fang, Jill A. Madden, Lisa Neums, J. Chien","doi":"10.1158/1557-3265.OVCA17-A51","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A51","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84384924","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}
Pub Date : 2018-08-01DOI: 10.1158/1557-3265.ovca17-a30
Sudeepti S. Kuppa, Balázs Rada, Mandi M. Murph
{"title":"Abstract A30: Autotaxin-induced miRNA exportation and associated mechanisms contributing to tumorigenesis and immune modulation","authors":"Sudeepti S. Kuppa, Balázs Rada, Mandi M. Murph","doi":"10.1158/1557-3265.ovca17-a30","DOIUrl":"https://doi.org/10.1158/1557-3265.ovca17-a30","url":null,"abstract":"","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":"87103928","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}
Pub Date : 2018-08-01DOI: 10.1158/1557-3265.OVCA17-PR06
R. Coleman, A. Oza, D. Lorusso, C. Aghajanian, A. Oaknin, A. Dean, N. Colombo, J. Weberpals, A. Clamp, G. Scambia, A. Leary, R. Holloway, D. O’Malley, T. Cameron, L. Maloney, S. Goble, K. Lin, James X. Sun, H. Giordano, J. Ledermann
Background: Rucaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved in the United States for treatment of women with deleterious BRCA mutation (germline and/or somatic) associated advanced OC who have been treated with two or more chemotherapies. Rucaparib has also demonstrated antitumor activity in the treatment setting in patients (pts) with BRCA wild-type associated recurrent OC whose tumor has high genomic loss of heterozygosity (LOH). ARIEL3 evaluated rucaparib vs placebo as maintenance treatment in pts with recurrent platinum-sensitive OC. Methods: Eligible pts received ≥2 prior platinum-based therapies, had platinum-sensitive OC (disease progression ≥6 mo after penultimate platinum), and achieved a complete response (RECIST v1.1) or partial response (RECIST v1.1 or Gynecologic Cancer InterGroup CA-125 criteria) to their most recent platinum. All pts were required to have CA-125 less than the upper limit of normal. Pts were randomized 2:1 to receive oral rucaparib 600 mg BID or placebo. Investigator-assessed progression-free survival (PFS) (primary endpoint) was assessed in a step-down procedure for 3 nested cohorts: (1) BRCA mutant (deleterious germline or somatic BRCA mutation); (2) homologous recombination deficient (HRD) (BRCA mutant or BRCA wild type/LOH high); and (3) intent-to-treat (ITT) population. PFS was also assessed by blinded independent central review (BICR) (secondary endpoint) and LOH status in pts with BRCA wild type OC (exploratory endpoint). Adverse events (AEs) were summarized descriptively. Results: ARIEL3 enrolled 564 pts (375, rucaparib; 189, placebo). Nearly 200 pts (n=196) had BRCA mutation-associated OC. Of these pts, 130 had a germline BRCA mutation (82 [21.9%], rucaparib; 48 [25.4%], placebo), 56 had a somatic BRCA mutation (40 [10.7%], rucaparib; 16 [8.5%], placebo), and 10 pts had tumors with germline and/or somatic BRCA status unknown (8 [2.1%], rucaparib; 2 [1.1%], placebo). Median investigator-assessed PFS in the BRCA-mutant cohort (130, rucaparib; 66 placebo) was 16.6 mo vs 5.4 mo (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.16-0.34; P Conclusion: Rucaparib significantly improved PFS vs placebo in pts with platinum-sensitive, recurrent OC in all primary analysis groups of pts with platinum-sensitive, recurrent OC. Additionally, rucaparib significantly improved PFS vs placebo in pts with BRCA wild-type OC (LOH high and LOH low). Clinical trial identification: NCT01968213. This abstract is also being presented as Poster A47. Citation Format: Robert L. Coleman, Amit M. Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Johanne I. Weberpals, Andrew Clamp, Giovanni Scambia, Alexandra Leary, Robert W. Holloway, David M. O’Malley, Terri Cameron, Lara Maloney, Sandra Goble, Kevin Lin, James Sun, Heidi Giordano, Jonathan A. Ledermann. ARIEL3: A phase 3, randomized, double-blind study of rucaparib vs placebo following response to platinum-based chemothera
