bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5007: A novel polyisoprenylated cysteinyl amide inhibitor, NSL-BA-055, selectively inhibits proliferation of hepatocellular carcinoma cells
Authors: Naidoo Michelle K. , Lamango Nazarius , Ogunwobi Olorunseun O. 
Published: August 2015

Abstract
The monomeric GTP-ase, Ras, is mutated in over 30% of cancers where it promotes uncontrolled proliferation of cancer cells. Ras signaling is one of many pathophysiological pathways implicated in hepatocellular carcinoma that results in cell survival, differentiation, proliferation, and angiogenesis. Ras is bound to the cytoplasmic face of the plasma membrane where it relays intracellular signals. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) effectively disrupt the functions of polyisoprenylated proteins such as Ras. Many hepatocellular carcinomas (HCCs) have dysregulated Ras signaling. However, the effects of PCAIs on hepatocellular carcinoma (HCC) are unknown. The aim of this study was to investigate the effect of a novel PCAI, NSL-BA-055, on HCC. Concentrations of NSL-BA-055 ranging from 0 to 10 μM were used for experimentation. Effects on proliferation of BNL CL.2 (non-tumorigenic mouse hepatocytes) and BNL 1ME A.7R.1 (mouse HCC cells derived from BNL CL.2 hepatocytes) were analyzed. Next, the effects of NSL-BA-055 on Akt protein expression, a downstream component of Ras signaling, were examined by western blotting. NSL-BA-055 significantly inhibited the proliferation of BNL 1ME A. 7R.1 HCC cells, but not the non-tumorigenic BNL CL.2 hepatocytes. Also, concentrations of the NSL-BA-055 compound as low as 4 μM significantly inhibited the proliferation of BNL 1ME A.7R.1 HCC cells. Western blotting revealed that NSL-BA-055 inhibited Akt protein expression at 4μM. Therefore PCAIs such as NSL-BA-055 is a novel class of agents that selectively inhibit the proliferation of HCC cells, but not normal hepatocytes. This effect may be via inhibition of Akt, a downstream intermediate of Ras signaling. Consequently, NSL-BA-055 is a novel candidate agent for HCC therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Michelle K. Naidoo, Nazarius Lamango, Olorunseun O. Ogunwobi. A novel polyisoprenylated cysteinyl amide inhibitor, NSL-BA-055, selectively inhibits proliferation of hepatocellular carcinoma 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 5007. doi:10.1158/1538-7445.AM2015-5007
Abstract 5018: HLA class I expression in a tumor is higher than that out of a tumor: Promising new findings for antigen-specific cancer immunotherapy
Authors: Nobuoka Daisule , Takahashi Mari , Yoshikawa Toshiaki , Yagi Takahito , Fujiwara Toshiyoshi , Nakatsura Tetsuya 
Published: August 2015

Abstract
Background: We have demonstrated that intratumoral peptide injection is an attractive strategy that enhances tumor cell antigenicity by means of additional peptide loading onto HLA class I molecules (Nobuoka D, et al. Cancer Immunol Immunother, 62: 639-652, 2013). However, HLA class I expression has been reported to be down-regulated in various malignancies, which may explain why most studies on antigen-specific cancer immunotherapy did not demonstrate a remarkable benefit.
Methods: The tissue samples of histologically confirmed hepatocellular carcinoma were obtained from 20 patients who underwent hepatectomy. The paraffin-embedded blocks of tumor area and nontumorous liver were analyzed using monoclonal anti-HLA class I antibody, EMR 8-5. The fresh tissue samples were analyzed using another monoclonal anti-HLA class I antibody, W6/32. Moreover, HLA class I expression in a tumor and that out of a tumor were compared in various types of cancer.
Results: Among 20 patients with hepatocellular carcinoma, 14 (70%) were graded as having high expression (++) of HLA class I molecules using EMR 8-5 in cancer cells, whereas 15 patients (75%) were graded as having negative expression (-) in nontumorous hepatocytes. The immunoreactivity level in cancer cells was significantly higher than that in nontumorous hepatocytes (P &lt; 0.05). Moreover, similar observations were obtained using W6/32. In other types of cancer including intrahepatic cholangiocarcinoma, ampullary carcinoma, gallbladder carcinoma, pancreatic carcinoma, esophageal carcinoma, colon carcinoma, and breast carcinoma, most cancer cells has higher expression of HLA class I than surrounding normal cells.
Conclusions: HLA class I expression is not so down-regulated as previously reported. Intratumoral peptide injection is applicable in various malignancies.
Citation Format: Daisule Nobuoka, Mari Takahashi, Toshiaki Yoshikawa, Takahito Yagi, Toshiyoshi Fujiwara, Tetsuya Nakatsura. HLA class I expression in a tumor is higher than that out of a tumor: Promising new findings for antigen-specific cancer immunotherapy. [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 5018. doi:10.1158/1538-7445.AM2015-5018
Abstract 5035: Effect of FXR agonist on colitis and colorectal carcinogenesis in mice
Authors: Miyazaki Tsuneyuki , Kochi Takahiro , Sakai Hiroyasu , Shirakami Yohei , Shimizu Masahito , Tanaka Takuji , Moriwaki Hisataka 
Published: August 2015

