bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5157: Functional and regulatory role of src kinase in podoplanin expressing glioma cancer stem cells
Authors: Ezhilarasan Ravesanker , Goodman Lindsey D. , Love Patrice N. , Aldape Kenneth D. , Sulman Erik P. 
Published: February 2011

Abstract
The majority of patients with malignant gliomas, the most common and most lethal brain tumor, develop disease recurrence despite aggressive, multi-modality therapies. This treatment resistance has been attributed to a small population of tumor-initiating glioma cancer stem cells (GSCs). We recently described a new marker of GSCs, podoplanin (pdpn), based on analyses of gene expression profiling data and have found it to more accurately identify the stem cell population than other described markers, such as CD133, and to play a functional role stem cell phenotype. Pdpn expressing cells formed neurospheres at high rates in vitro, were more resistant to ionizing radiation, and initiated tumors in vivo. Pdpn belongs to a mesenchymal gene signature that is characteritic of poor patients survival from malignant gliomas. To identify the mechasism of pdpn within GSCs, we evaluated putuative binding partners to this transmembrane glycoprotein. One such partner, target of myb-like-1 (tom1l1) has been shown to regulate the Src oncogene pathway. The cytoplasmic tyrosine kinases of the Src family (SFK) play important roles in signal transduction induced by growth factors leading to DNA synthesis, cytoskeletal rearrangement, and receptor endocytosis. We therefore hypothesized that pdpn's role GSCs is due to its interaction with the Src pathway. Our aim for this study was to analyze downstream signaling events of Src in association with pdpn and its functional significance in glioma stem cell maintanence, invasion, and chemoradiation resistance. Using primary GSC and established glioma cell lines engineered to either overexpress or silence PDPN, we screened for SFK protein activation (phosphorylation) by immunblot. Changes in Src activation were correlated to in vitro invasion assays, in vivo tumor initiation, and radiation resistance. Preliminary data confirms binding of tom1l1 to pdpn and regulation of SFK activation. Engineered clones with shRNA targeting pdpn and/or tom1l1 were examined by expression profiling for downstream transcriptional changes. In summary, our data suggest a role of SFKs in the regulation of stemness by pdpn. These data integrate well with ongoing trials using Src-kinase inhibitors which may directly target the pdpn-expressing, GSC population in tumors and perhaps overcome the treatment resistance of these critical 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 5157.
Abstract 5159: Kruppel-like factor 9 modulates the growth and differentiation of glioblastoma-derived neoplastic stem cells
Authors: Ying Mingyao , Xia Shuli , Laterra John 
Published: February 2011

Abstract
Glioblastoma (GBM) is the most prevalent brain tumor with high frequency of recurrence. During the past decade, the identification of neoplastic stem-like cells in diverse human cancers including GBM represents an important conceptual advance in cancer biology and suggests new therapeutic strategies. We found that retinoic acid (RA) induces growth arrest and cell differentiation of GBM-derived stem-like cells (GBM-SCs). RA treatment also inhibited the growth of GBM-SC xenografts in mice. We studied gene expression changes during RA-induced GBM-SC differentiation and found that kruppel-like factor 9 (KLF9) expression increased 8-fold after RA treatment. KLF proteins are evolutionarily conserved zinc finger-containing transcription factors that bind to GC-rich DNA regions. KLF9 is known to function as a progesterone receptor cofactor to regulate progesterone-responsive genes but its function in cancer and stem cell biology is essentially unknown. We used lentivirus-based methods to modulate KLF9 expression in GBM-SCs. KLF9 gain-of-function induced GBM-SC differentiation and inhibited GBM-derived neurosphere formation in clonogenic and neurosphere cell growth assays. KLF9 gain-of-function also prevented the growth of GBM-SC subcutaneous xenografts in mice. Knockdown of KLF9 suppressed RA-induced differentiation of GBM-SCs. These data indicate that KLF9 and possibly other KLF family members modulate transcriptional mechanisms that regulate GBM-SC growth, differentiation, and possibly tumor initiation. Currently, we are utilizing gene expression microarray and chromatin immunoprecipitation assays to study the KLF9 target genes. Our findings provide new insights pertaining to the molecular regulation of the GBM-SC phenotype and could lead to innovative therapeutic strategies for targeting the stem-like cell pool in malignant brain tumors.
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 5159.
Abstract 5160: Tumor cells potentiate mesenchymal stem cells-pericytes transition and requirement through PDGF-BB-NRP-1 axis
Authors: Dhar Kakali , Dhar Gopal , Majumder Monami , Haque Inamul , Banerjee Sushanta K. , Mehta Smita , Vanveldhuizen Peter J. , Banerjee Snigdha 
Published: February 2011