背景:Rucaparib是一种聚(adp -核糖)聚合酶(PARP)抑制剂，在美国被批准用于治疗接受两种或两种以上化疗的女性有害BRCA突变(种系和/或体细胞)相关晚期卵巢癌。Rucaparib在BRCA野生型相关复发性OC患者(pts)的治疗环境中也显示出抗肿瘤活性，这些患者的肿瘤具有高基因组杂合性损失(LOH)。ARIEL3评估了鲁卡帕尼与安慰剂作为复发性铂敏感OC患者的维持治疗。方法:符合条件的患者接受了≥2次铂基治疗，患有铂敏感的OC(在第二次铂治疗后疾病进展≥6个月)，并且对他们最近的铂治疗达到完全缓解(RECIST v1.1)或部分缓解(RECIST v1.1或妇科癌症组间CA-125标准)。所有患者均要求CA-125低于正常值上限。患者按2:1随机分配，接受口服鲁卡帕尼600mg BID或安慰剂。研究者评估的无进展生存期(PFS)(主要终点)在3个嵌套队列的逐步下降过程中进行评估:(1)BRCA突变(有害的种系或体细胞BRCA突变);(2)同源重组缺陷(HRD) (BRCA突变型或BRCA野生型/LOH高);(3)意向治疗人群。还通过盲法独立中心评价(BICR)(次要终点)和BRCA野生型OC患者的LOH状态(探索性终点)来评估PFS。对不良事件(ae)进行描述性总结。结果:ARIEL3纳入564名患者(375名，rucaparib;189年,安慰剂)。近200名患者(n=196)患有BRCA突变相关的OC。在这些患者中，130例有种系BRCA突变(82例[21.9%]，rucaparib;48例[25.4%]，安慰剂)，56例有体细胞BRCA突变(40例[10.7%]，rucaparib;16例[8.5%]，安慰剂)，10例患者的肿瘤种系和/或躯体BRCA状态未知(8例[2.1%]，rucaparib;2例[1.1%]，安慰剂)。brca突变队列中研究者评估的PFS中位数(130,rucaparib;66安慰剂)为16.6个月vs 5.4个月(风险比[HR]， 0.23;95%置信区间[CI]， 0.16-0.34;结论:在铂敏感的复发性OC患者的所有主要分析组中，鲁卡帕尼与安慰剂相比显著改善了铂敏感的复发性OC患者的PFS。此外，与安慰剂相比，鲁卡帕尼显著改善了BRCA野生型OC患者的PFS (LOH高和LOH低)。临床试验鉴定:NCT01968213。此摘要也以海报A47的形式呈现。引文格式:Robert L. Coleman, Amit M. Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Johanne I. webpals, Andrew Clamp, Giovanni Scambia, Alexandra Leary, Robert M. Holloway, David M. O 'Malley, Terri Cameron, Lara Maloney, Sandra Goble, Kevin Lin, James Sun, Heidi Giordano, Jonathan A. Ledermann。ARIEL3:一项针对复发性卵巢癌(OC)铂基化疗反应的鲁卡帕尼与安慰剂的3期随机双盲研究。[摘要]。AACR会议论文集:解决卵巢癌研究和治疗中的关键问题;2017年10月1-4日;宾夕法尼亚州匹兹堡。费城(PA): AACR;临床癌症杂志，2018;24(15 -增刊):摘要nr PR06。
{"title":"Abstract PR06: ARIEL3: A phase 3, randomized, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian cancer (OC)","authors":"R. Coleman, A. Oza, D. Lorusso, C. Aghajanian, A. Oaknin, A. Dean, N. Colombo, J. Weberpals, A. Clamp, G. Scambia, A. Leary, R. Holloway, D. O’Malley, T. Cameron, L. Maloney, S. Goble, K. Lin, James X. Sun, H. Giordano, J. Ledermann","doi":"10.1158/1557-3265.OVCA17-PR06","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-PR06","url":null,"abstract":"Background: Rucaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved in the United States for treatment of women with deleterious BRCA mutation (germline and/or somatic) associated advanced OC who have been treated with two or more chemotherapies. Rucaparib has also demonstrated antitumor activity in the treatment setting in patients (pts) with BRCA wild-type associated recurrent OC whose tumor has high genomic loss of heterozygosity (LOH). ARIEL3 evaluated rucaparib vs placebo as maintenance treatment in pts with recurrent platinum-sensitive OC. Methods: Eligible pts received ≥2 prior platinum-based therapies, had platinum-sensitive OC (disease progression ≥6 mo after penultimate platinum), and achieved a complete response (RECIST v1.1) or partial response (RECIST v1.1 or Gynecologic Cancer InterGroup CA-125 criteria) to their most recent platinum. All pts were required to have CA-125 less than the upper limit of normal. Pts were randomized 2:1 to receive oral rucaparib 600 mg BID or placebo. Investigator-assessed progression-free survival (PFS) (primary endpoint) was assessed in a step-down procedure for 3 nested cohorts: (1) BRCA mutant (deleterious germline or somatic BRCA mutation); (2) homologous recombination deficient (HRD) (BRCA mutant or BRCA wild type/LOH high); and (3) intent-to-treat (ITT) population. PFS was also assessed by blinded independent central review (BICR) (secondary endpoint) and LOH status in pts with BRCA wild type OC (exploratory endpoint). Adverse events (AEs) were summarized descriptively. Results: ARIEL3 enrolled 564 pts (375, rucaparib; 189, placebo). Nearly 200 pts (n=196) had BRCA mutation-associated OC. Of these pts, 130 had a germline BRCA mutation (82 [21.9%], rucaparib; 48 [25.4%], placebo), 56 had a somatic BRCA mutation (40 [10.7%], rucaparib; 16 [8.5%], placebo), and 10 pts had tumors with germline and/or somatic BRCA status unknown (8 [2.1%], rucaparib; 2 [1.1%], placebo). Median investigator-assessed PFS in the BRCA-mutant cohort (130, rucaparib; 66 placebo) was 16.6 mo vs 5.4 mo (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.16-0.34; P Conclusion: Rucaparib significantly improved PFS vs placebo in pts with platinum-sensitive, recurrent OC in all primary analysis groups of pts with platinum-sensitive, recurrent OC. Additionally, rucaparib significantly improved PFS vs placebo in pts with BRCA wild-type OC (LOH high and LOH low). Clinical trial identification: NCT01968213. This abstract is also being presented as Poster A47. Citation Format: Robert L. Coleman, Amit M. Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Johanne I. Weberpals, Andrew Clamp, Giovanni Scambia, Alexandra Leary, Robert W. Holloway, David M. O’Malley, Terri Cameron, Lara Maloney, Sandra Goble, Kevin Lin, James Sun, Heidi Giordano, Jonathan A. Ledermann. ARIEL3: A phase 3, randomized, double-blind study of rucaparib vs placebo following response to platinum-based chemothera","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88878627","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}
Pub Date : 2018-08-01DOI: 10.1158/1557-3265.OVCA17-A38
Y. Klymenko, R. B. Wates, Yueying Liu, R. Lombard, Holly E. Weiss-Bilka, L. Campbell, D. Wagner, M. Ravosa, M. Stack
{"title":"Abstract A38: Modeling ascites-induced changes in peritoneal mechanobiology and ovarian cancer metastatic success","authors":"Y. Klymenko, R. B. Wates, Yueying Liu, R. Lombard, Holly E. Weiss-Bilka, L. Campbell, D. Wagner, M. Ravosa, M. Stack","doi":"10.1158/1557-3265.OVCA17-A38","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A38","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79280395","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}
Pub Date : 2018-08-01DOI: 10.1158/1557-3265.OVCA17-A50
Conghong Fan, J. Reader, Gautam G. Rao, Paul N. Staats, M. Ching, A. Fulton, D. Roque
{"title":"Abstract A50: EP4 receptor antagonism in paclitaxel-resistant ovarian clear cell carcinomas","authors":"Conghong Fan, J. Reader, Gautam G. Rao, Paul N. Staats, M. Ching, A. Fulton, D. Roque","doi":"10.1158/1557-3265.OVCA17-A50","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A50","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72735246","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}
Pub Date : 2018-08-01DOI: 10.1158/1557-3265.OVCA17-A15
A. Mukherjee, F. Coscia, J. Fahrmann, Chun-Yi Chiang, Justin Smith, K. Nieman, A. Ladányi, Iris L. Romero, O. Fiehn, M. Mann, E. Lengyel
Introduction: Omental metastasis is a defining feature of ovarian cancer and other cancers with peritoneal spread. We and others have previously shown that ovarian cancer (OvCa) cells readily home to the omentum in an adipokine-dependent manner and take up lipids from omental adipocytes to fuel metastasis. The complex interactions between omental adipocytes and OvCa cells, and the mechanisms by which OvCa cells adapt to this unique lipid-rich microenvironment, are still unclear and warrant further study. Here we used multiple omics platforms to study adipocyte-induced alterations in OvCa cells. Methods: We cocultured human primary adipocytes (HPA) with OvCa cell lines and then used mass spectrometry-based proteomic and global untargeted metabolomic analysis to study the altered cellular