bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1616: Survivin regulates endothelial cell proliferation, survival and angiogenesis.
Authors: Eberlein Cath , Opoku-Ansah Grace , Legg James , London Tim , Gebhardt Frank , Davies Gareth , Tigue Natalie , McCourt Matthew , White Julia , Cross Darren , Schaeper Ute , Valge-Archer Viia E. 
Published: August 2014

Abstract
Background - Survivin is a member of the inhibitor of apoptosis protein (IAP) family, and is reported to be overexpressed in a number of human cancers with high unmet medical need including breast, non-small-cell lung (NSCLC), colorectal, gastric, glioblastoma, and pancreatic cancers. Multiple studies have described survivin as a key regulator of tumour cell proliferation, survival and drug resistance, which has led to the advancement of survivin inhibitors, including antisense and small molecule drugs, and cancer vaccines, into clinical testing. In the tumour micro-environment, survivin overexpression has also been reported in tumour blood vessels and conditional deletion of survivin in endothelial cells results in murine embryonic lethality secondary to haemorrhage and defective vascular development. We therefore hypothesised that inhibition of survivin function in endothelial cells could have anti-angiogenic or vascular disruptive effects.
Methods and Results - To better understand the role of survivin in primary endothelial cells we designed siRNAs capable of targeting multiple isoforms of human survivin. Using high content imaging assays we demonstrated that the siRNA were highly selective for survivin, inhibited the expression of multiple survivin splice variants, and had potent in vitro effects on endothelial cells. Survivin knockdown resulted in inhibition of cell cycle progression with the formation of enlarged, multi-nucleated cells, and in reduced endothelial cell survival. Survivin knockdown also impaired the formation of tube-like networks in vitro when co-cultured with human fibroblasts, but did not disrupt more established networks.
Conclusion These data show an important role for survivin in primary endothelial cells, and suggest that targeted inhibition of survivin may have anti-angiogenic effects, but may not disrupt more established blood vessels.
Citation Format: Cath Eberlein, Grace Opoku-Ansah, James Legg, Tim London, Frank Gebhardt, Gareth Davies, Natalie Tigue, Matthew McCourt, Julia White, Darren Cross, Ute Schaeper, Viia E. Valge-Archer. Survivin regulates endothelial cell proliferation, survival and angiogenesis. [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 1616. doi:10.1158/1538-7445.AM2013-1616
Abstract 1622: Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.
Authors: Chen Zhi-Yuan , Shi Ming , Peng Li-Xia , Wei Wei , Li Xin-Jian , Guo Zhi-Xing , Li Shu-Hong , Zhong Chong , Qian Chao-Nan , Guo Rong-Ping 
Published: August 2014

Abstract
Background: Dovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor β. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC), however, its cellular target is not clarified.
Method: In this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib.
Results: Tumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-β was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-β, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.05 μmol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells.
Conclusion: Our findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.
Citation Format: Zhi-Yuan Chen, Ming Shi, Li-Xia Peng, Wei Wei, Xin-Jian Li, Zhi-Xing Guo, Shu-Hong Li, Chong Zhong, Chao-Nan Qian, Rong-Ping Guo. Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis. [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 1622. doi:10.1158/1538-7445.AM2013-1622
Abstract 1628: Molecular cross-talk between head and neck squamous cell carcinoma cells and cancer-associated fibroblasts.
Authors: Ansell Anna , Kankainen Matti , Monni Outi , Johansson Ann-Charlotte 
Published: August 2014

