bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3988: Deregulated sphingosine 1-phosphate signaling contributes to a more aggressive phenotype in oral squamous cell carcinoma cells.
Authors: Johnson Steven , Yap Lee Fah , Narayanan Sathya , Paterson Ian 
Published: August 2014

Abstract
Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide, accounting for more than 250,000 new cases each year. Early death usually occurs as a result of local invasion and regional lymph node metastases and overall five year mortality rates are approximately 50%. Novel therapeutic targets are urgently required. Sphingosine 1-phosphate (S1P) regulates many biological processes associated with tumour development and progression, with the specific effects of S1P being determined, in part, by the profile of receptor expression in tumor cells. Sphingosine kinase 1 (SphK1), an enzyme responsible for the production of S1P, has been reported to be overexpressed in OSCC tissues, but the effect of S1P on the behavior of OSCC cells and the expression of S1P receptors in OSCC has not been examined. The effect of S1P on OSCC cells was examined by treating OSCC cell lines in vitro. S1P inhibited the proliferation of OSCC cells but stimulated cell scattering in colony dispersal assays, causing colonies to disperse into single, highly migratory cells. S1P-induced cell migration was dependent on the MEK, ROCK and Rac-1 signaling pathways. Additionally, S1P enhanced tumor cell invasion in 3-dimensional organotypic invasion assays. S1P also protected OSCC cells from Cisplatin-induced apoptosis, as determined in clonogenic survival assays. Using QPCR, we show that OSCC cell lines express S1P receptors 1-3 and that the expression of S1P1 and S1P2 was significantly lower in 8/8 OSCC cell lines compared to normal oral keratinocytes (p&lt;0.001), whilst S1P3 mRNA levels were significantly higher in 6/8 cell lines (p&lt;0.001). S1P receptor expression was similarly deregulated in two dysplasia cell lines, suggesting that alterations in S1P signalling occur early in tumor progression. The results of the present study demonstrate that de-regulated S1P signaling contributes to a more motile, invasive and chemo-resistant phenotype in OSCC and indicate that the S1P-receptor axis may represent a promising target for therapy. Work is ongoing to examine the protein expression of S1P receptors in OSCC tissues and to determine the precise role of the S1P3 receptor in mediating the tumor promoting effects of S1P in OSCC cells.
Citation Format: Steven Johnson, Lee Fah Yap, Sathya Narayanan, Ian Paterson. Deregulated sphingosine 1-phosphate signaling contributes to a more aggressive phenotype in oral squamous cell carcinoma 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 3988. doi:10.1158/1538-7445.AM2013-3988
Abstract 3990: The role of Th17 cells in the microenvironment of oral squamous cell carcinoma.
Authors: Bu Rongfa 
Published: August 2014

Abstract
Objective: To find out if there is any abnormal in the Th17 level of OSCC patients in vivo, to affirm their inhibitory effects on OSCC and find relative mechanism.To find new way to control OSCC though Th-17 relatived pathway.
Methods: Flow cytometry was used to evaluate the level of Th17 and Treg in the peripheral blood samples of OSCC patients and control group. Th17 and Treg in The tumor microenvironment were detected too and the relation between them was evaluated. Stable transfection was performed to transfect human tongue carcinoma cell line TCA8113 with human-IL-17a gene. TCA8113/IL-17 cell and hu-PBL -SCID-beige mice were used to investigate the change of the tumor microenvironment and the possible mechanism of how Th17 inhibite the OSCC tumor grow.
