bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 182: Cancer stem cells and tumor angiogenesis in serous adenocarcinoma of ovary
Authors: Krishnapriya S , Sidhanth C , Manasa P , Sneha S , Bindhya S , Nagare R P. , Ganesan T S. 
Published: August 2019

Abstract
The traditional view of tumour vascularization is that tumours acquire blood supply from the neighbouring normal stroma. However, recently the origin of tumour endothelial cells or pericytes in part has been shown to be derived from cancer stem cells (CSCs) in glioblastoma. In high grade serous ovarian cancer (HGSOC), the origin of endothelial cells is not known. Our objective was to determine if components of a tumour blood vessel and lymphatic vessel are derived from CSCs in ovarian cancer. Using spheroids as an in vitro model, we have evaluated the role of CSCs in primary malignant cells (PMCs) from patients with serous adenocarcinoma of ovary cultured under specific conditions. The expression of endothelial, pericyte and lymphatic endothelial markers was evaluated by flow cytometry. In addition, functional assays were performed to assess the endothelial phenotype. Further, the ability of CSCs to express endothelial markers under appropriate growth conditions was also evaluated with Bevacizumab which antagonize VEGF. PMCs grown in endothelial growth medium (EGM) showed significantly higher expression of CD105 (n=32, p = 0.002) and CLEC14A (n=10, p = 0.012) and co-expression of CD105/CLEC14A (n=10, p= 0.012) than that of spheroids. Primary malignant cells when grown in pericyte and lymphatic endothelial specific conditions, showed significantly higher expression of desmin (n=10, p=0.03), Smooth muscle actin (SMA) (n=10, p=0.017) and VEGFR3 (n=10, p=0.028) than that of the spheroids. When the PMCs were grown as spheroids in endothelial conditions in the presence or absence of Bevacizumab (1 μg/μl), there was a reduction in the co-expression of CD105 and CLEC14A (P=0.04). The cells grown in endothelial conditions showed formation of tubes, uptake of Dil-ac-LDL and expressed eNOS, confirming their endothelial phenotype. GFP transduced spheroids from PMCs formed tumours in mice and the blood vessels in the tumour co-expressed CD31, SMA, VEGFR3 and GFP, suggesting that these cells are derived from CSCs. These results prove that a proportion of endothelial cells, pericytes and lymphatic endothelial cells are derived from CSCs in serous ovarian carcinoma and the VEGF pathway has a key role. This property of CSCs to contribute to tumour angiogenesis can be inhibited.
Citation Format: S Krishnapriya, C Sidhanth, P Manasa, S Sneha, S Bindhya, R P. Nagare, T S. Ganesan. Cancer stem cells and tumor angiogenesis in serous adenocarcinoma of ovary [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 182.
Abstract 1825: Epithelial adherens junctions suppress the pro-tumorigenic MIR17HG lncRNA by recruiting RISC
Authors: Bridges Mary C. , Nair-Menon Joyce , Kourtidis Antonis 
Published: August 2019

