bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3362: IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway
Authors: Yadav Arti , Kumar Bhavna , Datta Jharna , Teknos Theodoros N. , Kumar Pawan 
Published: June 2012

Abstract
Distant metastases in head and neck cancer patients almost invariably herald a poor prognosis. Five year survival rates for early stage localized head and neck cancers are over 80% but this drop to 40% where disease has spread to neck nodes, and to below 20% for patients with distant metastatic disease. Uncontrolled cell proliferation and angiogenesis are key characteristics of initiation and early growth of epithelial origin cancers. However, it is the subsequent acquisition of motility and invasiveness that leads to metastatic dissemination of these tumor cells. A key process in this metastatic cascade that converts an adherent epithelial cell into a migratory cell which can invade through the extracellular matrix is known as epithelial-mesenchymal transition (EMT). EMT plays a critical role in epithelial tumor cell metastasis and is commonly observed in tumor samples from head and neck cancer patients. However, the precise molecular events that initiate this complex process of EMT in head and neck cancers are poorly understood. There is increasing evidence that suggest an important role of tumor microenvironment in promoting EMT changes in tumor cells. We have previously shown that head and neck tumors exhibit significantly higher levels of Bcl-2 expression in tumor associated endothelial cells and overexpression of Bcl-2 alone in tumor-associated endothelial cells was sufficient to enhance tumor metastasis of oral squamous cell carcinoma in a SCID mouse model. In this study, we show that endothelial cells expressing Bcl-2 (EC-Bcl-2) when co-cultured with head and neck tumor cells significantly enhance EMT-related changes in tumor cells and this EC-Bcl-2-induced EMT in tumor cells is mediated predominantly by IL-6 secretion. Treatment with recombinant IL-6 or stable IL-6 overexpression in CAL27 cells or normal oral epithelial cells (NOE) significantly induced the expression of vimentin while repressing E-cadherin expression via the JAK/STAT3/Snail signaling pathway. This phenotype was further associated with enhanced tumor and NOE cell scattering and motility. STAT3 knock-down significantly reversed IL-6-mediated tumor and NOE cell motility by inhibiting FAK activation. Furthermore, tumor cells overexpressing IL-6 showed marked increase in lymph node and lung metastasis, in vivo. These results suggest a novel function for IL-6 in mediating head and neck tumor EMT and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3362. doi:10.1158/1538-7445.AM2011-3362
Abstract 3385: A systems view of epithelial – mesenchymal transition signaling states
Authors: Haley John D. , Thomson Stuart , Bean James , Argast Gretchen M. , Epstein David M. 
Published: June 2012

Abstract
Epithelial – mesenchymal transition (EMT) is an important contributor to the invasion and metastasis of epithelial-derived cancers. While considerable effort has focused in the regulators involved in the transition process, we have focused on consequences of EMT to prosurvival signaling. Changes in distinct metastable and ‘epigentically-fixed’ EMT states were measured by correlation of protein, phosphoprotein, phosphopeptide and RNA transcript abundance. The assembly of 1167 modulated components into functional systems or machines simplified biological understanding and increased prediction confidence highlighting four functional groups: cell adhesion and migration, metabolism, transcription nodes and proliferation/survival networks. A coordinate metabolic reduction in a cluster of 17 free-radical stress pathway components was observed and correlated with reduced glycolytic and increased oxidative phosphorylation enzyme capacity, consistent with reduced cell cycling and reduced need for macromolecular biosynthesis in the mesenchymal state. An attenuation of EGFR autophosphorylation and a switch from autocrine to paracrine-competent EGFR signaling was implicated in the enablement of tumor cell chemotaxis. A similar attenuation of IGF1R, MET and RON signaling with EMT was observed. In contrast, EMT increased prosurvival autocrine IL11/IL6-JAK2-STAT signaling, autocrine fibronectin-integrin α5β1 activation, autocrine Axl/Tyro3/PDGFR/FGFR RTK signaling and autocrine TGFβR signaling. A relatively uniform loss of polarity and cell-cell junction linkages to actin cytoskeleton and intermediate filaments was measured at a systems level. A more heterogeneous gain of ECM remodeling and associated with invasion and migration was observed. Correlation to stem cell, EMT, invasion and metastasis datasets revealed the greatest similarity with normal and cancerous breast stem cell populations, CD49fhi/EpCAM-/lo and CD44hi/CD24lo respectively.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3385. doi:10.1158/1538-7445.AM2011-3385
Abstract 3391: Regenerative stem cell therapy for multiple myeloma osteolytic bone damage
Authors: Higgs Jerome T. , Jarboe John , Ponnazhagan Selvarangan 
Published: June 2012