Results: The level of Th17 cells in the peripheral blood of OSCC patients is higher than the normal control group; The level of CD4 + CD25high CD127lowT cell in peripheral blood of OSCC patients was higher than the normal control. The level of CD31+Treg in peripheral blood of OSCC patients was higher than the normal control. Th17 cells and Treg infiltration were found in the local tumor microenvironment of OSCC and a inverse relationship between them was found. The second part: TCA8113/IL-17 cell which stable express IL-17A was successfully established, and the shape was good. The proliferation of cells in vitro was samiliar to TCA8113 and TCA8113/PCDNA3.1 cells.The Hu-PBL-SCID-beige mice immune reconstitution model was successfully established, and human-IgG can be detected in peripheral blood of all mice with an average concentration of 2.105g/L. The success rate of reconstruction was 100%.Experimental mouse model of OSCC were constructed with TCA8113, TCA8113/IL-17, and TCA8113/pcDNA3.1 cell. Success rate was 95%.Tumor growth rate in T +17 group was lower than T and T+P group. The final tumor volume of T+17 group (1.219 ± 0.626cm3) was lower than T group (2.858 ± 1.188cm3) and T+P group (2.59±1.199 cm3).The mRNA and protein expression levels of IL-17a, IL-6, granzyme B and RORγt in T+17 group were higher than the T group and T + P group.
Conclusion:Th17 and Treg levels of peripheral blood were increased in OSCC patients, but there was no relation between them. The immune environment in OSCC patients was in a suppressive state. CD4 + CD25highCD127low was a better way than o CD4+CD25highFoxP3+ to marked Treg in OSCC. Infiltration of Th17 and Treg in tumor microenviroment could be evaluated, and negative correlation between them could be investigated. Treg in the OSCC microenvironment may inhibited the Th17 differentiation and function.
Citation Format: Rongfa Bu. The role of Th17 cells in the microenvironment of oral squamous cell carcinoma. [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 3990. doi:10.1158/1538-7445.AM2013-3990
Abstract 4003: Influence of extracellular calcium on MAPK signalling cascade in colon cancer cells.
Authors: Tennakoon Samawansha , Schmid Johannes , Marian Brigitte , Kallay Enikö 
Published: August 2014

Abstract
Background: The calcium sensing receptor (CaSR) is a G-protein coupled receptor, which is capable of sensing even minute changes in extracellular calcium levels. The main role of the CaSR is regulation of calcium homeostasis. Besides the organs responsible for calcium homeostasis the receptor is expressed in a number of tissues including colonic epithelium and can be activated by several ligands, stimulating various downstream signalling pathways. Thus the CaSR is involved in numerous biological processes such as cell proliferation, differentiation and lipid membrane metabolism. Previous studies demonstrated that calcium regulates cell proliferation in colonocytes but the pathways or factors involved in this process still need to be elucidated.
Aim: The aim of this study is to investigate the impact of CaSR activation on the Mitogen-Activated Protein Kinase (MAPK) signalling cascade in colon cancer cell lines. We hypothesize that in colonocytes, activated CaSR down regulates proliferative pathways.
Methods: We studied the effect of CaSR ligands on downstream pathways through gene expression assays and protein analysis.
Results and Conclusion: We could show that the differentiation status of the cells (TC-7 a colon cancer cell line) determines whether a pathway is activated or rather inhibited by calcium treatment. Gene expression studies performed by luciferase assay and protein analysis by western blots reflect that extracellular calcium activated MAPK cascade in subconfluent TC-7 cells. On the other hand, short time (10 to 30 minutes) treatment of confluent/ differentiated cells with extracellular calcium showed no activation of ERK. Treatment for longer time (e.g 8h) inhibited ERK phosphorylation. The treatment of the cells with 100nM R-568, a calcimimetic that act only through the CaSR slightly inhibited ERK phosphorylation compared with the vehicle control, suggesting an anti-proliferative role of the CaSR.
Citation Format: Samawansha Tennakoon, Johannes Schmid, Brigitte Marian, Enikö Kallay. Influence of extracellular calcium on MAPK signalling cascade in colon 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 4003. doi:10.1158/1538-7445.AM2013-4003
Abstract 4016: Rapamycin-resistant HIF-1α expression in hepatocellular carcinoma (HCC) cells and high sensitivity of endothelial cells within HCC tissues to rapamycin.