Abstract
One of the main components of the tumor stroma is the cancer-associated fibroblasts (CAFs), which are known to stimulate tumor cell proliferation, angiogenesis and metastasis. Increasing evidence suggests that CAFs also influence the tumor cell response to various treatments. In this study we aimed to characterize the molecular cross-talk between CAFs and head and neck squamous cell carcinoma (HNSCC) cells. Tumor cell lines and CAF cultures were established from tumor biopsies derived from five HNSCC patients at Linköping University Hospital. Patient-matched tumor cells and CAFs were co-cultured for seven days in cell culture flasks, allowing cell-cell contact. After cell sorting the gene expression in mono-cultured and co-cultured tumor cells was investigated by Affymetrix microarray. Molecular networks were analyzed by Ingenuity Pathway Analysis (IPA). The expression of selected genes was verified by quantitative real-time PCR (qPCR) analysis. Fiftyeight genes were found to be differentially expressed (q&lt;0.05) in tumor cells co-cultured with CAFs when compared to tumor cells in mono-culture. The top functions of these genes were cancer, cellular movement, and embryonic development as analyzed by IPA. Four genes (POSTN, GREM1, COL1A2, and COL6A3) were upregulated by more than 2-fold while 14 genes were found to be downregulated by at least 50%. The four upregulated genes have all been associated with epithelial-to-mesenchymal transition (EMT), increased migration, and TGFβ-pathway signaling. By qPCR analysis the expression of POSTN, GREM1 and COL1A2 was found to be induced by several hundred-fold in some of the cell lines under co-culture conditions. There were no significant changes in the expression of these genes when tumor cells and CAFs were co-cultured in a trans-well system, suggesting that the effect may be contact-dependent. Functional analyses are now being performed to determine the importance of these findings.
Citation Format: Anna Ansell, Matti Kankainen, Outi Monni, Ann-Charlotte Johansson. Molecular cross-talk between head and neck squamous cell carcinoma cells and cancer-associated fibroblasts. [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 1628. doi:10.1158/1538-7445.AM2013-1628
Abstract 1640: Combined inhibition of EMMPRIN and EGFR abrogates growth and migration of head and neck squamous cell carcinoma cells.
Authors: Suzuki Shinsuke 
Published: August 2014

Abstract
Head and neck cancer squamous cell carcinoma (HNSCC) is the most common malignancy of the upper aerodigestive tract. Despite intense efforts to improve different treatment modalities, mortality rates in advanced cases remain high. A deeper understanding of the HNSCC progression mechanisms is needed to improve survival in patients with HNSCC. The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase, which regulates crucial cellular signaling pathways contributing to tumor progression. EGFR is frequently amplified and overexpressed in several human solid tumors including a high percentage of HNSCCs. Evidence accumulated in several studies has shown that EGFR stimulation induces expression of matrix metalloproteinases (MMPs), which degrade extracellular matrix, and its activation process is critical for tumor development. Recently, extracellular matrix metalloproteinase inducer (EMMPRIN), which is known as CD147 and is a member of the immunoglobulin superfamily, has been reported to be highly expressed in malignant tumors including HNSCC. It has been reported that EGFR expression is associated with EMMPRIN in some solid tumors; however, the relationship of EMMPRIN with EGFR in head and neck cancers is not fully understood. To determine the relationship between EMMPRIN and EGFR in HNSCC, HNSCC cells were stimulated with epidermal growth factor (EGF), a ligand of EGFR. Immunoblotting analysis showed that EMMPRIN expression in HNSCC cells was upregulated by EGF in a dose- and time-dependent manner. In addition, gelatin zymography showed that EGF stimulation-induced cell invasion and MMP-9 expression of HNSCC cells. Interestingly, this increase in invasion and MMP-9 expression were abrogated by downmodulation of EMMPRIN expression using the siRNA technique. Furthermore, to determine the effects of combined EMMPRIN and EGFR targeting in the HNSCC cell line, HNSCC cells were investigated in cell proliferation and migration assays. The effects of combined treatment with the EMMPRIN function blocking antibody and the EGFR inhibitor AG1478 were examined on the proliferation and migration of HNSCC cells. This combined treatment resulted in greater inhibition of HNSCC cell proliferation and migration compared with the individual agents alone. These results suggest that EMMPRIN mediates EGFR-induced invasion and MMP-9 expression in cases where combined targeting of EMMPRIN and EGFR may be an efficacious treatment approach.
Citation Format: Shinsuke Suzuki. Combined inhibition of EMMPRIN and EGFR abrogates growth and migration of head and neck 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 1640. doi:10.1158/1538-7445.AM2013-1640
Abstract 1643: Physical and functional interactions between acid sensing ion channel 1 (ASIC1) and integrin β1 in glioma cells.
Authors: Rooj Arun K. , McNicholas Carmel M. , Fuller Catherine M. 
Published: August 2014