Abstract
The adherens junctions (AJs) are essential architectural elements of epithelial tissues. Compromised junctional integrity is a common precursor to colon cancer. Recently, we identified a novel mechanism whereby the AJs of non-transformed colon cells recruit the microprocessor and RISC, core elements of the RNAi machinery, as well as miRNAs, to suppress oncogenic mRNAs. Knockdown of the AJ component PLEKHA7, disrupts this RNAi-mediated signaling program, leading to pro-tumorigenic cell transformation. Interestingly, PLEKHA7 RNA-CLIP and subsequent RNA-Seq analysis identified association with numerous long non-coding RNAs (lncRNAs). While a number of lncRNAs have been associated with tumorigenesis, the underlying mechanisms of their regulation during tumor progression are still unclear. As lncRNAs can interact with the RNAi machinery, we hypothesize that the AJs regulate lncRNAs via this localized RNAi mechanism. Examination of PLEKHA7-depleted cells by RNA-seq revealed differential expression of 49 junction-associated lncRNAs. From this set, the top upregulated lncRNA is MIR17HG, an oncogenic polycistronic host transcript of the miR-17-92 cluster. Junctional localization of MIR17HG was confirmed by RNA-FISH. Adherens junctions destabilization by E-cadherin knockdown also led to the upregulation of MIR17HG, demonstrating the role of junctional integrity in MIR17HG suppression. Data from Ago2 knockdown, anti-miR, and miRNA mimic experiments show that PLEKHA7 suppresses the levels of the MIR17HG transcript through the junction-associated RISC and two miRNAs, miR-203a and miR-372. PLEKHA7 depletion also results in increased levels of a subset of MIR17HG hosted miRNAs, including miR-19a and miR-19b, both known cancer promoters. Ectopic expression of PLEKHA7 in the aggressive HCT116 colon cancer cells that lack endogenous PLEKHA7 expression, suppressed anchorage independent growth, as well as MIR17HG levels, which are elevated in these cells. We are currently examining the role of MIR17HG as a functional intermediate of PLEKHA7’s loss on colon cell transformation. In summary, our data point towards a novel mechanism of lncRNA regulation that tethers epithelial architecture with cell behavior.
Note: This abstract was not presented at the meeting.
Citation Format: Mary C. Bridges, Joyce Nair-Menon, Antonis Kourtidis. Epithelial adherens junctions suppress the pro-tumorigenic MIR17HG lncRNA by recruiting RISC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1825.
Abstract 1828: Genetic profiling of breast cancer confirms a pivotal role of EGFR pathway in the development of acquired resistance to tamoxifen
Authors: Bahnnasy Abeer A. , Malash Ibrahim , Al-Lahlouby Nasr , Mansour Osman , Shaarawy Sabry , Abdellateif Mona S. , Yousef Hend , Lotfy Mai M. , Gaafar Rabab , elsesy Mohamed. , Zekri Abdel-Rahman N. 
Published: August 2019

Abstract
Background: Metastatic breast cancer (MBC) represents a major health problem in Egypt and worldwide. Prognostic and predictive factors for patients with MBC are highly needed, for better management and improved survival. The aim of this study was to assess the prognostic and predictive value(s) of CYP2D6 polymorphisms in MBC patients on Tamoxifen and to determine the genetic profile(s) of Tamoxifen responders and non-responders. Methods: We assessed 157 females with hormone receptor positive, locally recurrent inoperable and/or metastatic breast cancer (MBC) patients from Egypt for 1) CYP2D6 polymorphisms and 2) genetic aberrations in the EGFR pathway (92 genes). All patients received Tamoxifen and according to their response they were divided into Tamoxifen-responders and refractory. RNA was extracted from tumor and normal tissue samples and used to assess the genetic profiles of the patients using the SABioscience array (Qiagen) with four house-keeping genes. Results: 92(58.6%) patients were ER and PR positive, 51 (32.5%) were ER positive and 14 (8.9%) were PR positive. CYP2D6 *3/*4 was significantly prevalent in the refractory group (86.6%).Variants *10/*10 and *10/*3 were more common in the responders (85.5%) compared to refractory (P=0.027). CYP2D6 polymorphism associated significantly with Her-2 amplification (P&lt;0.001), and reduced overall survival rate of patients in both refractory and responder groups (P&lt; 0.001). Fifty-six genes were differentially over-expressed in the refractory group compared to responders, of which only JAK1, COL1A1, GAB1, FN1and MKNK1 showed a significant difference. In the refractory group 34 genes were differentially reduced compared to responders; none of them showed significant difference. Response to Tamoxifen associated significantly with disease site since patients with bone only disease showed better response than those with visceral metastases (P&lt;0.005). Conclusion: A panel of 5 genes in EGFR pathway (MJAK1, COL1A1, GAB1, FN1 and MKNK1) together with CYP2D6 polymorphism scan predict response to Tamoxifen in metastatic BC patients though this has to be verified in an extended study including larger sample.
Citation Format: Abeer A. Bahnnasy, Ibrahim Malash, Nasr Al-Lahlouby, Osman Mansour, Sabry Shaarawy, Mona S. Abdellateif, Hend Yousef, Mai M. Lotfy, Rabab Gaafar, Mohamed. elsesy, Abdel-Rahman N. Zekri. Genetic profiling of breast cancer confirms a pivotal role of EGFR pathway in the development of acquired resistance to tamoxifen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1828.
Abstract 1829: HSF1 suppresses AMPK to promote lipogenesis, cholesterol biosynthesis and protein lipidation
Authors: Su Kuo-Hui , Dai Chengkai 
Published: August 2019

