bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 354: Resistance to TGF-beta-induced apoptosis is not associated with the de-differentiation in hepatocellular carcinoma
Authors: Kogiso Tomomi , Hashimoto Etsuko , Kodama Kazuhisa , Ikarashi Yuichi , Torii Nobuyuki , Taniai Makiko , Tokushige Katsutoshi , Shiratori Keiko 
Published: August 2015

Abstract
Aim: Transforming growth factor (TGF)-beta is a cytokine which induces apoptosis of hepatocellular carcinoma (HCC) cells. However, some HCC cells show resistance to the induction of apoptosis by TGF-beta. The analyses of the molecular mechanism underlying these phenomena may be related with the mechanisms of acquirement of drug-resistance. Thus, we examined molecularly the apoptosis-resistant HCC cells which we previously established, especially emphasizing on the analyses of the stem-cell marker expression in this study.
Methods: Previously established HuH7R cells, which acquired a resistance to TGF-beta-induced apoptosis after a long-term culture under small amount of TGF-beta, and control parental HuH7 cells, were used. Apoptosis rate and cell cycle state of these cells after TGF-beta treatment were determined by a flow-cytometry. The expression levels of stem-cell surface markers, such as epithelial cell adhesion molecule (EpCAM) and CD133, and those of transcriptional factors: Oct4, HNF3alfa, HNF4beta, and C/EBPbeta, were analyzed by fluorescent labeling using specific antibodies, at 24hrs and 48hrs after TGF-beta treatment.
Results: 1) HuH7 cells showed apoptosis after 48hrs of TGF-beta treatment, whereas HuH7R did not show apoptosis but entered cell-cycle arrest. 2) The expression levels of CD133 were not affected at both 24hrs and 48hrs after TGF-beta treatment, while EpCAM expression levels increased from 24hrs, in both HuH7 and HuH7R cells. 3) The expression levels of Oct4, HNF3alfa, HNF4beta, and C/EBPbeta were also increased in HCC cells. However, those expression profiles were almost comparable in between HuH7 and HuH7R cells.
Conclusions: The acquisition of the resistance to TGF-beta-induced apoptosis in HCCs were not related with the expression changes of stem-cell markers. The acquisition of drug-resistance in HCC cells was considered through mechanisms other than the changes of the cellular differentiation status of HCC cells.
Citation Format: Tomomi Kogiso, Etsuko Hashimoto, Kazuhisa Kodama, Yuichi Ikarashi, Nobuyuki Torii, Makiko Taniai, Katsutoshi Tokushige, Keiko Shiratori. Resistance to TGF-beta-induced apoptosis is not associated with the de-differentiation in hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 354. doi:10.1158/1538-7445.AM2015-354
Abstract 3546: Arming a tumor targeted oncolytic herpes simplex sirus type 1 with matrix metalloproteinase 9 for enhanced vector distribution and killing activity
Authors: Li Aofei , Marzulli Marco , Zhang Mingdi , Goins William , Kaur Balveen , Bolyard Chelsea , Amankulor Nduka , Leronni Daniela , Sette Paola , Cohen Justus , Glorioso Joseph , Grandi Paola 
Published: August 2015