Abstract
New blood vessel formation or angiogenic switch is an essential event in the development of solid tumors and their metastatic growth. Tumor blood vessel formation and remodeling is a complex and multi-step processes. The differentiation and recruitment of mural cells including vascular smooth muscle cells and pericytes are essential steps in tumor angiogenesis. However, the role of tumor cells in differentiation and recruitment of mural cells is unknown. In this study we focus on the role of tumor cells in governing the differentiation of mesenchymal stem cells (MSCs) to pericytes and their recruitment in tumor angiogenesis process. We show that C3H/10T1/2 mouse embryonic mesenchymal stem cells, under the influence of different tumor cells-derived conditioned media, differentiate into mature pericytes. These differentiated pericytes, in turn, are recruited to bind with capillary-like networks formed by endothelial cells on the matrigel under in vitro condition. The degree of recruitment of pericytes into in vitro neo-angiogenesis is tumor cell phenotype specific. Interestingly, the invasive cells recruit less pericytes as compared to non-invasive cells. We identify tumor cell-secreted platelet derived growth factor (PDGF-BB) as a crucial factor controlling differentiation and recruitment processes through a cross-talk with NRP-1. These new insights into the roles of tumor cell-secreted PDGF in MSCs-fate determination may help in developing new antiangiogenic strategies to prevent the tumor growth and metastasis and also to treat cancers more effectively.
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 5160.
Abstract 5174: Characterization of glycolipid ligands for E-selectin
Authors: Marshall Jocelyn , Abram Courtney , Wood S. Matthew , Nimrichter Leonardo , Burdick Monica M. 
Published: February 2011

Abstract
The prevention, treatment, and curing of cancer are three of the most researched and highly anticipated areas of modern medicine. One of the greatest barriers to making advances within these fields is the lack of understanding of the molecular mechanisms responsible for cancer metastasis. Head and neck cancer (HNC) is the fifth most diagnosed cancer in the United States, according to the American Cancer Society, and claims the lives of many of its victims because it is often not diagnosed until metastasis has already occurred. After the onset of metastasis, the five-year survival rate drops to below thirty-five percent. Therefore, the study of how metastasis occurs is essential to finding a treatment for HNC.
It is believed that metastasis occurs when cancer cells break free from the primary tumor and travel through the blood stream, attaching themselves onto endothelium of blood vessel walls and in turn, forming secondary tumors in new organs. The cell adhesion mediated by glycolipids on cancer cells to E-selectin on vascular endothlelium may be a significant contributor to cancer metastasis. E-selectin plays a significant role in the first two steps of the adhesion cascade, tethering and rolling, which initiate the recruitment process. In our preliminary studies, it has been shown that HNC cells express glycolipids that can bind to E-selectin. Flow cytometry shows that HNC cells express sialofucosylated molecules that could act as E-selectin ligands, and flow chamber adhesion assays confirm that HNC cells bind to cytokine-stimulated endothelial cells in a wholly E-selectin-dependent manner. Enzyme treatment further reveals that sialofucosylated glycolipids are major adhesive ligand(s) for E-selectin. Through the use of specialized flow chambers mimicking physiological conditions, optical tweezers, gas chromatography-mass spectrometry, the mediators of these adhesive interactions can be studied in depth, leading to the discovery of characteristics of cancer glycolipids that promote adhesion.
The purpose of this investigation is to gain further insight as to which specific glycolipids located on HNCcells are potent ligands for E-selectin binding. With increased understanding of selectin-ligand adhesion interactions, the identity and properties of molecules responsible for metastasis can be used to determine possible therapeutic methods.
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 5174.
Abstract 5178: Homing of circulating prostate cancer cells to bone is regulated by alpha 1,3 fucosyltransferase 7
Authors: Barthel Steven R. , Wiese Georg K. , Cho Jaehyung , Opperman Matthew J. , Hays Danielle L. , Siddiqui Javed , Pienta Kenneth J. , Furie Bruce , Dimitroff Charles J. 
Published: February 2011

Abstract
Circulating cancer cells are known to bind vascular surfaces and then to extravasate into target tissues. How such binding occurs is an essential, yet ill-defined step in metastasis. We and others have proposed that cancer cells exploit identical adhesive determinants as hematopoietic cells in order to bind microvascular endothelial cells. In particular, sialyl Lewis X (sLe(X)) on prostate cancer (PCa) cells is thought to promote metastasis by mediating PCa cell binding to microvascular endothelial (E)-selectin. Nonetheless, regulation of sLe(X) and related E-selectin ligand expression in PCa cells is a poorly understood factor in PCa metastasis. Here, we describe an important glycobiological mechanism regulating E-selectin-mediated adhesion and metastatic potential of PCa cells to the bone marrow. We demonstrate that alpha1, 3 fucosyltransferases (FT) 3, 6, and 7 are markedly elevated in bone- and liver-metastatic PCa tissue and dictate synthesis of sLe(X) and E-selectin ligands on metastatic PCa cells. Upregulated FT3, FT6, or FT7 expression induced robust PCa PC-3 cell adhesion to bone marrow endothelium and to inflamed postcapillary venules in an E-selectin-dependent manner. Membrane proteins, CD44, carcinoembryonic antigen (CEA), podocalyxin-like protein (PCLP), and melanoma cell adhesion molecule (MCAM) were major scaffolds presenting E-selectin-binding determinants on FT-upregulated PC-3 cells. Strikingly, elevated FT7 expression promoted PC-3 cell trafficking to and retention in bone marrow through an E-selectin dependent event. These results highlight alpha1, 3 FTs as potent enhancers of PCa cell metastatic efficiency to the bone marrow via an E-selectin-dependent trafficking mechanism.
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 5178.
Abstract 518: Plasminogen activator inhibitor-1 (PAI-1) protects tumor cells from extrinsic apoptosis
Authors: Fang Hua , DeClerck Yves A. 
Published: February 2011