Abstract
The local microenvironment of a cancer cell plays important roles in tumor metastasis. Major components of this local niche are ion channels, integrin receptors, and the extracellular matrix.
Glioma cells express a specific amiloride-sensitive and constitutively active non-selective cation channel composed of ASIC1, α- and gENaC subunits, members of the Deg/ENaC superfamily of non-voltage gated sodium channels. Inhibition of this channel is associated with reduced migration and proliferation of the glioma cell. As gliomas are highly invasive, we hypothesized that channel activity was engaging an intracellular signaling pathway regulating migration and proliferation by interacting with integrin β1. We have shown the physical proximity of the ASIC1 subunit and integrin β1 by co-immunoprecipitation in D54MG glioma cells. A functional interaction between these two proteins was demonstrated when we found that stable (shRNA) knock-down of integrin β1 attenuated the amiloride-sensitive current by 89±24% (n≥9; ±SD P&lt;0.001). Furthermore, prolonged (24h) inhibition of this glioma channel by PcTX-1, a specific ASIC1 inhibitor, down-regulated integrin β1 expression (by 60% ± 12% (SD) n≥3 P&lt;0.001).
The surface expression of ASIC1 in glioma cells is also regulated by integrin β1. Using biotinylation, we found that stably knocking down integrin β1 inhibited the surface expression of ASIC1. In contrast, up-regulating membrane expression of integrin β1 by coating dishes with either fibronectin or vitronectin, increased the surface expression of ASIC1. This effect was not observed when dishes were coated with poly-L-lysine. We have previously shown that knockdown of ASIC1 reduced the phosphorylation level of ERK1/2, a key mediator of tumor cell proliferation and migration (Rooj et al. J. Biol. Chem. 287:4053, 2012). In the present study, phosphorylation of ERK1/2 was also reduced by knockdown of integrin β1 (by 58% ± 20% (SD) n≥3 P&lt;0.001). Our data reveal a novel interaction between ASIC1 and integrin β1 in the regulation of the MAPK pathway that may form a mechanism by which changes in Na+ current can modulate cell proliferation and migration.
Citation Format: Arun K. Rooj, Carmel M. McNicholas, Catherine M. Fuller. Physical and functional interactions between acid sensing ion channel 1 (ASIC1) and integrin β1 in glioma 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 1643. doi:10.1158/1538-7445.AM2013-1643
Abstract 1644: Microglia promote glioma cell migration and dispersal by activating the PLCγ1 and Pyk2 signaling cascade.
Authors: Rolon-Reyes Kimberleve , Mendez Miguel , Rivera-Aponte David E. , Skatchkov Serguei N. , Eaton Misty J. , Kucheryavykh Lilia 
Published: August 2014

Abstract
Glioblastoma multiforme is one of the most aggressive and fatal brain cancers mostly because of the highly invasive nature of glioma cells. The ability of glioma cells to disperse to healthy brain stroma makes surgical and chemotherapeutic treatments mostly ineffective. Microglia infiltrate most gliomas and release factors, which favor tumor growth and dispersal. We hypothesize that microglia residing within the tumor stimulate glioma cell migration and dispersal through the phospholipase C (PLC)γ1 and proline rich tyrosine kinase 2 (Pyk2) signaling cascade. In the present study, we investigated rodent C6 and GL261 as well as human glioma cell lines with varying levels of invasiveness: U-87MG, A172, and HS683. Using a standard invasion assay, we demonstrated that the presence of rodent or immortalized human microglia in the bottom compartment of Boyden chambers activated invasion of all glioma cell types. Knock-down of PLCγ1 and Pyk2 proteins using siRNA reversed the stimulatory effect of microglia on glioma invasion in both cell lines. Pharmacological blockers of PLC (U73872 1nM) and Pyk2/focal adhesion kinase (FAK) (PF562271 20nM) also completely eliminated the ability of microglia to stimulate glioma cell migration in a wound healing assay. Using Western blot, we found upregulation of phosphorylated Tyr579/580 Pyk2 protein in glioma cells treated with microglia conditioned medium. Taken together, these data indicate that microglial cells activate glioma cell migration/dispersal through the pro-migratory Pyk2 and PLCγ1 signaling pathway in glioma cells. This research was made possible by NIH grant numbers: G11 HD052352, G12 RR03035, 8G12MD007583-27, U54 NS039408, UCC Pilot Project Program and Title V PPOHA grant number P031M105050 from the US Dept. of Education.
Citation Format: Kimberleve Rolon-Reyes, Miguel Mendez, David E. Rivera-Aponte, Serguei N. Skatchkov, Misty J. Eaton, Lilia Kucheryavykh. Microglia promote glioma cell migration and dispersal by activating the PLCγ1 and Pyk2 signaling cascade. [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 1644. doi:10.1158/1538-7445.AM2013-1644
Abstract 1645: Characterization of a novel anti-insoluble-fibrin chimeric antibody (AFCA) for cancer stromal target (CAST) therapy and diagnosis.
Authors: Hisada Yohei , Yasunaga Masahiro , Matsumura Yasuhiro 
Published: August 2014

