bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3714: Metabolomics and proteomics reveal inhibition of glycolysis in withaferin A-mediated prevention of mammary carcinogenesis in MMTV-neu mice.
Authors: Singh Shivendra V. , Hahm Eun-Ryeong , Lee Joomin , Kim Su-Hyeong , Sehrawat Anuradha , Arlotti Julie A. 
Published: August 2014

Abstract
Plants used in Ayurvedic medicine, which has been practiced for centuries in India for the treatment of different ailments, continue to draw attention for identification of novel small molecule cancer chemopreventive agents. Withaferin A (WA) is one such promising small molecule constituent of the medicinal plant Withania somnifera (also known as Ashwagandha) with in vivo activity against xenografted human breast cancer cells. We have also shown recently that mammary cancer development and pulmonary metastasis in MMTV-neu transgenic mice is inhibited significantly by WA administration. In the present study, we performed metabolomics profiling using plasma and tumor tissues (n=8) and proteomics profiling using tumor tissues (n=3) from control and WA-treated MMTV-neu mice to gain insights into the mechanism underlying in vivo preventive effect of WA. A total of 320 and 328 biochemicals of known identity were detectable in the plasma and tumor tissue, respectively. The WA-mediated mammary cancer prevention in MMTV-neu mice was associated with a statistically significant alteration (P≤0.05) in the levels of 76 biochemicals in the plasma (24 increase, 52 decrease). Metabolomics using tumor tissues revealed alterations in the levels of 24 biochemicals (2 increase, 24 decrease) upon WA administration. One change that was highly consistent in the plasma and tumor tissue from WA-treated mice compared to controls was a decrease in glucose utilization, glycolysis, and TCA cycle activity. Proteomics using tumor tissues confirmed downregulation of many glycolysis-related proteins in the tumor of WA-treated mice compared with control, including M2-type pyruvate kinase, phosphoglycerate kinase, glyceraldehyde-3-phosphate dehydrogenase, and fructose-bisphosphate aldolase A isoform 2. Downregulation of TCA cycle-related proteins in the tumor of WA-treated mice compared with control included pyruvate carboxylase and isocitrate dehydrogenase. Other altered biochemicals were reflective of changes in arginine metabolism, polyamine biosynthesis, glutathione metabolism, lipid metabolism, and catabolism of branched-chain amino acids. These observations indicate that WA treatment prevents mammary cancer in MMTV-neu mice by suppressing glycolysis (Warburg effect) and TCA cycle. This study was supported by the grant CA142604 awarded by the National Cancer Institute.
Citation Format: Shivendra V. Singh, Eun-Ryeong Hahm, Joomin Lee, Su-Hyeong Kim, Anuradha Sehrawat, Julie A. Arlotti. Metabolomics and proteomics reveal inhibition of glycolysis in withaferin A-mediated prevention of mammary carcinogenesis in MMTV-neu mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3714. doi:10.1158/1538-7445.AM2013-3714
Abstract 3725: Anti-DLL4 (demcizumab) inhibits tumor growth and reduces cancer stem cell frequency in patient-derived ovarian cancer xenografts.
Authors: Yen Wan-Ching , Fischer Marcus M. , Shah Jalpa , Wei Jie , Cain Jennifer , Yeung Pete , Beviglia Lucia , Cancilla Belinda , Kapoun Ann , Lewicki John , Gurney Austin , Hoey Timothy 
Published: August 2014

Abstract
Ovarian cancer in a major cause cancer related death in women and this disease is often characterized by resistance to chemotherapy and tumor recurrence. Cancer stem cells (CSCs) have been shown to be relatively insensitive to chemotherapeutic agents. Several lines of evidence indicate that aberrant Notch signaling plays a major role in ovarian cancer progression and resistance to standard therapies. DLL4 is a key ligand that activates the Notch pathway and has been shown to regulate both CSC function and tumor angiogenesis. DLL4 expression in tumor and endothelial cells has also been associated with resistance to bevacizumab treatment. In these studies, we investigated the role of anti-DLL4 in a panel of patient-derived ovarian cancer xenograft models. We utilized anti-human DLL4 (OMP-21M18) and anti-murine DLL4 to block Notch signaling in both the tumor and stromal/vascular cells in the xenografts. We found that anti-DLL4 treatment was broadly efficacious in these ovarian cancer models, significantly inhibiting tumor growth both as a single agent and in combination with paclitaxel. We carried out serial transplantation studies to investigate the effect on cancer stem cells and found that anti-DLL4 in combination with paclitaxel profoundly reduced the tumor initiating cell frequency. In contrast, treatment with paclitaxel alone had the opposite effect and increased ovarian CSC frequency. These data suggest that anti-DLL4 treatment sensitizes chemoresistant ovarian tumorigenic cells to therapy and provide compelling evidence that anti-DLL4 (demcizumab) is a promising strategy for the clinical treatment of ovarian cancer.