Abstract
Multiple Myeloma (MM) remains the second most common hematologic malignancy occurring in adults, which affects primarily the skeletal system. Current therapies, which include chemotherapy, radiotherapy, autologouos stem cell transplantation and in some cases surgery, have the extended median survival between 3 and 10 years. However, MM is still incurable and therefore improving current therapies or developing novel ones to extend survival rate will be highly beneficial for patient management.
The long term goal of this study is to develop a novel therapeutic approach to the treatment of MM using genetically-engineered mesenchymal stem cells (MSC) for inhibiting osteoclast activity by stable expression of osteoprotegin (OPG). Studies have shown that osteoclast activity is increased in myeloma patients through increased expression of Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL) leading to RANKL/RANK signaling, resulting in osteoclast activation and ultimately bone resorption. Osteoprotegerin is a soluble decoy receptor for RANKL, and is decreased in expression in myeloma patients possibly because of a marked decrease in osteoblast and or MSC, which produce OPG. Thus, we hypothesize that therapy with MSC, overexpressing OPG, will greatly decrease osteolytic damage and reduce morbidity. Despite the potential of OPG in inhibiting osteoclast activation, OPG also binds to tumor related apoptosis-inducing ligand (TRAIL) making MM cells resistant to apoptosis.
In order to eliminate TRAIL binding while still possessing RANKL binding, we have created mutant OPG constructs by site-directed mutagenesis based on interactive domain identification, and superimposing structural models of TRAIL, OPG and DR5, the death receptor that binds to TRAIL. The mutant OPGs were produced in HEK 293 cells for characterization of the five potential mutants and their TRAIL binding ability. One of the mutants abolished TRAIL binding while possessing RANKL binding as determined by TRAIL assay and osteoclast assay respectively. Finally, to achieve biphasic effects of MSC-OPG therapy with anti-tumor activity, the regenerative MSC therapy will be tested in combination with chemotherapy and anti-angiogenic therapy. These studies are performed in preclinical mouse models of MM. Currently, other OPG mutants are being characterized for their RANKL and TRAIL binding properties which will be confirmed via the assays mentioned and immunoprecipitation. Thus far, we conclude that using site-directed mutagenesis targeted at the N-terminal of OPG effectively retains RANKL binding and abolishes TRAIL binding.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3391. doi:10.1158/1538-7445.AM2011-3391
Abstract 3393: Extrinsic uPA initiates glioma stem cell transformation under hypoxic conditions via Lhx-2
Authors: Gondi Christopher S. , Gorantla Bharathi , Asuthkar Swapna , Rao Jasti S. 
Published: June 2012