Abstract
Background: A large body of clinicopathological evidence supports the conclusion that abnormal coagulation occurs in a variety of cancers. In the non-malignant condition, fibrin clots (insoluble fibrin) form only at the onset or active state of disease and subsequently disappear because of plasmin digestion or replacement with collagen within a few weeks. However, in cancer, fibrin clot formation and subsequent replacement with collagen continue for as long as cancer cells survive in the body. In this context we considered that the fibrin clot could be a pathophysiologically specific target in cancer and accordingly developed an anti-insoluble-fibrin chimeric antibody (AFCA). Here, we characterize AFCA and demonstrate its potential as a tool for drug delivery to the cancer stroma.
Method: The specificity of AFCA was evaluated by ELISA using insoluble fibrin, fibrinogen (the precursor of fibrin), soluble fibrin, and D-dimer (the degradation product of insoluble fibrin) as antigens. To compare AFCA with commercially available anti-fibrin antibodies, we performed ELISA with insoluble fibrin, fibrinogen, and D-dimer as antigens. We also conducted western blotting with native fibrinogen and denatured fibrinogen. To evaluate the accumulation of AFCA in tumors, we gave fluorescence-labeled AFCA to transgenic mice with pancreatic cancer.
Results: AFCA recognized only insoluble fibrin, not any fibrin-related proteins. AFCA had higher specificity against insoluble fibrin than did commercially available anti-fibrin antibodies. Western blotting analysis revealed that AFCA reacted with denatured fibrinogen but not native fibrinogen. AFCA, but not isotype control IgG, accumulated in the pancreatic cancer tissues.
Conclusion: These findings imply that the epitope of AFCA is a distinctive sequence that is uncovered only on the fibrin clot. Because lasting asymptomatic fibrin clot formation is a cancer-specific phenomenon, AFCA should be a useful tool for drug delivery to insoluble fibrin present around cancers.
Citation Format: Yohei Hisada, Masahiro Yasunaga, Yasuhiro Matsumura. Characterization of a novel anti-insoluble-fibrin chimeric antibody (AFCA) for cancer stromal target (CAST) therapy and diagnosis. [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 1645. doi:10.1158/1538-7445.AM2013-1645
Abstract 1646: Combining molecular target drugs to inhibit cancer-stromal cell interaction in gastric cancer.
Authors: Onoyama Mieko , Kitadai Yasuhiko , Shinagawa Kei , Yuge Ryo , Ohnishi Mayu , Tanaka Shinji , Yasui Wataru , Chayama Kazuaki 
Published: August 2014

