bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2291: Downregulation of uPA/uPAR inhibits epithelial to mesenchymal transition (EMT) in intermittent hypoxic DAOY and D283 medulloblastoma cells
Authors: Gupta Reshu , Chetty Chandramu , Bhoopathi Praveen , Lakka Sajani S. , Fassett Daniel , Klopfenstein Jeffrey D. , Dinh Dzung H. , Gujrati Meena , Rao Jasti S. 
Published: February 2011

Abstract
Medulloblastoma is the most common, rapidly growing tumor of the cerebellum, which arises in childhood and has a tendency to metastasize via cerebrospinal fluid (CSF) pathways. In addition to surgical resection, post-operative radiotherapy and chemotherapy are the mainstays in treating patients with medulloblastoma. However, these tumors remain among the most challenging pediatric brain tumors. Factors related to the tumor microenvironment are being recognized as fundamental to tumor progression, increased resistance and metastasis. Hypoxia, one of these factors, leads to epigenetic and genetic adaptation of clones and increased EMT, invasiveness and metastasis. Thus, hypoxia is closely associated with tumorigenesis and provides tumors the ability to outgrow the existing vasculature. In this study, we show that intermittent hypoxia has a more pronounced effect than chronic hypoxia and is responsible for EMT, invasion, migration, and survival of hypoxic-conditioned medulloblastoma cells. We also show that Akt and SNAIL are activated under hypoxia, and this response is blocked by plasmid vector-mediated delivery of uPA/uPAR siRNA. The linkage of uPAR to Akt activation under hypoxia provides one mechanism by which uPAR may regulate SNAIL, and thus, promote EMT. The results presented here suggest that, in cells that express high levels of uPAR, induction and maintenance of EMT depends on simultaneous activation of numerous cell-signaling factors downstream of uPAR. This study provides valuable evidence of the anti-tumor efficacy of plasmid vector-mediated delivery of uPA/uPAR siRNA in hypoxic-conditioned medulloblastoma cells to target intermittent hypoxia-induced cell invasion, migration, angiogenesis and EMT and to achieve better therapeutic outcomes in the treatment of malignant medulloblastomas
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2291.
Abstract 2315: Influence of epithelial to mesenchymal transition on viral oncolysis in non small cell lung cancer
Authors: Schmitt Anthony D. , Fuchs Bryan C. , McGinn Christopher , Kuroda Toshihiko , Goodwin Jonathn M. , Tanabe Kenneth K. , Lanuti Michael 
Published: February 2011

Abstract
Background: Epithelial to mesenchymal transition (EMT) is distinguished by the loss of epithelial cell junction proteins such as E-cadherin and the relative gain of mesenchymal markers such as vimentin. We hypothesized that EMT may play a role in resistance to viral oncolysis in non-small cell lung cancer (NSCLC). Methods: Multiple human NSCLC cell lines obtained from the American Tissue Culture Collection (H292, H358, H441, H1437, A549, H1703 and SW1573) were evaluated for cell surface expression of E-cadherin via Western blot. Vimentin and Zinc finger E-box binding-1 (Zeb-1) mRNA expression were measured in all of the NSCLC cell lines using RT-PCR to further analyze a molecular profile. Herpes viral infectivity was tested in vitro at varying multiplicity of infection (MOI) using both wild type Herpes (KOS) and an attenuated (ICP-6 defective) HSV-1 mutant (hrR3). Cell surface levels of nectin-1 and herpes virus entry mediator (HVEM) were measured by fluorescence-activating cell sorting (FACS). Results: Western Blots on cell lysates revealed the presence of E-cadherin in H292, H358, H441, and H1437. The cell lines SW1573 and H1703 lacked E-cadherin and expressed higher transcript levels of Vimentin and Zeb-1, suggesting a more mesenchymal phenotype. Cell lines harboring epithelial markers appeared more susceptible to viral oncolysis at low MOI compared to those with mesenchymal markers. The mesenchymal-phenotype cells were 10-1000 fold more resistant to both wild type HSV-1 and replication conditional hrR3, thus suggesting a cell-growth independent mechanism. Viral cytotoxicity did not appear to be Nectin-1 mediated since there was no differential cell surface expression in mesenchymal or epithelial phenotypes. Conclusion: Infectivity and viral oncolysis of NSCLC cell lines may be related to epithelial or mesenchymal phenotype. Nectin-1 does not appear to be the major receptor for viral infectivity in NSCLC. Current and future studies focus on ways to reverse EMT in NSCLC, thus rendering tumor cells more susceptible to viral oncolysis and perhaps chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2315.
Abstract 2342: Prognosis for patients with adenocarcinomas of lower esophagus, gastro-esophageal junction and cardia can be directly evaluated by immunohistochemistry of uPAR
Authors: Illemann Martin , Ovrebo Kjell , Skarstein Arne , Christensen Ib J. , Alpízar-Alpízar Warner , Helgeland Lars , Danø Keld , Nielsen Boye S. , Laerum Ole D. 
Published: February 2011