Abstract
Early phase human clinical trials using several versions of oncolytic herpes simplex virus type 1 (oHSV) have shown promise in the treatment of GBM, but efficacy has been limited. Impediments to oHSV therapy include poor virus spread due in part to the tumor extracellular matrix, and insufficient replication in tumor cells as a result of attenuating mutations. Thus, the central goal of this project is to improve oncolytic vector delivery, replication and spread while maintaining safety and tumor specificity. We have already developed a new class of two stage tumor targeted oHSV combining (i) selective infection through tumor-specific receptors and (ii) selective replication based on differential expression of microRNAs (miRs) in tumor and normal cells. We further modify our vector by arming with the matrix metalloproteinase 9 (MMP9) as a means to reduce vector trapping in the tumor extracellular matrix. Here we show that MMP9 expression (i) enhances Oncolytic vector spreading in GBM neruospheres in vitro and (ii) improves tumor killing in a xenogeneic model of primary human GBM with significant long-term survival (≥50%) comparable to the control.
Citation Format: Aofei Li, Marco Marzulli, Mingdi Zhang, William Goins, Balveen Kaur, Chelsea Bolyard, Nduka Amankulor, Daniela Leronni, Paola Sette, Justus Cohen, Joseph Glorioso, Paola Grandi. Arming a tumor targeted oncolytic herpes simplex sirus type 1 with matrix metalloproteinase 9 for enhanced vector distribution and killing activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3546. doi:10.1158/1538-7445.AM2015-3546
Abstract 3547: Systemically delivered human telomerase reverse transcriptase (hTERT)-targeting p53-laden adenovirus shows strong antitumor effects in intrahepatic Hep3B xenograft mouse model
Authors: Lee Won Sup , Kang Hye Lim , Nagappan Arulkumar , Yun Jeong Won , Kim GonSup , Hong Soon Chan , Lee Sang-Jin , Kim In-Hoo 
Published: August 2015

Abstract
Human telomerase reverse transcriptase (hTERT) RNA and p53 tumour suppressor were previously suggested as useful targets for cancer gene therapy. In this study, we investigated the effects of systemically delivered adenoviruses harboring trans-splicing ribozyme that could target hTERT and induce p53 transcript in targeted cancer cells in vivo using mice with Hep3B human hepatocellular carcinoma cells that metastasized to the liver. We observed that intravenous injection of this virus (0.5 X1011 Virus) produced efficient regression of Hep 3B tumor metastasized nodules. Next we performed in vitro study to know whether it has a synergistic effects with CDDP, we observed that CDDP (2.5 ug/ml) increased cytotoxic effects in vitro given with the virus (10 MOI), but in vivo study revealed that addition of CDDP or arsenic hexoxide (As4O6) did not improve the therapeutic efficacy of the virus treatment. Next we performed toxicity test with 4 doses (0.5 X1011, 1 X1011, 2 X1011, and 5 X1011, Virus), which revealed that there were no toxic death, but 2-4 fold increased in AST and ALT with no changes in bilirubin, BUN, Creatinine levels. In conclusion, this study demonstrates that the adenoviruses harboring trans-splicing ribozyme targeting hTERT and inducing p53 transcript represents a safe and promising cancer treatment for hepatocellular carcinoma. [This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare & Family Affairs, Republic of Korea. (0820050), and National Research Foundation of Korea (NRF) grant funded by the Korea government(MEST) (20120002631).]
Keywords: Adenovirus, trans-splicing ribozyme, p53 tumour suppressor, Human Telomerase Reverse Transcriptase, cancer
Citation Format: Won Sup Lee, Hye Lim Kang, Arulkumar Nagappan, Jeong Won Yun, GonSup Kim, Soon Chan Hong, Sang-Jin Lee, In-Hoo Kim. Systemically delivered human telomerase reverse transcriptase (hTERT)-targeting p53-laden adenovirus shows strong antitumor effects in intrahepatic Hep3B xenograft mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3547. doi:10.1158/1538-7445.AM2015-3547
Abstract 355: A monoclonal antibody against laminin alpha 4 inhibits both MCAM and integrin-a6b1 binding, blocks tumor cell adhesion in vitro and slows melanoma tumor growth in vivo
Authors: Tam Stephen J. , Li Lauri E. , Lorenzana Carlos , Liu Yue , Flanagan Ken , Dolan Philip J. , Alexander Lana , Salmans Josh , Barbour Robin M. , Higaki Jeffrey N. , Nijjar Tarlochan , Zago Wagner , Yednock Ted A. , Kinney Gene 
Published: August 2015