Abstract
Background & Aims: Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and bile acids are endogenous ligand of FXR. FXR is highly expressed in the intestine and liver where FXR is essential for maintaining bile acid homeostasis. FXR activation has recently reported to inhibit intestinal inflammation and tumor development. The aim of this study was to investigate whether FXR agonist prevents colitis and colorectal carcinogenesis in mice.
Methods: We achieved two experiments. One experiment (Ex.1) used mouse colitis model with short term administration of FXR agonist, Nelumal A, and the other (Ex.2) employed mouse carcinogenesis model with long term administration. In Ex.1, male 5 week old A/J mice received drinking water containing 1.5% DSS for one week and were fed diets containing 100 or 400 ppm Nelumal A for 4 weeks. In Ex.2, male 5 week old A/J mice were administered once intraperitoneal injec¬]]tions of AOM (20 mg/kg body weight) and after one week, mice received drinking water containing 1.5% DSS for one week and were fed diets containing 100 or 400 ppm Nelumal A for 15 weeks.
Results: In Ex.1, DSS-treated mice all had colitis and multiple colonic mucosal ulcers. Both mucosal ulcer and inflammation grade in colon were significantly reduced in 400 ppm Nelumal A-treated mice, and also tended to be reduced in 100 ppm Nelumal A-treated mice. Body weight loss and colon length had no significant difference. The results of Ex.2 showed that the number of colonic mucosal ulcer, adenoma, and adenocarcinoma and total tumor number were decreased in 400 ppm Nelumal A-treated mice, but there was no statistically significant difference. The expression levels of FXR mRNA in colonic mucosa were increased by Nelumal A treatment. Moreover, administration of Nelumal A significantly decreased the expression levels of tumor necrosis factor α, monocyte chemoattractant protein 1, and proliferating cell nuclear antigen, and increased the level of Bax in colonic epithelium.
Conclusion: FXR agonist prevents chemically induced intestinal inflammation and carcinogenesis by inhibition of proinflammatory cytokine production and cell proliferation and promotion of apotosis in colonic mucosa.
Citation Format: Tsuneyuki Miyazaki, Takahiro Kochi, Hiroyasu Sakai, Yohei Shirakami, Masahito Shimizu, Takuji Tanaka, Hisataka Moriwaki. Effect of FXR agonist on colitis and colorectal carcinogenesis in mice. [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 5035. doi:10.1158/1538-7445.AM2015-5035
Abstract 5087: Precise characterization of macrophage secretory exosomes can lead to novel therapeutic approaches
Authors: Bednarczyk Robert Bronislaw , Kitadai Yuki , Tuli Neha Y. , Hanly Elyse K. , Benrahoma Ghada , Mittelman Abraham , Tiwari Raj K. 
Published: August 2015