Authors: Tanaka Hiroki , Yamamoto Masahiro , Miyakoshi Masaaki , Ogawa Katsuhiro 
Published: August 2014

Abstract
HIF-1 plays a pivotal role in cancer development via cellular growth,proliferation, survival, metabolism and angiogenesis. High expression of HIF-1α, a regulatory component of HIF-1, in cancer cells is due to increased synthesis of HIF-1α via the increased translation of HIF-1α mRNA under the influence of activated mTORC1 signaling as well as decreased HIF-1α degradation that is either on oxygen-dependent or independent mechanism. In mouse hepatocarcinogenesis, our previous data demonstrated that HIF-1α is overexpressed depending on the PI3K-Akt pathway from earliest stage and that HIF-1α knockdown by using siRNA resulted in marked growth retardation and cell death in HCC cells. We here demonstrated that Akt, 4E binding protein 1 (4EBP1) and p70 ribosomal protein S6 kinase (S6K) were hyperphosphorylated in mouse hepatic tumors and HCC cells, indicating that the PI3K-Akt-mTORC1 pathway was activated. However, although rapamycin, an inhibitor of mTORC1, effectively suppressed phosphorylation of 4EBP1 and S6K in HCC cells, HCC cells were resistant to rapamycin where HIF-1α continued to be expressed during rapamycin treatment. This HIF-1α expression was due to de novo synthesis of HIF-1α during rapamycin treatment as well as HIF-1α stabilization due to binding of HIF-1α to HSP90 that was constitutively over-expressed in the HCC cells. On the other hand, rapamycin induced extensive hemorrhagic necrosis in HCC tissues in vivo but not in normal liver or adenomas (benign lesions). Phosphorylated ribosome protein subunit 6 (rps6), the downstream phosphorylation target of mTORC1-S6K pathway, was specifically detected in the endothelial cells within HCCs but not those in normal liver or adenomas. Furthermore, rapamycin decreased proliferation of endothelial cells in vitro, reducing HIF-1α expression together with the decreased 4EBP and S6K phosphorylation, indicating that the endothelial cells within HCCs were especially sensitive to rapamycin. Dual treatment with inhibitors for mTOR and HSP90, therefore, could target both HCC cells and endothelial cells within HCCs, which might be an effective therapy for HCCs.
Citation Format: Hiroki Tanaka, Masahiro Yamamoto, Masaaki Miyakoshi, Katsuhiro Ogawa. Rapamycin-resistant HIF-1α expression in hepatocellular carcinoma (HCC) cells and high sensitivity of endothelial cells within HCC tissues to rapamycin. [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 4016. doi:10.1158/1538-7445.AM2013-4016
Abstract 4021: Transcriptomic landscape of Ewing sarcoma based on RNAseq.
Authors: Zehir Ahmet , Ambati Srikanth R. , Moore Malcolm AS 
Published: August 2014

Abstract
Ewing sarcoma is the second most common primary bone tumor in children, constituting 3% of all pediatric tumors. The 5 year survival rate is 59% to 76% for children younger than 15 years and from 20% to 49% for those aged 15 to 19 years. 85% of Ewing sarcoma are characterized by a chromosomal translocation between the Ewing sarcoma gene (EWS) breaking point and the ETS family of transcription factor FLI1, which creates a new type of fusion transcription factor with novel functions. While EWS-FLI1 is the predominating translocation event, other types of translocations between EWS and other ETS transcription factors have been reported. Mesenchymal stem cells (hMSC) are thought to be the cell of origin for Ewing sarcoma. The molecular mechanisms of transformation of hMSCs with ectopic EWS-FLI1 expression has been extensively studied, however, a complete transformation of hMSCs into Ewing sarcoma tumor cells is not yet achieved suggesting there are other elements required for the transformation of hMSCs.