Abstract
Laminin is an extracellular matrix molecule that is secreted as a trimeric protein composed of an α, β and γ chain. There are five distinct laminin α chains that impart distinct binding and signaling activities for cell adhesion, migration, and differentiation in a tissue-specific fashion. Laminin a4 (LAMA4) is expressed by vascular endothelial cells throughout the body, but is also overexpressed by cells within tumors of different origin compared to healthy human tissue. LAMA4 serves as a ligand for the cell adhesion receptors MCAM and a6b1 integrin, as well as for cell surface heparin sulfate proteoglycans. In order to probe how the MCAM/Laminin interaction contributes to tumor growth, we screened for LAMA4-specific monoclonal antibodies that block MCAM binding. We identified several such antibodies, and found that a subset also inhibits LAMA4 binding to a6b1 integrin, indicating that MCAM and a6b1 integrin recognize a similar region of LAMA4. Examining cells from multiple types of tumors, we found that these antibodies were potent inhibitors of tumor cell adhesion to LAMA4 in vitro. Finally, with in vivo administration, we demonstrated dose-dependent inhibition of human melanoma tumor growth in a mouse xenograft model, accompanied by morphologic changes in LAMA4 tumor distribution. These findings suggest that the MCAM/a6b1 integrin binding activity of LAMA4 contributes to both tumor adhesion and growth and that LAMA4 may provide a therapeutic drug target for several different oncology indications.
Citation Format: Stephen J. Tam, Lauri E. Li, Carlos Lorenzana, Yue Liu, Ken Flanagan, Philip J. Dolan, Lana Alexander, Josh Salmans, Robin M. Barbour, Jeffrey N. Higaki, Tarlochan Nijjar, Wagner Zago, Ted A. Yednock, Gene Kinney. A monoclonal antibody against laminin alpha 4 inhibits both MCAM and integrin-a6b1 binding, blocks tumor cell adhesion in vitro and slows melanoma tumor growth in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 355. doi:10.1158/1538-7445.AM2015-355
Abstract 356: Mutaome-based magnolin sensitivity in ovarian cancer cells
Authors: Song Ji-Hong , Kim Woo-Young , Cho Yong-Yeon 
Published: August 2015

Abstract
Signaling pathways mediated through Ras/Raf/MEK/ERK and/or PI3K/AKT/mTOR signaling pathways play a key role in cell transformation and cancer development. During carcinogenesis, genomic alterations, accumulation of mutations and amplification of growth signaling, induce cellular phenotype changes including escaping aging, metabolic change of energy source and resistance against therapeutic agents. Recently, our research group has identified a natural compound, magnolin, that inhibits ERK1 and ERK2 kinase activities with about 87 uM and 16.5 uM of IC50, respectively. However, the effect of magnolin in cancer cells has been poorly understood. To explore the effect of magnolin in cancer cells, we examined anti-proliferation effect of magnolin in pancreatic, colon and ovarian cancer cells. We found that striking differences of cancer cell proliferation was observed in ovarian cancer cells, TOV112D and SKOV3, by magnolin treatment. In TCGA mutaome data-base analysis, we found that TOV112D and SKOV3 harbor the different mutations in different genes which are known to involve in chemo-resistance. In cell cycle analysis, we found that TOV112D reduced S-phase of cell cycle and increased G1/G0-phase of cell cycle. Importantly, activation protein profiles in TOV112D and SKOV3 cells by Western blotting showed that phosphorylation of p90RSK including RSK2 was higher in SKOV3 cells compared with TOV112D cells. These results strongly suggested that alteration of p90RSK signaling may play an important role in expression of chemo-resistance in ovarian cancer cells.
Citation Format: Ji-Hong Song, Woo-Young Kim, Yong-Yeon Cho. Mutaome-based magnolin sensitivity in ovarian cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 356. doi:10.1158/1538-7445.AM2015-356
Abstract 3569: Inhibition of the TRPM7 kinase domain inhibits breast cancer cell migration and invasion and tumor metastasis
Authors: Kaoud Tamer S. , Xie Xuemei , Park Jihyun , Tavares Clint D.J. , Mitra Shreya , Cano Micael , Sammons Rachel M. , Radwan Mohamed F. , Bartholomeusz Chandra , Dalby Kevin N. 
Published: August 2015