Abstract
Adenocarcinomas of lower esophagus, gastro-esophageal junction and cardia in humans are highly invasive tumors with poor prognosis. In order to elucidate proteolytic mechanisms for the invasive behavior, we have studied the localization of urokinase-type plasminogen activator receptor (uPAR) in 65 cases. uPAR was expressed in nearly all cases of invasive adenocarcinomas by populations of cancer cells, macrophages and myofibroblasts. In areas with local carcinoma in situ lesions (15 cases), or with Barrett's metaplasia (21 cases) adjacent to the tumor tissue, and in six control cases with Barrett's metaplasia only, no uPAR-immunoreactivity was found. High local expression of uPAR therefore appears to be a characteristic marker for invasive behavior in this tumor.
Using a simple scoring system for semi-quantitative estimation of uPAR-positivity on immmunohistochemically stained specimens, a significant association between high uPAR-score in cancer cells in the tumor core and short survival was found independent of tumor TNM-stage (HR=1.74, 95% CI: 1.05-2.88). High uPAR-score for each individual cell type (cancer cells, macrophages and myofibroblasts) was also associated with short survival. A diagnostic procedure for scoring of uPAR-positivity might be useful for this type of tumors. High local proteolytic activity mediated through the plasminogen activation system, with combined action of malignant and non-malignant accessory cells may be an important mechanism for the rapid progression and high mortality in this tumor type.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2342.
Abstract 2355: Role of secreted frizzled-related protein 3 (sFRP3) in human renal cell carcinoma
Authors: Hirata Hiroshi , Hinoda Yuji , Ueno Koji , Majid Shahana , Saini Sharanjot , Dahiya Rajvir 
Published: February 2011

Abstract
Wnt/beta-catenin signaling is involved in renal cancer. Among Wnt antagonist families, sFRP3 is generally thought to be an inhibitor of Wnt signaling in several cancers. Here we reported the functional significance of sFRP3 in renal cell carcinoma. We performed immunohistochemistry on kidney tissue microarray and confirmed the expression level of sFRP3 in normal kidney and renal cancer cell lines (primary and metastatic). We transfected sFRP3 to the primary renal cancer cell lines and performed several functional analysis (MTS, colony formation, apoptosis, cell cycle, invasion, angiogenesis, and in vivo study). We also knocked down sFRP3 mRNA in metastatic cell lines using siRNA technique and performed several functional analysis. We found the level of sFRP3 protein was high in normal kidney, low in primary renal cancer tissues and high in metastatic renal cancer tissues. We performed dual sFRP3 mRNA expression experiments to determine the role of sFRP3 using primary and metastatic renal cancer cell lines. Functional analysis showed increased numbers of viable and invaded cells, tube formation and decreased numbers of apoptotic cells in sFRP3 transfected A498 cells. Promotion of tumor growth was also observed in nude mice injected with sFRP3 transfected A498 cells. In contrast, the number of viable cells and invasive cells was decreased in sFRP3 mRNA knocked down metastatic cells (ACHN and Hs891.T). To investigate the mechanism of sFRP3 function, we performed microarray analysis to see which genes were up or down regulated by sFRP3 expression. Among these genes, MMP-3 and ANGPT1 were significantly up-regulated in sFRP3 transfected cells. This is the first report to show that sFRP3 expression promotes cell growth, invasion, and inhibition of apoptosis in renal cancer cells. Furthermore, our results suggest that sFRP3 may play a role in invasion and angiogenesis by enhancing MMP-3 and ANGPT1 expression. The changes in sFRP3 expression levels in normal, primary cancer, and metastatic renal cancer tissues suggest that sFRP3 may play dual roles as a tumor suppressor gene and an oncogene during renal cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2355.
Abstract 2360: Cell size and shear stress resistance do not correlate with metastatic efficiency
Authors: Barnes James M. , Henry Michael D. 
Published: February 2011