Citation Format: Wan-Ching Yen, Marcus M. Fischer, Jalpa Shah, Jie Wei, Jennifer Cain, Pete Yeung, Lucia Beviglia, Belinda Cancilla, Ann Kapoun, John Lewicki, Austin Gurney, Timothy Hoey. Anti-DLL4 (demcizumab) inhibits tumor growth and reduces cancer stem cell frequency in patient-derived ovarian cancer xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3725. doi:10.1158/1538-7445.AM2013-3725
Abstract 3731: Targeting ovarian cancer stem cells using a novel ALDH inhibitor.
Authors: Chefetz Ilana , Yang Kun , Larsen Scott D. , Buckanovich Ronald J. 
Published: August 2014

Abstract
Background: Cancer cells with stem cell-like properties (CSC) are resistant to chemotherapy and are believed to be the source of cancer recurrence. Aldehyde dehydrogenase enzymatic activity (ALDH), alone and in combination with the stem cell marker CD133, can be used to define a hierarchy of Ovarian Cancer Stem Cells (OvCSC). ALDH is functionally important for stem cells, regulating motile cellular metabolic functions and the biosynthesis of retinoic acid. ALDH agonists have been demonstrated to enhance ‘stemness’ in some tissues. We therefore sought to determine the impact of ALDH antagonist on OvCSC.
Methods and Results: We screened a variety of novel derivatives with confirmed or potential ALDH activity based on the molecular homology to the known ALDH inhibitor DEAB. Using the ALDEFLUOR assay and A2780 cancer cell line as a source of ALDH+CD133+ cells, we identified a lead compound 673 which effectively inhibits ALDH activity. Interestingly this compound also potently depletes CD133+ ovarian cancer cells. Supporting functional depletion of OvCSC, treatment of primary human ovarian tumor ascites cells with 673 resulted in 4-20 fold decrease tumor sphere formation. 673 treatment is highly synergistic with cisplatin both in-vitro and in-vivo as assessed by cell growth curves and tumor growth. Importantly, pre-treatment of tumor cells with 673 significantly reduced tumor in tumor initiation and growth rates. Finally, 673 is non-toxic to normal stem cells.
Conclusions: We have identified a novel ALDH inhibitor, 673, which depletes the ovarian cancer cells expressing CSC markers. CSC marker independent functional assays, with both cell lines and primary human ovarian cancer cells, indicate 673 is depleting OvCSC activity. Thus this may be a powerful new therapeutic approach to target CSC. Future studies will elucidate the molecular mechanism that underlies 673 OvCSC depletion activities as well as to identify a specific ALDH isoforms targeted in ovarian cancer.
Citation Format: Ilana Chefetz, Kun Yang, Scott D. Larsen, Ronald J. Buckanovich. Targeting ovarian cancer stem cells using a novel ALDH inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3731. doi:10.1158/1538-7445.AM2013-3731
Abstract 3758: RIG-I plays a critical role in negatively regulating stemness properties in hepatoma cell lines.