physiology of cancer cells upon encountering omental adipocytes. Stable cell lines were generated using lentivirus-mediated gene silencing and, subsequently, functional characterization was carried out using microarray and cell-based metabolic analysis. Since fatty acid binding protein 4 (FABP4) was identified in this analysis, we used a small-molecule inhibitor against FABP4 in an orthotopic xenograft mouse model to determine its role in promoting metastatic tumor burden. Results: Proteomic analysis revealed that HPA increases the expression of several proteins, especially those involved in lipid metabolism, such as cluster of differentiation 36 (CD36), FABP4, and alcohol dehydrogenase 1 (ADH1) in OvCa cancer cells. While we found that CD36 was essential for lipid uptake by the cancer cells, we determined that FABP4 was indispensable for their retention of intracellular lipid accumulation. Corollary metabolomic analysis showed that FABP4 knockdown dramatically reduced intracellular triacylglycerol levels induced by adipocyte coculture. We also found that FABP4 was responsible for the increased rate of β-oxidation observed in adipocyte cocultured cancer cells. Moreover, cancer cells exhibited increased oxidative stress when cultured with adipocytes or adipocyte conditioned media as evidenced by flow-cytometry analysis of reactive oxygen species. These observations were corroborated by detection of elevated oxidative stress markers such as oxidized lipids (15-HETE, 9-HODE, and 2-hydroxypalmitate), oxidized cholesterol (7-beta-hydroxy cholesterol), and oxidized glutathione. This increase in reactive oxygen species was found to be dependent on the levels of adipocyte-induced FABP4, suggesting that FABP4 plays a critical role in the alteration of cancer cells in contact with adipocytes. To determine the functional consequence of FABP4 inhibition in cancer cells, we carried out microarray and ingenuity pathway analysis (IPA) analysis after FABP4 knockdown, which revealed that FABP4 makes a significant contribution to proliferative and metastatic signatures in cancer cells. Knockdown of FABP4 also reduced colony-forming capacity in clonogenic assays and targeting FABP4
导言:大网膜转移是卵巢癌和其他伴有腹膜扩散的肿瘤的一个重要特征。我们和其他人之前已经表明，卵巢癌(OvCa)细胞很容易以脂肪因子依赖的方式回到网膜，并从网膜脂肪细胞中摄取脂质以促进转移。网膜脂肪细胞和OvCa细胞之间复杂的相互作用，以及OvCa细胞适应这种独特的富含脂质微环境的机制尚不清楚，需要进一步研究。在这里，我们使用多个组学平台来研究脂肪细胞诱导OvCa细胞的改变。方法:我们将人原代脂肪细胞(HPA)与OvCa细胞系共培养，然后采用基于质谱的蛋白质组学和全局非靶向代谢组学分析来研究癌细胞在遇到大网膜脂肪细胞时的细胞生理改变。使用慢病毒介导的基因沉默生成稳定的细胞系，随后使用微阵列和基于细胞的代谢分析进行功能表征。由于脂肪酸结合蛋白4 (FABP4)在本分析中被鉴定出来，我们在原位异种移植小鼠模型中使用了一种小分子抑制剂来抑制FABP4，以确定其在促进转移性肿瘤负荷中的作用。结果:蛋白质组学分析显示，HPA增加了OvCa癌细胞中几种蛋白质的表达，特别是与脂质代谢有关的蛋白质，如CD36、FABP4和乙醇脱氢酶1 (ADH1)。虽然我们发现CD36对于癌细胞的脂质摄取是必不可少的，但我们确定FABP4对于癌细胞保持细胞内脂质积累是必不可少的。相应的代谢组学分析显示，FABP4敲除显著降低脂肪细胞共培养诱导的细胞内甘油三酯水平。我们还发现，在脂肪细胞共培养的癌细胞中，FABP4负责β-氧化率的增加。此外，癌细胞在脂肪细胞或脂肪细胞条件培养基中培养时表现出增加的氧化应激，这一点通过对活性氧的流式细胞术分析得到了证实。这些观察结果通过检测氧化应激标志物如氧化脂质(15-HETE, 9-HODE和2-羟基铝酸盐)，氧化胆固醇(7- β -羟基胆固醇)和谷胱甘肽的升高得到证实。研究发现，活性氧的增加依赖于脂肪细胞诱导的FABP4水平，这表明FABP4在与脂肪细胞接触的癌细胞的改变中起着关键作用。为了确定FABP4抑制在癌细胞中的功能后果，我们在FABP4敲除后进行了微阵列和独创性途径分析(IPA)分析，结果显示FABP4对癌细胞的增殖和转移特征有重要贡献。在克隆实验中，敲除FABP4也降低了集落形成能力，在原位异种移植小鼠模型中，使用小分子抑制剂靶向FABP4可显著减少转移性负担。结论:靠近脂肪细胞的癌细胞增加了脂质利用基因。这些基因增强了癌细胞利用大网膜中丰富的脂肪酸作为额外燃料来源的能力。脂质伴侣蛋白FABP4被发现在调节癌细胞脂质利用和氧化还原平衡中发挥关键作用，帮助它们适应网膜微环境。因此，FABP4可能有潜力作为转移性卵巢癌的治疗靶点。引文格式:Abir Mukherjee, Fabian Coscia, Johannes Fahrmann, chunyi Chiang, Justin Smith, Kristin Nieman, Andras Ladanyi, Iris Romero, Oliver Fiehn, Matthias Mann, Ernst Lengyel。脂肪酸结合蛋白4是卵巢癌转移过程中不可缺少的物质。[摘要]。AACR会议论文集:解决卵巢癌研究和治疗中的关键问题;2017年10月1-4日;宾夕法尼亚州匹兹堡。费城(PA): AACR;临床肿瘤杂志，2018;24(增刊1):1 - 5。