Abstract
Emerging evidence indicate that the capacity of a tumor to grow and propagate resides primarily in a small population of tumor cells, which are known as cancer stem cells. The origin of these cancer stem cells remains controversial. Hypoxia promotes tumor progression through multiple mechanisms, including modification of angiogenesis, metabolic switches and invasion. Researchers have demonstrated that hypoxia is one of the factors necessary for neural stem cell tropism to glioma. Although hypoxia has been shown to maintain multiple normal stem cell populations, its role in cancer stem cells is fairly unknown. Recently, researchers have identified hypoxia as a critical microenvironmental factor in regulating self-renewal of cancer stem cells, which is partially mediated by enhancing the activity of stem cell factors such as Oct4, c-Myc and Nanog. In this study, we show that under hypoxic conditions, urokinase plasminogen activator (uPA) is one of the factors necessary for the maintenance and transformation of glioma cells to glioma stem cells. Glioma cells grown under hypoxic conditions showed an increase in expression of stem cell markers Oct-4, c-Myc, CD133 and Stro-1. Supplementing normoxic or hypoxic cells with external uPA increased Lhx-2 expression and was not influenced by the presence or absence of native uPA. Hypoxic cells down regulated for Lhx-2 did not show activation of stem cell marker proteins Oct-4, c-Myc, CD133 and Stro-1. Hypoxic cells subcutaneously implanted into nude mice developed at least 2-fold larger tumors when compared to normoxic cells. Intratumoral injection of plasmids expressing siRNA targeting uPA retarded tumor development in both normoxic and hypoxic tumors. In contrast, injection of plasmids expressing siRNA targeting Lhx-2 retarded hypoxic tumors with reduced effect on normoxic tumors. In conclusion, our results demonstrate that a hypoxic environment in a high uPA environment can induce glioma stem cell transformation mediated by Lhx-2 and suppression of uPA and Lhx-2 can specifically target glioma stem cell populations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3393. doi:10.1158/1538-7445.AM2011-3393
Abstract 3397: Validation of targets involved in supporting the stem cell niche in glioblastoma multiforme
Authors: Bandopadhyay Gagori , Mayne Cerys M. , Lees Nick , Papadopoulou Nektaria , Coughlan Teresa C. , Coyle Beth , Watson Susan A. , Grabowska Anna M. 
Published: June 2012

Abstract
Introduction: Glioblastoma multiforme (GBM) is a cytologically malignant tumour of the central nervous system, associated with poor prognosis and fatal outcome (5 year survival, &lt;6%). GBM cancer stem cells (CSCs), which can be identified using the immunocytochemical marker CD133, are associated with poor prognosis. The gastrin receptor, CCK2R, is also expressed in glioblastoma cell-lines and promotes cancer progression. In this study we investigated the functional role of these two molecules in GBM to elucidate any potential therapeutic benefits.
Materials and methods: A panel of glioblastoma cells was grown either as monolayers, or, to provide a 3D in vitro tumour model, as neurospheres, which enrich for the cancer stem cell phenotype. Quantitative RT-PCR was used to quantify CD133 and CCK-2R gene expression over time in these cultures, and flow cytometry (FACS) to investigate expression at the protein level. CD133 and CCK-2R promoter reporters were constructed in pGL4 and promoter activity quantified using luciferase assays. Gene knockdown or specific inhibitors were used to investigate the role of these genes in glioblastoma cell tumorigenicity in vitro (using MTT, wound-healing, and neurosphere formation) and in an in vivo xenograft model.
Results: CD133 and CCK-2R gene and protein expression were higher in the more tumorigenic glioblastoma cell-line, U251, compared with the less tumorigenic line, U373. For both markers, higher gene expression correlated with higher promoter activity and FACS demonstrated the presence of a small population of positively-stained cells. Expression of both genes was upregulated during neurosphere formation, which was accelerated in hypoxia. Knockdown of CD133 and CCK-2R inhibition in cell line U251 reduced neurosphere-forming potential (p&lt;0.05). Knockdown of CD133 also significantly reduced migration (p&lt;0.001) and increased susceptibility to the chemotherapeutic agent etoposide (p&lt;0.05).
Conclusions: CD133 and CCK-2R expression correlate with tumorigenic potential of GBM cells and are upregulated during neurosphere formation, which enriches for cancer stem cells. CD133 knockdown and CCK-2R inhibition reduced neurosphere formation. In addition, CD133 knockdown reduced GBM invasive capacity, and increased resistance to chemotherapeutic drugs. Therefore, use of CD133 and CCK-2R-targeted therapies, in combination with established standard of care may improve GBM patient outcome.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3397. doi:10.1158/1538-7445.AM2011-3397
Abstract 3412: Hypoxia induces EMT in primary melanoma and MET in metastatic melanoma
Authors: Cheng Chieh-Fang , Giaccia Amato J. , Powell Marianne B. 
Published: June 2012