Authors: Chen Ping-Yu , Lai Chao-Kuen , Kuo Min-Linag 
Published: August 2014

Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide due to its high rate of recurrence. Cancer stem cells are considered to generate tumors through the stem cell processes including self-renewal and differentiation into multiple cell types. And these distinct populations of cells are suggested to cause relapse and metastasis by eliciting new tumors. Retinoic acid-inducible gene I (RIG-I) has been identified as a pattern recognition receptor in innate immune defense for sensing intracellular viral RNAs, like Hepatits C virus which is one of the major risks of HCC, and inducing type I interferons production. In previous studies, RIG-I-like receptors recognizing some potentially oncogenic agents may have functional consequences that can lead to association of such single nucleotide polymorphisms with risk of some diseases or even cancers. Thus these gene polymorphisms may affect cancer risk indirectly. On the other hand, a previous study have demonstrated that RIG-I is an essential regulator of physiological myelopoiesis suggesting RIG-I possesses the potential of modulating stem cell differentiation. In our present study, we examined Huh7 and its RIG-I-mutant cell line by sphere formation assay and found solely the mutated cells possessed the self-renewal ability. After transfection of dominant-negative mutant of RIG-I to Huh7, the self-renewal ability were rescued as expected. We also injected 1000 cells for each two cell lines into NOD/SCID mice subcutaneously and observed the mutated cells formed tumors whereas Huh7 didn't. Hence, our study reveals the potential of RIG-I to suppress the stemness properties in the HCC cell lines and provides a new possible remedy target of liver cancer.
Citation Format: Ping-Yu Chen, Chao-Kuen Lai, Min-Linag Kuo. RIG-I plays a critical role in negatively regulating stemness properties in hepatoma cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3758. doi:10.1158/1538-7445.AM2013-3758
Abstract 3762: The role of aldehyde dehydrogenase isoenzymes in cancer cell proliferation, migration and drug resistance.
Authors: Moreb Jan S. , Mona Mahmoud , Chang Lung-Ji , Yeh Yu-Ling , Amory John , Goldstein Alex 
Published: August 2014

Abstract
Aldehyde dehydrogenase (ALDH) proteins are a superfamily of 19 human genes that play crucial role in epithelial cell homeostatsis. Several of these enzymes have been studied in cancer and were shown to protect cells against cytotoxic drugs and oxidative stress in addition to the promotion of cancer cell proliferation and invasion. Our study focuses on 5 less studied isoenzymes (ALDH1B1, ALDH3B1, ALDH4A1, ALDH5A1, and ALDH7A1) using lentiviral mediated overexpression of the enzymes in H1299 lung cancer cell line which is previously known to have negligible amount of ALDH activity. H1299 wild type cells (WT) and cells expressing GFP or RFP were used as controls. Expression of the proteins was confirmed by Western blots and ALDH enzymatic activity assay. We used cell culture, colorimetric MTT assay, wound healing assay, aldefluor assay, colony-forming assay, and in vitro treatment with doxorubicin (Doxo) and 4-hydroperoxycyclophosphaimde (4-HC). All the proteins were highly expressed and resulted in increased ALDH activity detected by using propionaldehyde or benzaldehyde as substrates with NAD+ as a co-factor. The activity of ALDH4A1, 5A1 and 7A1 was not detected by aldefluor flow cytometry assay. Cells expressing ALDH1B1, ALDH4A1 or ALDH7A1 had delayed wound healing at 6 hr, while overall cell proliferation was depressed for ALDH1B1, ALDH3B1 and ALDH5A1 and normal for the other isoenzymes. Cells overexpressing ALDH4A1 or ALDH7A1 showed higher clonal efficiency as well. Only ALDH1B1 and ALDH7A1 showed significant protection against the toxicity of 4-HC (10 μM for 72 hrs) as measured by MTT assay with an increase in average cell survival of 52 and 23%, respectively. Cells overexpressing ALDH5A1 showed significantly increased sensitivity to Doxo (1 and 10 μM for 72 hrs). There was a trend for ALDH7A1 to be protective against Doxo toxicity but did not reach statistical significance. In conclusion, the overexpression of ALDH isoenzymes in this manner may contribute to better understanding of their role in cancer biology and may lead to new cancer treatment approaches that incorporate specific inhibition or stimulation of these enzymes. This is an important goal especially in view of the high ALDH activity in cancer stem cells and their potential contribution to cancer recurrence.