Abstract
AMP-activated protein kinase (AMPK), a key cellular metabolic sensor, suppresses anabolic pathways, including lipogenesis and cholesterol biosynthesis, thereby maintaining energy homeostasis. Heat shock factor 1 (HSF1) is the master regulator of the evolutionarily conserved proteotoxic stress response (PSR), thereby preserving proteostasis in the face of environmental insults. In contrast to its beneficial role in enhancing survival under proteotoxic stress, it has been demonstrated that HSF1 acts as a potent pro-oncogenic factor. Our previous study has shown that metabolic stressors, via AMPK activation, inactivate HSF1 and disrupt proteostasis to suppress tumor growth. Interestingly, our new study now reveals that HSF1, in reciprocal, also suppresses AMPK activation. HSF1 does so independently of its canonical transcriptional action. Furthermore, Hsf1 deficiency promotes the interactions between AMPK and LKB1, a key upstream kinase activating AMPK. Congruent with the suppression of lipogenesis by AMPK, Hsf1 deficiency depletes cellular lipid content and reduces body fat mass in mice. Importantly, these defects can be largely rescued by either pharmacological or genetic inhibition of AMPK. At the molecular level, Hsf1 deficiency leads to inactivation of acetyl-CoA Carboxylase (ACC) and sterol regulatory element-binding transcription factor 1c (SREBP1c), both of which are key players in de novo lipogenesis. In addition to impaired lipogenesis, Hsf1-deficient cells and mice display reduced cholesterol levels. Of particular interest, this defect leads to impaired cholesteroylation of sonic hedgehog (SHH), the best known signaling molecule undergoing this covalent modification. In consequence, SHH secreted by HSF1-deficient cells are less potent in activating its downstream signaling cascade, indicated by reduced DNA binding of GLI1, a transcription factor responding to activation of SHH signaling. Conversely, HSF1 overexpression increases the lipid content, cholesterol levels and the amount of cholesteroylated SHH proteins in xenografted melanomas. Taken together, our results reveal that HSF1, through AMPK suppression, promotes lipogenesis, cholesterol biosynthesis and protein lipidation, thereby supporting malignant growth.
Citation Format: Kuo-Hui Su, Chengkai Dai. HSF1 suppresses AMPK to promote lipogenesis, cholesterol biosynthesis and protein lipidation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1829.
Abstract 185: Direct cytotoxic effect of a novel anti-angiogenic drug F16 towards U87MG glioblastoma cell line
Authors: Algahtani Mohammad , Alhazzani Khalid , Venkatesan Thiagarajan , Alaseem Ali , Dhandayuthapani Sivanesan , Rathinavelu Appu 
Published: August 2019

Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive and lethal types of brain cancers with low 5-year survival rate. Therefore, search for better drugs and effective treatment strategies for GBM to improve patient outcomes is continuing. Since GBM is one of the most highly vascularized solid tumors and its growth is angiogenesis-dependent, antagonizing tumor angiogenesis by using angiogenesis inhibitors seems to be one of the promising approaches. In this context, intensive pre-clinical evaluation of our patented anti-angiogenic compound, code-named F16, has exhibited potent anti-angiogenic and anti-tumor activities via selectively antagonizing VEGFR-2 in both in vitro and in vivo models. More importantly, assessment of biochemical parameters that are reflecting the safety of F16 in the in vivo system showed no alterations in the toxicological parameters of heart, liver, kidney, and pancreas, after 30 days of treatment, at the dose of 100 mg/kg body weight. Hence, we tested the direct effects of F16 for inhibiting the growth, angiogenesis and the migratory abilities of the U87MG glioblastoma cells, which are known to express high levels of VEGFR. Our in vitro studies have confirmed potent inhibitory effects of F16 towards the migration and invasion of U87MG cells, and also revealed potent cytotoxic effects (IC50 26 µM) against U87MG cells in comparison to Temozolomide (IC50 430 µM) treatment. In addition, F16 inhibited the phosphorylation of VEGFR-2 through competitive binding and also induced cell cycle arrest and apoptosis by activating p53 pathway in U87MG cells. Furthermore, our in vivo results with ectopically implanted xenograft model confirm the fact that F16 can significantly inhibit tumor growth in the mice implanted with U87MG glioblastoma cell line. Based on our preliminary results, we are proposing that F16 could be a potential candidate for treating GBM, either in monotherapy or in combination with a cytoreductive drug. (This research was supported by the generous funds provided by the Community Foundation of Broward, Florida and also by the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida)
Citation Format: Mohammad Algahtani, Khalid Alhazzani, Thiagarajan Venkatesan, Ali Alaseem, Sivanesan Dhandayuthapani, Appu Rathinavelu. Direct cytotoxic effect of a novel anti-angiogenic drug F16 towards U87MG glioblastoma cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 185.
Abstract 1850: Role of microRNAs in circulating tumor cells glutamine metabolism pathways
Authors: Zhu Ziwen , Owen Sarah N. , Achreja Abhinav , Nagrath Sunitha , Nagrath Deepak 
Published: August 2019