Abstract
Metastasis is the leading cause of death in patients with epithelial cancers. It has been observed both clinically and experimentally that metastasis is a very inefficient process. It is believed that the majority of primary cancer cells entering the bloodstream are cleared rapidly, likely by destruction under hemodynamic shear forces, thus greatly reducing the number of surviving cells which can go on to colonize a secondary site. It would thus seem advantageous for metastatic cancer cells to adapt mechanisms to resist this type of stress. One factor which may influence shear stress susceptibility is cell size; the larger a cell is the more shear stress this cell will experience while in circulation. Here, we report the cell size and shear stress analysis of a panel of well described cancer cell lines and their metastatic derivatives obtained from metastatic lesions in mice. We found no correlation between the ability of a cancer cell to metastasize with a reduction in cell size or an increase in shear force resistance. Our data suggest that the loss of tumor cells by hemodynamic shear force is lower than often estimated. We conclude that the metastatic cascade does not generally select for cells of a smaller size and that shear stress resistance does not predict the aggressiveness of a particular cancer cell line. These findings support the hypothesis that the later steps in metastasis, such as extravasation and colonization, dictate the inefficiency of this process. Interestingly, although metastatic derivatives did not tend to exhibit increased resistance to shear force, there were certainly differences between cancer cell lines of different tissue origin. This fact may become important when designing isolation methods for circulating tumor cells, the analysis of these studies, and the prognostic value of quantifying circulating tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2360.
Abstract 2361: Fractalkine and CX3CR1 are involved in the early stages of skeletal metastasis
Authors: Jamieson Whitney L. , Dorgham Karim , Deterre Philippe , Fatatis Alessandro 
Published: February 2011

Abstract
It is estimated that eighty percent of breast cancer (BCa) and ninety percent of prostate cancer (PCa) patients develop late-stage skeletal metastases. Metastatic disease is the major cause of death in these patients and only palliative treatments for clinically established skeletal metastases are available. In order to develop effective preventive and curative therapies, it is essential that mechanisms involved in cancer cell bone colonization are fully understood. Our previous in vitro experiments have shown that the chemokine fractalkine (FKN, CX3CL1) and its receptor, CX3CR1, mediate adhesion of PCa cells to bone marrow endothelial cells as well as their migration toward osteoblasts. We have also shown that CX3CR1 is highly expressed in BCa and PCa cell lines as well as ex vivo prostate and mammary human cancer tissues, whereas FKN is expressed by stromal cells of the bone marrow. Therefore, we hypothesize that FKN and CX3CR1 are involved in the arrival and arrest of cancer cells to the bone during the metastatic process. To test our hypothesis, we employed a mouse model of metastasis in which fluorescent human cancer cells are inoculated in the left cardiac ventricle. Using a histology-stereomicroscopy combination approach, we detect single cancer cells in the bone microenvironment as early as 24 hours after their delivery into the blood stream. Analyses at later time-points also reveal the progression of small cancer foci into macroscopic metastases. Inoculation of PCa or BCa cells in FKN-null mice shows a significant decrease in the number of cancer cells disseminated to the skeleton by hematogenous route. In parallel experiments, exogenous over-expression of CX3CR1 in BCa cells increases their arrival to bone. On the other hand, upon expression of a CX3CR1 functional mutant - unable to mediate adhesion to FKN - the dissemination of BCa cells to the skeleton is significantly impaired. Finally, we used a newly engineered inhibitor of CX3CR1 to counteract skeletal metastases in vivo.
In conclusion, our data present strong evidence that the FKN/CX3CR1 pair is involved in the early stages of prostate and breast cancer bone metastasis. Thus, altering the interactions between FKN and its receptor represents an attractive therapeutic approach for the prevention of skeletal metastases from prostate and breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2361.
Abstract 2374: Integrin-linked kinase (ILK) promotes melanoma angiogenesis by activating IL-6 signaling pathway
Authors: Wani Aijaz A. , Li Gang 
Published: February 2011