Citation Format: Jan S. Moreb, Mahmoud Mona, Lung-Ji Chang, Yu-Ling Yeh, John Amory, Alex Goldstein. The role of aldehyde dehydrogenase isoenzymes in cancer cell proliferation, migration and drug resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3762. doi:10.1158/1538-7445.AM2013-3762
Abstract 3778: Breast Cancer Antiestrogen Resistance 3 (BCAR3) promotes cell motility by regulating actin cytoskeletal and adhesion remodeling in invasive breast cancer cells.
Authors: Wilson Ashley L. , Schrecengost Randy S. , Guerrero Michael S. , Thomas Keena S. , Bouton Amy H. 
Published: August 2014

Abstract
Metastatic breast cancer is currently incurable and associated with a 5-year survival rate of only 23%. Thus it is critical to develop a better understanding of the molecular mechanisms that regulate metastasis and the underlying process of cell motility in order to improve patient survival. The adaptor molecule Breast Cancer Antiestrogen Resistance 3 (BCAR3) functions in cellular processes that contribute to cell motility. Previous work from our group has shown that elevated BCAR3 protein levels enhance breast cancer cell motility, while depletion of BCAR3 decreases cell motility and invasion in vitro. Here, we show BCAR3 controls membrane protrusion, Rac1 activity, and adhesion disassembly in invasive breast cancer cells in response to adhesion signals. Conversely, RhoA signaling pathways appear to predominate when BCAR3 is depleted from these cells, as evidenced by an increase in ROCK-mediated myosin light chain phosphorylation and the presence of stress fibers and large ROCK/mDia1-dependent focal adhesions. Thus, through its ability to tip the balance in favor of Rac1 signaling, BCAR3 functions as a positive regulator of cytoskeletal remodeling and adhesion turnover in invasive breast cancer cells, thereby promoting a more invasive, pro-migratory phenotype. Interestingly, we demonstrate that BCAR3 also controls actin cytoskeletal and adhesion remodeling in invasive breast cancer cells in response to epidermal growth factor. Considering that BCAR3 protein levels are elevated in advanced breast cancer cells lines, we propose that BCAR3 functions in the transition to advanced disease by triggering intracellular signaling events that are essential to the metastatic process. BCAR3 function is intimately linked to two other proteins, the adaptor molecule p130Cas (Cas) and the non-receptor tyrosine kinase c-Src. While BCAR3 protein levels have yet to be thoroughly assessed in human breast tumors, high expression of Cas and/or c-Src is associated with more aggressive breast cancer behaviors. Future work will determine whether this BCAR3/Cas/c-Src signaling network serves as a useful biomarker for invasive disease, and whether BCAR3 promotes breast tumor progression and metastasis in mouse models of human breast cancer.
Citation Format: Ashley L. Wilson, Randy S. Schrecengost, Michael S. Guerrero, Keena S. Thomas, Amy H. Bouton. Breast Cancer Antiestrogen Resistance 3 (BCAR3) promotes cell motility by regulating actin cytoskeletal and adhesion remodeling in invasive breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3778. doi:10.1158/1538-7445.AM2013-3778
Abstract 378: The significance of vascular endothelial growth factor C in the lymphangiogenesis and lymph node metastasis of ovarian cancer.
Authors: Hisamatsu Takeshi , Mabuchi Seiji , Sasano Tomoyuki , Takahashi Ryoko , Kawano Mahiru , Matsumoto Yuri , Hashimoto Kae , Isobe Aki , Sawada Kenjiro , Morishige Kenichiro , Kimura Tadashi 
Published: August 2014

Abstract
Purpose: Vascular endothelial growth factor-C (VEGF-C) is commonly expressed in malignant cells, creating a favorable environment for generation of new lymphatic vessels. It has been recently reported that mammalian target of rapamycin (mTOR) stimulates tumor-lymphangiogenesis by inducing the production of VEGF-C. In the current study, we investigated the significance of VEGF-C in tumor lymphangiogenesis and lymph node metastasis of ovarian cancer. Moreover, we investigated whether mTOR complex 1 (mTORC1) is involved in the VEGF-C-induced lymphangiogensis and lymph node metastasis in ovarian cancer.