Abstract
Multiple cell types interact within the tumor microenvironment (TME) through crosstalk events that are mediated by many biomolecules including cytokines, mRNA, and miRNA-containing exosomes that can influence cancer progression as well as suppression. Inflammation within the TME is a major determinant in tumor progression. Since tumor associated macrophages (TAMs) are a major cellular factor in tumor inflammation, we hypothesized that crosstalk events initiated by macrophage secreted factors such as cytokines and exosomes will modulate breast cancer phenotype. We evaluated the cytokine profile of a human monocytic cell line, THP-1, following stimulation with a phorbol ester TPA (12-O-Tetradecanoylphorbol-13-acetate) in vitro. Activated THP-1 cells exhibited an M1 macrophage phenotype. In addition, we assessed the morphological and cellular growth changes of luminal (T47D, MCF-7) and basal-like (MDA-MB 231) breast cancer cell lines in vitro following treatment with activated THP-1 conditioned medium (CM). Each cell line displayed mesenchymal-like features and decreased cellular growth following activated THP-1 CM treatment. MCF-7 and MDA-MB 231 displayed increased MEK/ERK signaling, while all three cell lines showed increased p-AKT expression. Furthermore, epithelial-like T47D and MCF-7 cells exhibited an increase in EMT transcription factor expression. Moreover, although T47D and MCF-7 did not show drastic changes in E-cadherin expression via western blot analysis, immunofluorescence examination showed a decrease in E-cadherin following activated THP-1 CM treatments emphasizing a possible partial EMT event. Lastly, activated THP-1 exosomes were isolated and used to treat MDA-MB 231 to determine the effects on breast cancer cell proliferation and senescence. MDA-MB 231 exhibited significantly decreased cellular growth and increased senescence following incubation with activated THP-1 exosomes. The variety of secretory factors within the TME as a result of inflammation may contribute to tumor suppression as well as tumor progression via a secretion of cytokines and exosomes.
Citation Format: Robert Bronislaw Bednarczyk, Yuki Kitadai, Neha Y. Tuli, Elyse K. Hanly, Ghada Benrahoma, Abraham Mittelman, Raj K. Tiwari. Precise characterization of macrophage secretory exosomes can lead to novel therapeutic approaches. [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 5087. doi:10.1158/1538-7445.AM2015-5087
Abstract 5091: Inhibiting endothelium directed tumor cell streaming by targeting the HGF/C-Met and EGF/CSF-1 signaling pathways
Authors: Leung Edison , Wang Yarong , Smith Bryan , Flynn Daniel , Condeelis John 
Published: August 2015

Abstract
In vivo, tumor cells need to migrate towards blood vessels in order to metastasize. Streaming, a specialized mode of migration involving chemotactic signaling between macrophages and tumor cells, allows linear streams of tumor cells to migrate directionally towards blood vessels on collagen I-containing ECM fibers in vivo. We have successfully reconstructed tumor cell streaming in vitro by co-plating tumors cells, macrophages, and endothelial cells on 2.5 um micro-patterned substrates. We found that tumor cells and macrophages do not demonstrate directional migration in only one direction but random walk. Directional streaming migration of tumor cells in only one direction was established when beads coated with human umbilical vein endothelial cells (HUVEC) were placed at one end of the micro-patterned “collagen fibers” within the assay. Using this in vitro reconstituted streaming system, we found that directional streaming can be blocked by inhibiting multiple signaling pathways - notably the HGF/C-Met signaling pathway between endothelial cells and tumor cells and the EGF/CSF-1 paracrine loop between macrophages and tumor cells. These pathways were blocked using gefitinib (EGFRi), DCC-3014 (CSFRi), and altiratinib (DCC-2701)(c-Meti), which led to a marked decrease in endothelium directed streaming of the tumor cells. The inhibitors showed different efficacies of inhibition of streaming at different distances from the endothelium indicating that HGF from the endothelium organized the random walk of paired macrophages and tumor cells into a directional migration. Key observations made with the in vitro reconstituted system were reproduced in mammary tumors using the in vivo invasion assay. These results highlight a promising role for combinations of these inhibitors in blocking tumor cell streaming and metastasis in vivo and for use in human trials.
Citation Format: Edison Leung, Yarong Wang, Bryan Smith, Daniel Flynn, John Condeelis. Inhibiting endothelium directed tumor cell streaming by targeting the HGF/C-Met and EGF/CSF-1 signaling pathways. [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 5091. doi:10.1158/1538-7445.AM2015-5091
Abstract 5104: Isorhapontigenin (ISO) inhibits cancer invasion by enhancing FOXO1 transcription through targeting STAT1 phosphorylation at Tyr701
Authors: Xue Lei , Jiang Guosong , Li Jingxia , Huang Chuanshu 
Published: August 2015