Abstract
Integrin-linked kinase (ILK) is a highly conserved serine-threonine protein kinase involved in cell-ECM interactions, cytoskeletal organization, and cell signaling. Overexpression of ILK in epithelial cells leads to anchorage-independent growth with increased cell cycle progression. Previously, we have shown that ILK upregulation strongly correlates with melanoma progression, invasion and inversely correlates with 5-year survival of melanoma patients. We also found that ILK knockdown impeded melanoma cell migration, invasion and impaired the growth of melanoma xenografts in severe combined immunodeficient (SCID) mice. However, the molecular mechanism by which ILK enhances melanoma angiogenesis is currently unknown. In the present study, we found that pro-angiogenic molecule interleukin-6 (IL-6) is the downstream transcriptional target of ILK in melanoma cells. ILK overexpression increased IL-6 whereas shRNA mediated silencing of ILK suppressed IL-6 expression both transcriptionally and translationally. By electromobility shift assays, we found that ILK enhanced the binding of transcription factor (NF-κB) to IL-6 promoter and this binding was reduced in ILK knockdown cells. Furthermore, Conditioned media (CM) from ILK- overexpressing cells enhanced the tube forming ability of HUVEC cells in vitro. This tube formation by HUVEC cells was IL-6 dependent as CM from IL6-siRNA treated ILK-overexpressing melanoma cells inhibited the tube formation of HUVEC cells. In order to delineate the mechanism by which ILK-upregulated IL-6 can enhance the growth of endothelial cells, further analysis of the downstream targets of IL-6 signaling showed an increase in activity and nuclear translocation of STAT3 in ILK-overexpressing cells. As STAT3 binds to VEGF promoter, we found that VEGF levels were elevated in ILK-overexpressing cells and declined in ILK knockdown cells, suggesting that ILK may regulate VEGF expression through IL-6 pathway by upregulating and activating STAT3.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2374.
Abstract 2378: Involvement of leptin-activated canonic and non-canonic kinases in VEGF regulation in breast cancer
Authors: Xu Yanbo , Watters Amber , Zhang Yuanyuan , Gillespie Corey , Zhou Weiqiang , Guo Shanchun , Leibovich Samuel J. , Gonzalez-Perez Ruben Rene 
Published: February 2011