Abstract
Recent studies in molecular and cellular biology have shown that tumor growth and metastasis are not determined by cancer cells alone but also by various stromal cells. Many human tumors secrete platelet-derived growth factor (PDGF) ligands, and PDGF receptors (PDGF-Rs) are expressed by various stromal cell populations, including carcinoma-associated fibroblasts (CAFs).
Tumor cells in surgical specimens and orthotopic tumors have been shown to express PDGF-B, whereas PDGF-Rβ has been shown to be expressed predominantly by stromal cells, including CAFs, pericytes, and lymphatic endothelial cells.
mTOR (mammalian target of rapamycin) is a central regulatory kinase that increases the production of proteins that stimulate key cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis. mTOR also increases the translation of hypoxia-inducible factor-1a (HIF-1a), which drives the expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF), resulting in new vasculature.
In the present study, we examined the effects of PDGF-R tyrosine kinase inhibitors (imatinib, nilotinib) and mTOR inhibitor (everolimus) on tumor stroma in an orthotopic nude mouse model of human gastric cancer. Treatment with PDGF-R tyrosine kinase inhibitors did not inhibit tumor growth but did significantly decrease the stromal reaction, lymphatic invasion, lymphatic vessel area, and pericyte coverage of tumor microvessels. In contrast, treatment with mTOR inhibitor reduced tumor growth and microvessel density but did not decrease the stromal reaction. PDGF-R inhibitor and mTOR inhibitor used in combination reduced both the growth rate and stromal reaction. (control (5/5, 0.3±0.1g), nilotinib (6/6, 0.3±0.1g), everolimus (4/6, 0.08±0.02g: p&lt;0.05), combination (1/6, 0.04g))
Target molecule-based inhibition of cancer-stromal cell interaction may hold promise as an effective anti-tumor therapy.
Citation Format: Mieko Onoyama, Yasuhiko Kitadai, Kei Shinagawa, Ryo Yuge, Mayu Ohnishi, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama. Combining molecular target drugs to inhibit cancer-stromal cell interaction in gastric 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 1646. doi:10.1158/1538-7445.AM2013-1646
Abstract 1651: Regulation of omental seeding of ovarian cancer cells by SPARC.
Authors: Matthews Dylan P. , Said Neveen A. 
Published: August 2014

Abstract
Epithelial Ovarian cancer is the leading cause of death from malignant gynecologic tumors, as most patients have extensive late metastatic disease at the time of diagnosis. Ovarian cancer (OvCa) cells have specific predilection to metastasize to omentum, a condition known as “peritoneal ovarian carcinomatosis, POC” but rarely leave the peritoneal cavity. Despite aggressive surgical debulking and cytoreduction, recurrence of omental implants is high with poor patient survival. We have recently reported that the tumor suppressor role of matricellular glycoprotein SPARC (secreted protein acidic and rich in cysteine) in POC through differential effects on OvCa cells and their interactions with components of the peritoneal microenvironment. Given that SPARC is the first known matricellular protein involved in adipose tissues homeostasis, we sought to elucidate the potential roles of SPARC on the omental adipocyte-OvCa cells cross-talk and its impact on POC, in vivo and in vitro. Using primary omental SP−/− and SP+/+ omental stromal cells, we found that adipocyte-SPARC delayed the adipogenic differentiation of omental stromal cells. SP−/- omental adipocytes expressed significantly higher levels of adipogeneic markers and accumulated significantly less oil droplets than SP+/+. Primary SP−/− adipocytes promoted homing of ID8 murine OvCa cells to the omentum in vivo and their migration and invasion in 3D-cocultures in vitro. Mechanistic studies using human and murine adipocyte-OvCa genetically manipulated for SPARC expression in 3D co-cultures, revealed that the effect of SPARC suppressing adipocyte-OvCa cell cross-talk mediated by the effect suppressing the activation of cEBP-β, NFκB and AP-1 in OvCa cells as well as in adipocytes with subsequent decrease in chemokines/adipokines as well as fatty acid exchange between OvCa cells and adipocytes. Our data indicates the metastasis suppressor effect of SPARC in POC is mediated in part via inhibiting the key transcription factors involved in adipocytes differentiation and OvCa progression identifying SPARC as a potential inhibitor of OvCa cell omental seeding and dormancy.
Citation Format: Dylan P. Matthews, Neveen A. Said. Regulation of omental seeding of ovarian cancer cells by SPARC. [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 1651. doi:10.1158/1538-7445.AM2013-1651