Abstract
Circulating tumor cells (CTCs) has an important role in the spread of cancers and metastasis. CTCs are believed to be the most promising model to understand metastatic progression in patients with cancer. Glutamine, an alternative carbon source to glucose, has recently been shown to be important for the cancer cell survival, growth and progression. The role of glutamine metabolism in CTCs is not known. MicroRNAs (miRNAs) are a group of highly conserved noncoding RNAs and approximately 22 nucleotides in length. Here, we postulate that CTCs have unique microRNAs (miRNAs) expression compared to resident tumor cells. And miRNAs control CTC glutamine metabolism for the metastasis. In this study, we used 3 primary CTC cultures to study how miRNA controlling glutamine metabolism. We identified several miRNAs have high expressions in CTCs and these miRNAs are regulating glutamine metabolism in CTCs. Our results demonstrate the metabolic miRNA targets of CTCs on cancer progression. These insights will present a unique opportunity for diagnosing and treating cancer through CTCs.
Note: This abstract was not presented at the meeting.
Citation Format: Ziwen Zhu, Sarah N. Owen, Abhinav Achreja, Sunitha Nagrath, Deepak Nagrath. Role of microRNAs in circulating tumor cells glutamine metabolism pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1850.
Abstract 1851: Novel roles of DNA-PK in metabolic regulation in prostate cancer
Authors: Dylgjeri Emanuela , Goodwin Jonathan , Shafi Ayesha , Kothari Vishal , Zadra Giorgia , Seifert Erin , Feng Felix , Knudsen Karen 
Published: August 2019

Abstract
DNA dependent protein kinase catalytic subunit (DNA-PK) is a multifunctional kinase involved in repairing double-strand DNA breaks through non-homologous end joining (NHEJ), with parallel roles as a master transcriptional regulator of gene networks supporting cell migration and invasion. In prostate cancer (PCa), DNA-PK was found to be highly upregulated and hyperactivated. Strikingly, DNA-PK is the most deregulated kinase in metastatic castration resistant prostate cancer (CRPC), and is independently predictive of metastasis and overall survival in patients with high-risk disease. Combined, these findings highlight the importance of understanding DNA-PK functions beyond DNA repair and transcriptional regulation, which promote the acquisition of aggressive tumor phenotypes. Rapid immunoprecipitation of endogenous proteins (RIME) was performed to identify the DNA-PK interactome, which uncovered novel DNA-PK interactors that play key roles in metabolism. To assess the role of DNA-PK in regulation of metabolism, metabolic profiles of CRPC models were investigated upon DNA-PK modulation. Data presented will describe novel roles of DNA-PK in cancer metabolism and subsequent effects of DNA-PK modulation in key metabolic pathways.
Citation Format: Emanuela Dylgjeri, Jonathan Goodwin, Ayesha Shafi, Vishal Kothari, Giorgia Zadra, Erin Seifert, Felix Feng, Karen Knudsen. Novel roles of DNA-PK in metabolic regulation in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1851.
Abstract 1852: Down-regulation of PRMT6 drives Warburg effect through ERK induced relocalization of PKM2 to promote tumorigenicity and sorafenib resistance in hepatocellular carcinoma
Authors: Wong Tin-Lok , Chan Lok-Hei , Ma Stephanie 
Published: August 2019