Abstract
A low oxygen microenvironment (hypoxia) is observed in the skin and in solid tumors. In several different types of cancers hypoxia has been shown to induce primary tumor cell migration and cancer metastasis. Epithelial to mesenchymal transition (EMT) is an important process involving the transition of primary tumor cells to mobile metastatic tumor cells. Hypoxia has been reported to induce EMT in breast and ovarian cancers. However, little is known about the settlement process after metastatic tumor cells reach the distant metastatic site. In this study, we compared the effect of hypoxia on several primary and metastatic melanoma cell lines in cell morphology and cell motility. We observed different expression patterns of cell surface markers and transcription factors regulated by hypoxia that are important for the EMT process between primary and metastatic tumor cells. While hypoxia induces the expression of EMT markers in primary melanoma, it represses the expression of these markers as well as cell migration in metastatic melanomas. Furthermore, cell migration induced by hypoxia in primary melanoma cell is blocked by either HIF1α or HIF2α knock down. Cell migration repressed by hypoxia is reversed by knocking down HIF1α but not HIF2α in metastatic tumor cells. We propose that depending on the state of tumor progression, hypoxia can induce EMT in primary melanomas and MET in metastatic melanomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3412. doi:10.1158/1538-7445.AM2011-3412
Abstract 3418: TWIST1 a new determinant of epithelial to mesenchymal transition in EGFR mutated lung adenocarcinoma
Authors: Pallier Karine , Cessot Anatole , Cazes Aurelie , Just Pierre-Alexandre , Danel Claire , Riquet Marc , Côté Jean-Francois , Ansieau Stephane , Puisieux Alain , Laurent-Puig Pierre , Blons Helene F. 
Published: June 2012

Abstract
Metastasis, a recognized multistep biological process, is the main cause of mortality in cancer patients. Although EGFR mutated lung cancers are of better prognosis, a group of patients develop metastasis and died of disease. We previously showed that EGFR mutations were associated with a copy number variation at a locus encompassing the TWIST1 gene on chromosome 7. TWIST1 is a highly conserved developmental gene involved in embryogenesis that turned out to be frequently reactived in cancers promoting both malignant conversion and cancer progression. The aim of this study was to investigate the role of TWIST1 on progression in EGFR mutated lung cancer. Using 6 human lung cell lines with or without EGFR mutations or TWIST1 reactivation, we demonstrated that epithelial-mesenchymal transition (EMT) and the associated mobility were dependent upon TWIST1 expression in cells with EGFR mutation. Indeed, EGF treatment only induced EMT and mobility in cells with TWIST reactivation. EGF treatment induced a translocation of TWIST1 to the nucleus, up-regulated mesenchymal markers and down-regulated epithelial markers at mRNA and protein levels. Moreover, inhibition of either the oncogenic EGF pathway stimulation or TWIST1 expression by small RNA technology reversed the phenomenon suggesting that both EGF pathway activation and TWIST1 reactivation are necessary for EMT in lung cancer with EGFR mutation. In a second step, we analyzed surgical lung cancer specimens from non-smokers with and without EGFR mutations and looked for TWIST1 and epithelial or mesenchymal markers expression. Hierarchical clustering combining TWIST1, epithelial (CDH1, JUP) and mesenchymal (VIM, CDH2) gene mRNA expression in tumors perfectly individualizes the EGFR mutated group as the group with TWIST1 reactivation. Immunohistochemical analysis of lung cancer samples revealed that TWIST1 protein expression was associated with EGFR mutation and low CDH1 expression supporting our in vitro observations. Collectively, our observations support that TWIST1 collaborates with EGF/EGFR mutated signaling pathway in promoting EMT in lung cancers and thereby drives the metastatic dissemination in this group of patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3418. doi:10.1158/1538-7445.AM2011-3418
Abstract 3432: p38 and Snail are critical for downregulation of E-cadherin during EMT in HNSCC
Authors: John Maie St. , Lin Yuan , Wang Guanyu , Luo Jie , Sidell Douglas , Dennis Miranda , Mundi Jagmeet , Abemayor Elliot , Dubinett Steven 
Published: June 2012