RNAseq has proved to be a powerful new method for capturing multiple arrays of information simultaneously such as gene expression, nucleotide variation, alternative splicing patterns and fusion transcripts. RNAseq has been used only once in the literature in identification of a novel fusion transcript in Ewing sarcoma tumor cells. Here we obtained RNAseq data from Ewing sarcoma patients and cell lines to gather novel insight into the pathogenesis of Ewing sarcoma. We obtained sequencing data from two Ewing sarcoma cell lines (A673 and SK-PN-DW); human brain vascular pericytes (HBVP), 8 patient tumors and 3 matched normal control tissues. Initial data analysis was performed through an in-house developed pipeline that uses publicly available software and further data analysis was performed using R with various packages. We describe the gene expression changes in patients compared to normal tissues as well as HBVP. We also discovered a group of novel fusion transcripts that we subsequently confirmed with RT-PCR. Since EWS is also an RNA splicing protein, changes in alternative splicing are also described.
Citation Format: Ahmet Zehir, Srikanth R. Ambati, Malcolm AS Moore. Transcriptomic landscape of Ewing sarcoma based on RNAseq. [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 4021. doi:10.1158/1538-7445.AM2013-4021
Abstract 4027: Pathway analysis of chemoresistance in ovarian cancer cell lines.
Authors: Jackson William P. , Katre Ashwini A. , Dobbin Zachary A. , Steg Adam D. , Landen Charles N. 
Published: August 2014

Abstract
Introduction: Ovarian Cancer is the most deadly female reproductive cancer and fifth most common cause of death from cancer among women. Limited characterization of the chemoresistant population demonstrates the need for improved therapy for ovarian cancer. Pathway analysis of microarray data of paired chemosensitive and chemoresistant ovarian cancer cell lines may help to elucidate important contributors to chemoresistance, and paired analyses can eliminate the significant heterogeneity among patient samples. Significant genes may serve as potential targets for novel drug therapies. Some genes likely contribute to resistance of multiple chemotherapies and represent common pathways of resistance.
Methods: Microarray data of three pairs of chemosensitive and chemoresistant ovarian cancer cell lines were analyzed using GeneSpring Single Experiment Analysis of 517 pathways. These pairs include SKOV3ip1 and SKOV3TRip2 (taxane-resistant), HeyA8 and HeyA8MDR (multi-drug resistant), and A2780cp20 and A780cp55 (increasing cisplatin resistance). Significant genes within significant pathways were compared between types of drug resistance.
Results: Between SKOV3ip1 and SKOV3TRip2, 8 pathways were significantly (p&lt;0.001) modulated, dominated by the selenium pathway and folate/B12 metabolism. Between HeyA8 and HeyA8MDR, 9 pathways were significantly modified, led by DNA regulation and cell cycle progression. These differences between the SKOV3 model were interesting, given that both chemoresistant lines were developed in the same way. In A2780cp20 and A2780cp55, 7 pathways were significantly affected, highlighted by members of the Electron Transport Chain and controls on oxidative phosphorylation and autophagy. Validation of individual genes as important to chemoresistance will follow from this analysis.
Conclusions: Multiple pathways are implicated in chemoresistance, even when selected by the same chemotherapeutic agent. Pathways contributing to metabolism, DNA repair, cell cycle control, and stress responses dominated. The high variability in pathway overexpression highlights the importance of patient-specific approaches to overcoming chemoresistance in ovarian cancer.
Citation Format: William P. Jackson, Ashwini A. Katre, Zachary A. Dobbin, Adam D. Steg, Charles N. Landen. Pathway analysis of chemoresistance in ovarian cancer 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 4027. doi:10.1158/1538-7445.AM2013-4027
Abstract 403: The role of HER2 in the brain metastatic cascade in breast cancer.