Abstract
Muscle invasion of bladder cancer can progress to life threatening metastases. Isorhapontigenin (ISO) is a novel derivative of stilbene that isolated from a Chinese herb Gnetum cleistostachyum, which has been used for centuries as treatment for several cancers including bladder cancer. However, nothing is known whether ISO possesses an inhibitory effect on invasion in human cancers. Here, we found that 10 to 20 mmol/L of ISO, which were relevant to in vivo study, inhibited human bladder cancer cell invasion accompanied by up-regulation of the forkhead box class O1 (FOXO1) mRNA transcription. Accordingly, FOXO1 was significantly down-regulated in invasive human bladder cancer tissues, and forced expression of FOXO1 specifically suppressed invasion of human bladder cancer cells. Moreover, knockdown of FOXO1 expression abolished the ISO inhibition of invasion. Further studies showed that increased FOXO1 transcription was accompanied by reduction of STAT1 phosphorylation at Tyr701, and repressing STAT1 phosophorylation by the overexpression of dominant negative STAT1 could mimic the effect of ISO treatment on FOXO1 transcription, while the mutation of STAT1's binding site in the FOXO1 promoter profoundly impaired ISO-induced up-regulation of FOXO1 transcription. Furthermore, this study revealed that metalloproteinase-2 (MMP-2) was a FOXO1 downstream effector mediating its effect on bladder cancer invasion. These findings not only provide a novel insight into the understanding of underlying mechanism of bladder cancer's propensity to invasion, but also identify a new role and mechanisms underlying the natural compound ISO that specifically suppresses such invasion through targeting the STAT1-FOXO1-MMP2 axis.
Citation Format: Lei Xue, Guosong Jiang, Jingxia Li, Chuanshu Huang. Isorhapontigenin (ISO) inhibits cancer invasion by enhancing FOXO1 transcription through targeting STAT1 phosphorylation at Tyr701. [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 5104. doi:10.1158/1538-7445.AM2015-5104
Abstract 5106: Influence of chloride flux on cell motility in head and neck squamous cell carcinoma
Authors: Khan Nayel , Steehler Kevin , Kemp Carolyn , Kulkarni Sucheta , Davis Kara , Duvvuri Umamaheswar 
Published: August 2015

Abstract
Purpose: To assess the specific involvement of chloride flux through TMEM16A in the regulation of tumor cell motility.
Background: Head and neck squamous cell carcinoma (HNSCC) often features tumor metastases and is associated with decreased patient survival. A key feature of the metastatic process is the ability of the cancer cells to migrate. TMEM16A, a calcium-activated chloride channel (CaCC), has been shown to play a role in cell migration and tumor metastasis, most recently as a potential node between cell proliferation versus cell migration. However, the role of chloride flux in this phenomenon has yet to be elucidated.
Methods: HNSCC cell lines were engineered to stably overexpress or knock-down TMEM16A. Cell migration was assessed via wound healing and transwell migration assays in cell culture media with varying chloride concentrations and in the presence of a TMEM16A specific inhibitor. The impact of chloride manipulation on EMT markers (E-cadherin, vimentin, ZO-1) was assessed using immunoblotting.
Results: Data obtained by both cell migration assays showed that in conditions of physiologically normal chloride, OSC19 TMEM16A overexpressors migrated less when compared to OSC19 vector controls. However, in conditions of low chloride, the migration rates between both cell lines were similar. Furthermore, inhibition of chloride flux using chloride depleted media, or pharmacologic inhibition of TMEM16A lead to a decrease in cell motility. As expected, an increase in markers of epithelial phenotype (i.e., Zo-1) and decrease in markers of mesenchymal phenotype (i.e., alpha-smooth muscle actin) in cells incubated in low chloride media was observed.
Conclusion: This data further supports the evidence that increased TMEM16A expression is correlated with decreased cell motility and therefore potential for cell metastasis. In addition, we have shown a role of chloride flux in TMEM16A's ability to modulate cell motility with a correlated change in EMT.
Citation Format: Nayel Khan, Kevin Steehler, Carolyn Kemp, Sucheta Kulkarni, Kara Davis, Umamaheswar Duvvuri. Influence of chloride flux on cell motility in head and neck squamous cell 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 5106. doi:10.1158/1538-7445.AM2015-5106
Abstract 5112: In vivo molecular imaging of HIF-1α and septin 9 interaction by bimolecular fluorescence complementation
Authors: Golan Maya , Mabjeesh Nicola J. 
Published: August 2015