Abstract
Objectives: To determine the roles of Snail and p38 in the inflammation-induced promotion of EMT in HNSCC.
Study Design: A molecular biology study. Real-time quantitative RT-PCR, Western blot analysis, spheroid modeling, and immunohistochemical staining of human HNSCC tissue sections were used to determine how inflammation affects Snail and p38.
Setting: An academic hospital laboratory.
Subjects and Methods: Relative RNA levels were determined by RT-PCR, and protein expression was evaluated by immunofluorescence (IF) and in situ by immunohistochemical staining of human HNSCC tissue sections.
Results: p38 kinase inhibitor treated, and p38 shRNA HNSCC cell lines demonstrated a significant upregulation in E-cadherin mRNA and a decrease in the mRNA expression of the transcriptional repressor Snail. p38 shRNA HNSCC cell lines show a less invasive phenotype in a spheroid model. An inverse relationship between p38 and E-cadherin was demonstrated in situ by immunohistochemical staining of human HNSCC tissue sections. p38 is required for the robust IL-1β induced E-cadherin downregulation and Snail upregulation. IL-1β increases p-p38 and has a more rapid and robust effect on p38 in Snail overexpressing cell lines.
Conclusions: In gastrulation, it is a Snail-independent pathway in which p38 is required in the primitive streak to downregulate E-cadherin expression at the posttranscriptional level. Herein we provide the first report that p38 is required for the Snail-induced E-cadherin down-regulation and cell invasion in HNSCC. A Snail-p38 feedback loop jointly down regulates E-cadherin and drives a potent EMT in HNSCC. This newly defined pathway has important implications for targeted chemoprevention and therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3432. doi:10.1158/1538-7445.AM2011-3432
Abstract 3443: Targeting G2/M cell cycle regulators in medulloblastoma tumor-propagating cells
Authors: Markant Shirley L. , Barton Kelly , Sun Jesse , Wechsler-Reya Robert 
Published: June 2012

Abstract
Medulloblastoma is the most common malignant brain tumor in children. While the current treatment strategy of surgery, radiation and chemotherapy has a 60-80% cure rate, the survivors suffer severe side effects, including growth delays and cognitive deficits. Therefore, more effective, less toxic treatments are needed. One approach to achieving this is targeting the cells within a tumor that are capable of re-populating the tumor, known as tumor-propagating cells (TPCs). In the patched mutant mouse model of medulloblastoma, TPCs are marked by expression of the cell surface carbohydrate antigen CD15. Our previous studies suggest that CD15+ cells display increased expression of genes associated with G2/M phase of the cell cycle. Cell cycle analysis suggests that these CD15+ cells move quickly through the G1 and S phases of the cell cycle, but accumulate in G2/M phase. Therefore, inhibition of G2/M regulators, such as Aurora kinases, may represent one approach to targeting TPCs in these tumors. Treatment of tumor cells with the Aurora kinase inhibitor VX-680 (tozasertib) leads to inhibition of proliferation in vitro, with arrest in G2/M and apoptosis. Preliminary studies suggest that patched mutant tumors are also sensitive to Aurora kinase inhibition in vivo. Our findings suggest that targeting Aurora kinases may represent a novel approach for the treatment of hedgehog-associated human medulloblastoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3443. doi:10.1158/1538-7445.AM2011-3443