{"title":"Abstract A15: Fatty acid binding protein 4 is indispensable for ovarian cancer metastasis","authors":"A. Mukherjee, F. Coscia, J. Fahrmann, Chun-Yi Chiang, Justin Smith, K. Nieman, A. Ladányi, Iris L. Romero, O. Fiehn, M. Mann, E. Lengyel","doi":"10.1158/1557-3265.OVCA17-A15","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A15","url":null,"abstract":"Introduction: Omental metastasis is a defining feature of ovarian cancer and other cancers with peritoneal spread. We and others have previously shown that ovarian cancer (OvCa) cells readily home to the omentum in an adipokine-dependent manner and take up lipids from omental adipocytes to fuel metastasis. The complex interactions between omental adipocytes and OvCa cells, and the mechanisms by which OvCa cells adapt to this unique lipid-rich microenvironment, are still unclear and warrant further study. Here we used multiple omics platforms to study adipocyte-induced alterations in OvCa cells. Methods: We cocultured human primary adipocytes (HPA) with OvCa cell lines and then used mass spectrometry-based proteomic and global untargeted metabolomic analysis to study the altered cellular physiology of cancer cells upon encountering omental adipocytes. Stable cell lines were generated using lentivirus-mediated gene silencing and, subsequently, functional characterization was carried out using microarray and cell-based metabolic analysis. Since fatty acid binding protein 4 (FABP4) was identified in this analysis, we used a small-molecule inhibitor against FABP4 in an orthotopic xenograft mouse model to determine its role in promoting metastatic tumor burden. Results: Proteomic analysis revealed that HPA increases the expression of several proteins, especially those involved in lipid metabolism, such as cluster of differentiation 36 (CD36), FABP4, and alcohol dehydrogenase 1 (ADH1) in OvCa cancer cells. While we found that CD36 was essential for lipid uptake by the cancer cells, we determined that FABP4 was indispensable for their retention of intracellular lipid accumulation. Corollary metabolomic analysis showed that FABP4 knockdown dramatically reduced intracellular triacylglycerol levels induced by adipocyte coculture. We also found that FABP4 was responsible for the increased rate of β-oxidation observed in adipocyte cocultured cancer cells. Moreover, cancer cells exhibited increased oxidative stress when cultured with adipocytes or adipocyte conditioned media as evidenced by flow-cytometry analysis of reactive oxygen species. These observations were corroborated by detection of elevated oxidative stress markers such as oxidized lipids (15-HETE, 9-HODE, and 2-hydroxypalmitate), oxidized cholesterol (7-beta-hydroxy cholesterol), and oxidized glutathione. This increase in reactive oxygen species was found to be dependent on the levels of adipocyte-induced FABP4, suggesting that FABP4 plays a critical role in the alteration of cancer cells in contact with adipocytes. To determine the functional consequence of FABP4 inhibition in cancer cells, we carried out microarray and ingenuity pathway analysis (IPA) analysis after FABP4 knockdown, which revealed that FABP4 makes a significant contribution to proliferative and metastatic signatures in cancer cells. Knockdown of FABP4 also reduced colony-forming capacity in clonogenic assays and targeting FABP4 ","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80790883","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}
Pub Date : 2018-08-01DOI: 10.1158/1557-3265.OVCA17-IA07
A. Ahmed
{"title":"Abstract IA07: Targeting micrometastasis for the treatment of ovarian cancer","authors":"A. Ahmed","doi":"10.1158/1557-3265.OVCA17-IA07","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-IA07","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85785312","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}
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