Abstract
TRPM7 (transient receptor potential melastatin 7) is a non-selective cation channel fused to protein kinase domain at the C-terminal whose activity is linked to the control of actomyosin contractility. TRPM7 mediates adhesion and migration of breast cancer cells and promotes breast tumor metastasis. The lack of cell-permeable inhibitors of the kinase domain represents a barrier to understand the kinase function. Herein, we discovered the first small molecule (KD-1) that targets TRPM7 kinase activity. Mg2+ starvation, which promotes TRPM7 kinase activity, induces phosphorylation of eEF2. Treatment of Mg2+-starved HEK293 cells with KD-1 decreased eEF2 phosphorylation, consistent with TRPM7 kinase activity suppression in-cells. KD-1 decreased the binding of Myosin IIB to TRPM7 in HEK293 and MDA-MB-231 cells. And when MDA-MB-231 cells were treated with increasing doses of KD-1, no change in cell viability was seen. Interestingly, KD-1 inhibited MDA-MB-231 cells migration and invasion that is reportedly regulated by TRPM7 kinase activity. Finally, the bioluminescent signals (to assess metastasis) were significantly lower in KD-1-treated mice (25 and 50 mg/kg/day) than in mice treated with vehicle control (P ≤ 0.05, 2-sided t-test.). in conclusion, inhibition of TRPM7 kinase activity may reduce or block breast tumor progression and/or metastasis.
Citation Format: Tamer S. Kaoud, Xuemei Xie, Jihyun Park, Clint D.J. Tavares, Shreya Mitra, Micael Cano, Rachel M. Sammons, Mohamed F. Radwan, Chandra Bartholomeusz, Kevin N. Dalby. Inhibition of the TRPM7 kinase domain inhibits breast cancer cell migration and invasion and tumor metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3569. doi:10.1158/1538-7445.AM2015-3569
Abstract 3571: Furin activity: A driver of rhabdomyosarcoma progression
Authors: Jaaks Patricia AIM , Meier Gianmarco , Schäfer Beat W. , Bernasconi Michele 
Published: August 2015

Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The prognosis and survival rate is often very poor and therefore new therapy approaches are required. Thus, we focus on 1) employing RMS-specific peptides for targeted delivery of chemotherapeutics to the tumor site and 2) identifying novel therapeutic targets. In a previous study we discovered that RMS-homing peptides bind preferably to the proprotein convertase furin. Initial investigations confirmed a high expression of furin throughout different pediatric soft tissue sarcoma types and hinted that furin promotes the tumorigenic phenotype of RMS cells in vitro as well as in corresponding xenografts in vivo. Here we present a novel approach of tetracycline-induced shRNA-based silencing of furin in vitro and in vivo in order to investigate in depth the role of furin in RMS progression. Furin depletion was confirmed at mRNA, protein and activity level and led to impaired maturation furin substrates insulin like growth factor 1 receptor (IGF1R) and transforming growth factor beta 1 (TGFβ-1). We found that loss of furin activity suppresses the malignant phenotype of Rh30 cells by decreasing proliferation and affecting formation of colonies. Furthermore, we observed increased caspase 3/7 activity and enrichment of nucleosomes in the cytoplasm upon furin depletion, thus hinting initiation of apoptotic processes. Induction of furin silencing in RMS xenografts in NOD/SCID mice delayed tumour growth, indicating a crucial role of furin in early phases of tumour growth. Taken together, our data underscore the importance of furin for RMS progression and therefore targeting the activity of furin represents a promising tool for treatment of RMS.
Citation Format: Patricia AIM Jaaks, Gianmarco Meier, Beat W. Schäfer, Michele Bernasconi. Furin activity: A driver of rhabdomyosarcoma progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3571. doi:10.1158/1538-7445.AM2015-3571
Abstract 3636: Targeting the MLL complex in castration resistant prostate cancer
Authors: Malik Rohit , Khan Amjad P. , Asangani Irfan A. , Cieślik Marcin , Prensner John R. , Wang Xiaoju , Iyer Matthew K. , Jiang Xia , Borkin Dmitry , Escara-Wilke June , Stender Rachell , Wu Yi-Mi , Cao Xuhong , Feng Felix Y. , Grembecka Jolanta , Cierpicki Tomasz , Chinnaiyan Arul M. 
Published: August 2015