Abstract
We have previously reported that in vitro and in vivo leptin signaling up-regulates VEGF in mouse and human mammary tumor cells (MT) but the specific molecular mechanisms involved are largely unknown. Here we describe how leptin activated canonic and non-canonic signaling pathways to induce specific transcription factors (TF) essential for the transcriptional activation of VEGF gene in mouse MT (4T1, EMT6 and MMT). Basal expression of VEGF/VEGFR2, leptin/OB-R and ER-α was initially investigated in MT. Leptin dose-response and time-course effects on VEGF levels were determined by ELISA. Several pharmacological inhibitors for key leptin-target kinases and TF were used to dissect the signaling pathways involved in leptin-induced levels of VEGF protein and mRNA in MT. A series of VEGF-promoter Luc-reporters [full-length & transcription factor (TF)-binding deletions: HRE, AP1, AP2, NFκB and SP1] were transfected into MT to analyze leptin regulation of VEGF transcription. Our data show that MAPK, PI-3K (canonic) and PKC, JNK and p38 MAP kinase (non-canonic) signaling pathways were generally involved in leptin regulation of VEGF. Analysis of cis-acting elements of VEGF promoter shows that leptin activation of HIF-1α is essential for transcription in all MT. This was mainly linked to MAPK, PI-3K, PKC, JNK and p38 signaling. Leptin-induced MAPK, JNK and p38 to activate NFκB that was essential for VEGF expression in high producer MT (EMT6 and MMT). Leptin through all canonic signaling pathways activates SP1 required for VEGF regulation in 4T1 cells. In contrast, AP1 was not involved but AP2 repressed leptin-mediated transcription of VEGF. Overall, these data suggest that leptin signaling regulates VEGF gene in MT cells mainly through HIF-1α and NFκB. These results delineate for first time the mechanisms for leptin regulation of VEGF and, reinforce the idea that the disruption of leptin signaling could impact breast cancer growth by inhibiting MT proliferation and angiogenesis. This work was supported in part by NIH/NCI 1SC1CA138658-02; NIH/UAB Breast SPORE Career Development Award; BC 504370 Susan G. Komen Foundation for the Cure and the Georgia Cancer Coalition Distinguished Cancer Scholar Award (to RRGP).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2378.
Abstract 2385: Evidence and actions for nuclear localization of vascular endothelial growth factor receptor 1 (VEGFR1) in endothelial and cancer cells
Authors: Wu Li-Wha 
Published: February 2011

Abstract
Abstract:
Vascular endothelial growth factor receptor 1 (VEGFR1) is a receptor tyrosine kinase (RTK) predominantly expressed in endothelial cells. Recent studies have shown that VEGFR1 is also expressed in several types of human cancer cells, and its expression correlates with cancer progression. Moreover, higher VEGFR1 expression worsened the outcome of lung cancers, breast cancer, and pancreatic cancer patients following cancer treatment. A new mode of signal transduction mediated by RTK is through internationalization of ligand-bound receptor rather than through activation of intracellular signaling cascades by the interaction of ligand and receptor on the cell surface. Epidermal growth factor receptor is the prototype for such new mode of action. One previous study has shown that VEGFR1 was colocalized with nuclear STAT1 in chronic lymphocytic leukemia B cells treated with VEGF-A, indicating a possible role for VEGFR-1 in the nucleus. Consistent with the notion, we found that the intracellular domain of VEGFR1 behaved as a transcriptional activator in yeast two-hybrid system. Second, VEGFR1 could shuttle between cytosol and nucleus following VEGF-A treatment in endothelial cells. Third, nuclear and cytosolic fractionation indicated the presence of VEGFR1 in the nuclear compartment of oral cancer and human endothelial cells. We thus hypothesized that VEGFR1 might harbor a nuclear localization signal (NLS) in the protein. Using a cytosolic protein pyruvate kinase fused with green fluorescent protein (GFP) and the putative NLS derived from VEGFR1 together with serial deletions and fluorescence microscopy, we were able to alter the subcellular location of pyruvate kinase fusion protein. Moreover, mutations of crucial arginine or lysine residues in the putative NLS significantly reduced the nuclear presence of VEGFR1 in the transfected cells. More studies are needed to address the molecules involved in nuclear transport of VEGFR1 and the target DNA sequence recognized by nuclear VEGFR1. The functional consequence of VEGFR1 localization in different subcellular compartments will be also studied by the use of oral cancer cells as a model.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2385.