Abstract
Hypoxia is a common feature of many solid tumors that promotes tumor progression and leads to radiation and chemotherapy resistance. Hypoxia-inducible factor 1 (HIF-1), as one of the major mediators of the hypoxic response, has been shown to activate hypoxia-responsive genes, which are involved in multiple aspects of tumorigenesis and cancer progression.
Previously, we have described an interaction between septin 9 isoform 1 (SEPT9_i1) protein and HIF-1α, the oxygen regulated subunit of HIF-1. SEPT9_i1 is a member of the conserved family of septins, which are GTP-binding proteins that form cytoskeleton-like filaments essential for many functions in eukaryotic organisms including neoplasia. The interaction of SEPT9_i1 with HIF-1α increases protein stability and HIF-1 transcriptional activity in vitro and promotes proliferation, tumor growth and angiogenesis in vivo. Recent data indicated that SEPT9_i1 was also involved in the trafficking of cytoplasmic HIF-1α into the nucleus by direct interaction to the nuclear transporter importin-α. Herein, we utilized split YFP bimolecular fluorescence complementation (BiFC) methodology in order to monitor HIF-1α/SEPT9_i1 interactions in vivo. First, we generated split YFP protein chimeras fused to HIF-1α and to SEPT9_i1 on both their amino and carboxyl termini. Different pairs of HIF-1α and SEPT9_i1 chimeras were tested to functional complementation of the split YFP fragments using transient transfection in HEK293 cells. The complemented proteins capable of fluorescence were identified as SEPT9_i1-YN (the amino terminus of YFP fused to the carboxyl terminal of SEPT9_i1) and YC-HIF-1α (the carboxyl terminus of YFP fused to the N-terminal of HIF-1α). This pair was selected for further studies in PC-3 human prostate cancer cells. YFP complementation fluorescence derived from these chimeras was increased in the presence of hypoxia mimicking agents, such as CoCl2 and the iron chelators deferoxamine (DFO) and dibenzoylmethane (DBM). The chimera, YCΔHLH lacking the HLH domain that is essential for the interaction with SEPT9_i1 gave a significant reduction in YFP complementation fluorescence. Furthermore, expression of SEPT9_i1 252-379aa fragment, the domain essential for the interaction with HIF-1α, abolished almost completely the YFP complementation fluorescence. These results reconfirm our previous studies on HIF-1α/SEPT9_i1 interactions and make this system attractive for identifying new compounds capable of disrupting this complex in order to inhibit tumor growth and angiogenesis.
Citation Format: Maya Golan, Nicola J. Mabjeesh. In vivo molecular imaging of HIF-1α and septin 9 interaction by bimolecular fluorescence complementation. [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 5112. doi:10.1158/1538-7445.AM2015-5112
Abstract 517: The role of MYST4 in ovarian carcinoma
Authors: Mao Tsui Lien , Lin Hsuan-Ping , Sheu Jim 
Published: August 2015

Abstract
Histone acetyltransferases (HATs) play critical roles in the process of cell growth and development. However, little is known about the relationship between MYST4, a known HAT, and human tumors. In our previous studies, we found that MYST4 was overexpressed in ovarian high-grade serous carcinomas and patients with tumors overexpressing MYST4 had significantly worse survival. To explore the role of MYST4 in ovarian carcinoma, we built up stable ovarian cancer cell lines with MYST4 knockdown by shRNA. By cell proliferation assay and flow cytometry, we found that MYST4 enhanced cancer cell growth and regulated cell cycle progression. In addition, the migration distance was significantly decreased in MYST4 knockdown cell lines, suggesting that MYST4 promotes cellular migration. Further cDNA microarray revealed several target genes that were down-regulated by MYST4 knockdown, some have been reported to be involved in tumorigenesis and aggressive tumor behavior. Together, our study suggests that MYST4 promotes cancer cell growth and migration. Overexpression of MYST4 in cancer cells may contribute to tumors toward a more aggressive behavior. Thus, MYST4 may serve as a potential target in treating ovarian carcinomas overexpressing MYST4.
Citation Format: Tsui Lien Mao, Hsuan-Ping Lin, Jim Sheu. The role of MYST4 in ovarian 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 517. doi:10.1158/1538-7445.AM2015-517