Abstract
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration resistant prostate cancer (CRPC). Substantial prior work has focused on targeting AR directly; however, the identification and therapeutic targeting of co-activators of AR signaling remains an underexplored area of potential clinical significance. Here we demonstrate that the MLL (mixed-lineage leukemia) complex, a well-known contributor in MLL-fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via its critical subunit, menin. Small molecule inhibition of the menin-MLL interaction blocks AR signaling and inhibits the growth of castration resistant tumors in vivo. Furthermore, we find that menin is up-regulated in castration resistant prostate cancer and high expression correlates with poor overall survival. Taken together, our study identifies the MLL complex as a critical co-activator of AR that can be targeted in advanced prostate cancer.
Citation Format: Rohit Malik, Amjad P. Khan, Irfan A. Asangani, Marcin Cieślik, John R. Prensner, Xiaoju Wang, Matthew K. Iyer, Xia Jiang, Dmitry Borkin, June Escara-Wilke, Rachell Stender, Yi-Mi Wu, Xuhong Cao, Felix Y. Feng, Jolanta Grembecka, Tomasz Cierpicki, Arul M. Chinnaiyan. Targeting the MLL complex in castration resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3636. doi:10.1158/1538-7445.AM2015-3636
Abstract 365: Mobilizing prostate cancer cells from the endosteal niche by targeting the SDF-1/CXCR4 axis
Authors: Valkenburg Kenneth C. , Pienta Kenneth J. 
Published: August 2015

Abstract
Metastatic prostate cancer cells preferentially home to bone, and skeletal metastases are present in approximately 90% of patients upon autopsy. Our lab was the first to show that prostate cancer cells compete with hematopoietic stem cells (HSCs) for space within the endosteal niche. The HSC niche is located on the surface of endosteal osteoblasts, where HSCs are kept in a slow-cycling, protective state. The niche also provides prostate cancer cells with a chemoprotective environment in which they can remain dormant for an extended period of time, even decades. C-X-C chemokine receptor 4 (CXCR4) is required for HSC recruitment to the HSC niche. Osteoblasts secrete stromal cell derived factor 1 (SDF-1, also known as CXCL12), the ligand for CXCR4, which attracts HSCs to the niche via a chemotactic gradient. CXCR4 is also expressed by disseminated prostate cancer cells and is required for prostate cancer cells homing to bone. HSCs can be mobilized from the niche into the bloodstream physiologically via infection or stress and pharmacologically via proteins like granulocyte-colony stimulating factor (G-CSF) or small molecule inhibitors like AMD3100 (plerixafor). AMD3100, which antagonizes CXCR4, is capable of mobilizing both HSCs and prostate cancer cells from the niche. When combined with AMD3100, docetaxel (the standard of care for prostate cancer) is more effective at killing tumor cells than when given as a single agent. This indicates that mobilization of disseminated tumor cells (DTCs) from the endosteal niche by targeting the SDF-1/CXCR4 axis might cause these cells to be more sensitive to chemotherapy in patients. This strategy would theoretically kill DTCs, which, when they become metastatic lesions, lead to most of the morbidity and mortality that affects prostate cancer patients. We are engaged in a Phase 0 clinical trial in metastatic prostate cancer patients to test this strategy in human patients. To complement the human trial, we are testing several CXCR4 inhibitors combined with G-CSF and docetaxel. We are able to detect CTCs in human patients, as well as CTCs and DTCs in mice via several techniques, and will use this technology as a readout for the clinical trial, as well as the preclinical studies.
Citation Format: Kenneth C. Valkenburg, Kenneth J. Pienta. Mobilizing prostate cancer cells from the endosteal niche by targeting the SDF-1/CXCR4 axis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 365. doi:10.1158/1538-7445.AM2015-365