Authors: Liao Yunxiang , Osswald Matthias , Gril Brunilde , Steeg Patricia , Wick Wolfgang , Winkler Frank 
Published: August 2014

Abstract
Approximately 20% of brain metastases originate from breast cancer, which is the most common invasive cancer of women worldwide. HER2 inhibitors have revolutionized the treatment of HER2 positive breast cancer patients, but have no or marginal activity against brain metastases yet - which is becoming increasingly problematic, since 40% of HER2 positive breast cancer patients will eventually develop this devastating complication of the disease. Therefore we aimed to understand which step of the brain metastatic cascade is actually affected by HER2 overexpression; which is crucial for successful growth to a macrometastasis; and which is most amenable to a prophylactic therapy. For this we used our novel animal model which allows to non-invasively follow single metastasizing cancer cells through a chronic cranial window over time, using in vivo multiphoton microscopy. Human MDA-MB-231 breast cancer brain-seeking subclones with high HER2 expression or with control vector have been injected into the circulation of female nude mice. As shown before for other cancer entities, only a very small proportion of cancer cells initially arrested in brain capillaries can successfully form brain metastases, which was similar for both groups (1.02% vs 1.67% - for HER2 overexpression and vector control, respectively). However, more of the injected HER2+ cells managed to initially arrest compared with HER2- cells (47.5 vs. 27.7 per 100,000 injected cells). Moreover, they extravasated earlier, and showed more early interaction with brain capillaries leading to intensive vascular remodeling, but no angiogenesis. We therefore focussed on factors of early breast cancer cell - blood vessel - interaction, and found integrins to be overexpressed in HER2+ cells. In ongoing experiments, we test an integrin αvβ3-5 inhibitor regarding its activity to prevent the early metastatic steps, and find that these steps are markedly inhibitied in treated animals. Our results provide a better understanding of the breast cancer brain metastatic cascade, and the role of HER2. Importantly, they suggest that inhibition of crucial early steps involving cancer cell - blood vessel interactions via integrin pathways can serve as a well tolerated long-term prophylactic treatment for HER2-positive breast cancer patients which are at risk to develop brain metastases.
Citation Format: Yunxiang Liao, Matthias Osswald, Brunilde Gril, Patricia Steeg, Wolfgang Wick, Frank Winkler. The role of HER2 in the brain metastatic cascade in breast 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 403. doi:10.1158/1538-7445.AM2013-403
Abstract 4042: Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells.
Authors: Chien Wenwen , Sun Qiaoyang , Lim Su Lin , Varela Ana D S M , Sun Haibo , Gery Sigal , Koeffler H Phillip 
Published: August 2014

Abstract
Endoplasmic reticulum (ER) stress is associated with the proliferation of pancreatic tumor cells resulting from unfolded proteins. The unfolded protein response (UPR) is a signaling pathway activated to protect, restore, and aid cells in coping with ER stress. The direct correlation between pancreatic tumor cells and elevated UPR makes the many regulatory molecules of the pathway (e.g. IRE-1) critical targets for therapeutic approaches. The objective of our study was to assess potential therapeutic efficacy of inhibitors of UPR in pancreatic cancers and investigate the mechanisms underlying IRE-1 inhibitor-mediated pancreatic cancer apoptosis. Fourteen pancreatic cancer cell lines and one normal pancreatic epithelial cell line were studied. STF-083010 is a specific inhibitor of IRE-1, which is required for the splicing of XBP-1 mRNA. Spliced XBP-1 mRNA codes for a transcription factor that enhances transcription of chaperone proteins which reverse UPR. MTT assays showed a dose- and time-dependent growth inhibition of 8 pancreatic cancer cell lines by STF-083010, with IC50s ranging between 200 nM to 10 uM. Growth inhibition was also noted using a clonogenic growth assay in soft agar. Annexin V and cell cycle analysis showed that STF-083010 caused growth arrest at the G1 phase in 4 cell lines and induced cell apoptosis in 4 cell lines. Western blot analysis showed cleavage of caspase 3 and PARP, and the induction of the apoptotic molecule Bax. In addition, synergistic effects were found between STF-083010 and either gemcitabine or bortezomib. Our data suggest that an IRE-1 inhibitor is a novel therapeutic approach for treatment of pancreatic cancers.
Citation Format: Wenwen Chien, Qiaoyang Sun, Su Lin Lim, Ana D S M Varela, Haibo Sun, Sigal Gery, H Phillip Koeffler. Selective inhibition of unfolded protein response induces apoptosis in pancreatic 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 4042. doi:10.1158/1538-7445.AM2013-4042