Abstract
Cancer cells have a high dependence of glycolysis for ATP production, especially under hypoxic environment. Metabolic reprogramming in cancer drives an increased glycolytic rate that supports maximal production of nutrients for tumorigenesis. Our group has recently identified the post-translational modification enzyme, protein arginine methyltransferase 6 (PRMT6) to be frequently down-regulated and to exhibit a tumour suppressive effect in maintenance of cancer stemness in hepatocellular carcinoma (HCC) (Chan LH et al. Cell Reports 2018). Our current study finds transcriptome and metabolome profiling of HCC cells with PRMT6 repressed to exhibit enrichment of genes and metabolites involved in glycolysis. In vitro, PRMT6 negatively regulates glycolysis, glucose uptake, lactate production and pyruvate kinase activity in HCC cell lines and patient-derived organoids. Our previous work found PRMT6 to interfere with RAS/RAF binding by directly binding to CRAF and methylating arginine100 residue. Supporting the importance of PRMT6-mediated CRAF methylation, we find overexpression of catalytic inactive PRMT6 to exhibit no effect on glycolysis. MEK/ERK, known downstream effectors of RAS/RAF signalling, has been shown to induce nuclear PKM2 localization. Consistently, we find modulation of PRMT6 to negatively regulate ERK and PKM2 expression and localization. Rescue experiments involving the ERK inhibitor U0126 and shPKM2 further substantiate the importance of ERK/PKM2-mediated glucose metabolic reprogramming in HCC cells with PRMT6 suppressed. Functionally, inhibition of glycolysis by 2-deoxyglucose sensitized PRMT6 knockdown cells to sorafenib treatment in vitro and attenuated tumor growth in vivo. In addition, we also find PRMT6 expression to be regulated via hypoxia by binding of RE1-silencing transcription factor to the promoter region. Rescue experiments by re-expressing PRMT6 under hypoxic conditions further support the involvement of PRMT6 in driving glycolysis in oxygen deprived environments. Our work uncovers a critical function for PRMT6 in driving Warburg effect through regulating expression and localization of PKM2 via post-translational modification of CRAF, thereby promoting HCC initiation and sorafenib resistance.
Citation Format: Tin-Lok Wong, Lok-Hei Chan, Stephanie Ma. Down-regulation of PRMT6 drives Warburg effect through ERK induced relocalization of PKM2 to promote tumorigenicity and sorafenib resistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1852.
Abstract 1857: Proscillaridin A induces apoptosis and suppresses non-small cell lung cancer tumor growth via calcium-induced DR4 up-regulation
Authors: Li Run-Ze , Fan Xing Xing , Yao Xiao- Jun , Leung Elaine L. , Liu Liang 
Published: August 2019

Abstract
Non-small cell lung cancer (NSCLC) is the predominant histological type of lung cancer and is characterized by the highest mortality and incidence rates among these types of malignancies. Cardiac glycosides, a class of natural products, have been identified as a potential type of chemotherapeutic agent. This study aims to investigate the anti-cancer effects and the mechanisms of action of Proscillaridin A (P.A) in NSCLC cells. In vitro sodium-potassium pump (Na+/K+ ATPase) enzyme assays indicated that P.A is a direct Na+/K+ ATPase inhibitor. P.A showed potent cytotoxic effects in NSCLC cells at nanomolar levels. Treatment mechanism studies indicated that P.A elevated Ca2+ levels, activated the AMPK pathway and down-regulated phosphorylation of ACC and mTOR. Subsequently, P.A increased death receptor 4 (DR4) expression and down-regulated NF-κB. Interestingly, P.A selectively suppressed EGFR activation in EGFR mutant cells but not in EGFR wild-type cells. In vivo, P.A significantly suppressed tumor growth in nude mice compared to vehicle-treated mice. Compared with the Afatinib treatment group, P.A displayed less pharmaceutical toxicity, as the body weight of mice treated with P.A did not decrease as much as those treated with Afatinib. Consistent changes in protein levels were obtained from Western blotting analysis of tumors and cell lines. Immunohistochemistry analysis of the tumors from P.A-treated mice showed a significant suppression of EGFR phosphorylation (Tyr 1173) and reduction of the cell proliferation marker Ki67. Taken together, our results suggest that P.A is a promising anti-cancer therapeutic candidate for NSCLC. Acknowledgements This work was supported by the Macau Science Technology Development Fund (project code: 021/2013/A1, 005/2014/AMJ & 010/2016/A1).
Note: This abstract was not presented at the meeting.
Citation Format: Run-Ze Li, Xing Xing Fan, Xiao- Jun Yao, Elaine L. Leung, Liang Liu. Proscillaridin A induces apoptosis and suppresses non-small cell lung cancer tumor growth via calcium-induced DR4 up-regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1857.