Experimental design: Using human ovarian cancers, we first performed immunostaining for VEGF-C, and examined the correlation between VEGF-C expressions and the extent of lymphvascular space invasion (LVSI) or the number of lymph node metastasis. Using two pairs of ovarian cancer cell lines producing different level of VEGF-C (VEGF-C-low and VEGF-C-high cells), we next investigated the role of VEGF-C in tumor-lymphangiogenesis in a mouse xenograft model. We then examined whether mTORC1 is involved in the production of VEGF-C in ovarian cancer cells as well as in tumor-lymphangiogenesis in a mouse xenograft model. Finally, by using a mouse model of paraaortic-node metastasis, we investigated whether inhibition of mTORC1 suppress lymph node metastasis.
Results: VEGF-C expression was significantly associated with the extent of LVSI or the number of lymph node metastasis in ovarian cancer specimens. In a mouse xenograft model, tumors derived from VEGF-C-high cells showed greater lymphatic vessel density than that observed in tumors from VEGF-C-low cells. Inhibition of mTORC1 by everolimus decreased the expression of VEGF-C in ovarian cancer cells in vitro, lymphangiogenesis in tumors, and paraaortic-node metastasis in mouse models.
Conclusion: Inhibition of mTORC1 may represent a novel molecular-targeted approach for lymph node metastasis prevention in patients with ovarian cancer.
Citation Format: Takeshi Hisamatsu, Seiji Mabuchi, Tomoyuki Sasano, Ryoko Takahashi, Mahiru Kawano, Yuri Matsumoto, Kae Hashimoto, Aki Isobe, Kenjiro Sawada, Kenichiro Morishige, Tadashi Kimura. The significance of vascular endothelial growth factor C in the lymphangiogenesis and lymph node metastasis of ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 378. doi:10.1158/1538-7445.AM2013-378
Abstract 3791: Secreted plectin-rich exosomes from pancreatic cancer cells promote tumor aggressiveness.
Authors: Shin Soo J. 
Published: August 2014

Abstract
Background & Aims: We recently demonstrated that the aberrant extracellular localization of the cytoskeletal linker protein plectin is a robust biomarker for the progression of pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive malignancies. Exosomes are nanometer-sized particles containing cytoplasm and plasma membrane that are secreted by both normal and cancerous cells. Recently the importance of exosomes in cross-talk in the tumor microenvironment has been demonstrated. Fusion of exosomes to the cellular membrane in either a paracrine or autocrine manner can result in aberrant protein localization. Here, we assess the mechanism for plectin mislocalization and its functional role in PDAC.
Methods: A plectin-binding assay was developed to assess the presence of cell-surface localized plectin. To examine their potential contribution to aberrant extracellular localization of plectin, we determined whether plectin was present in PDAC-secreted exosomes collected by ultracentrifugation and evaluated by immunoblotting. Based on these observations, we then determined whether exosomes with or without plectin altered gross phenotypic tumor characteristics in vitro in tumor stromal and endothelial cells. Finally, we tested the ability to alter outgrowth kinetics by directly injecting exosomes with or without plectin in tumors in vivo.
Results: Plectin was localized on the cell surface as well as present in exosomes derived from PDAC cell lines but not from non-transformed human pancreatic ductal epithelial (HPDE) cells. Plectin presence in the exosomes hinged on the expression of integrin β4, a protein known to interact with cytosolic plectin. shRNA and overexpression studies collectively demonstrated a positive role of plectin and its localization in the exosomes in proliferation, migration, and invasion of PDAC cells and migratory capacity of microenvironment cells. Finally, plectin-rich exosomes enhanced in vivo tumor growth.
Conclusions: Plectin is expressed in PDAC and is aberrantly localized to the cell surface via exosomes in an integrin β4-dependent manner. Additionally, plectin-rich exosomes induce pronounced increase in tumor growth in vitro and in vivo further they increased invasion and migration in vitro. Plectin-positive exosomes had profound effects on stromal and endothelial cells. Because cell surface plectin has been shown to be a biomarker for transition of pre-invasive to invasive PDAC, the elucidation of the mechanisms of its deregulation may provide important insights for successful detection and management of PDAC.
Citation Format: Soo J. Shin. Secreted plectin-rich exosomes from pancreatic cancer cells promote tumor aggressiveness. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3791. doi:10.1158/1538-7445.AM2013-3791