Abstract
Plasminogen-activator inhibitor-1 (PAI-1) is a member of the serine protease (serpin) family of inhibitors that control the proteolytic activity of urokinase and tissue-type PA. The expression of PAI-1 in most cancer types has been shown to be a marker of poor rather than favorable outcome, suggesting that PAI-1 has a pro-tumorigenic activity. The observation that PAI-1 positively contributes to angiogenesis has in part provided a mechanism in support of the pro-tumorigenic effect of PAI-1. Consistent with such a role, we have previously reported that PAI-1 protects endothelial cells (EC) from FasL-mediated apoptosis by controlling FasL cleavage by plasmin (Bajou et al, Cancer Cell, 2008). Here we hypothesized that PAI-1 may play a similar protective role in cancer cells by preventing them from undergoing apoptosis. We observed that downregulation of PAI-1 by small interfering RNA (siRNA) induces apoptosis in breast cancer MDA-MB-231 cells (14.1 ±1.1% apoptotic cells in PAI-1 siRNA-treated cells vs. 1.5 ± 0.5% apoptotic cells in scramble control; p &lt; 0.001) and increases caspase-3 activity by 5 fold. Consistent with an involvement of the extrinsic apoptotic pathway, we observed that downregulation of PAI-1 in MDA-MB-231 cells did not alter mitochondrial membrane potential but resulted in an increase in caspase-8 activity by 3 fold. PAI-1 silencing also enhanced the production of urokinase (uPA) and the cell-associated activity of plasmin, and inhibited migration and invasion in vitro. The data thus suggest that like in EC, PAI-1 protects tumor cells from extrinsic apoptosis and provides an additional mechanism explaining the pro-tumorigenic activity of PAI-1.
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 518.
Abstract 5180: MUC4 mucin upregulates N-cadherin: A novel mechanism for human ovarian tumor metastasis
Authors: Ponnusamy Moorthy Palanimuthu , Lakshmanan Imayavaramban , Jain Maneesh , Batra Surinder K. 
Published: February 2011

Abstract
The human MUC4 protein is a high molecular weight transmembrane glycoprotein which is over-expressed in ovarian tumors and plays a role in increasing the cellular motility of the ovarian cancer cells. Previous reports have indicated that gain of expression of N-cadherin in tumor cells is associated with increased motility and metastasis. We hypothesize that MUC4 upregulates N-cadherin and plays a major role in metastasis of ovarian cancer. The aim of the present study was to analyze the mechanism of MUC4 induced cellular motility, invasion and metastasis in ovarian cancer cells. For this we have used a MUC4 gene construct (entire coding sequence along with 10% of the central tandem repeat region) for ectopic expression to determine the metastatic function of MUC4 in human ovarian cancer cells (SKOV3). Interestingly, we observed that N-cadherin was up-regulated in MUC4 overexpressing ovarian cancer cells (SKOV3-MUC4) compared to control (vector transfected) cells. We further discovered that N-cadherin upstream pathways such as FAK, MKK7, JNK and c-Jun are activated in the MUC4 expressing SKOV3 cells. Additionally, inhibition of pFAK led to the downregulation of N-cadherin by inhibiting the activation of MKK7, JNK and c-Jun in MUC4 overexpressing SKOV3 cells. On other hand, knockdown of N-cadherin decreased the activation of ERK, AKT and MMP9 in the MUC4 expressing SKOV3 cells. Inhibition of pFAK, pJNK and knockdown of N-cadherin in the MUC4 overexpressing cells further led to a significant decrease in cellular motility. Upon tumorigenisis and metastasis analysis with NOD-SCID mice, the SKOV3-MUC4 cells produced significantly larger tumors and demonstrated a higher incidence of metastasis to distant organs (peritoneal wall, colon, intestine, stomach, lymph nodes, liver and diaphragm) than the SKOV3-vector cells. Taken together, our result suggests that MUC4 mediated upregulation of N-cadherin plays a major role in promoting the metastatic property of ovarian cancer 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 5180.
Abstract 5182: Sialofucosylated glycosphingolipids expressed on head and neck cancer cells mediate adhesion to endothelial cells
Authors: Wood Steven M. , Marshall Jocelyn , Abram Courtney , Burdick Monica M. 
Published: February 2011

Abstract
The development of innovative strategies can be used to detect and prevent cancer metastasis once the molecular mediators are known. Cancer metastasis is the spread of cancer from a primary site, from which cancer cells break away and travel to a new organ via the bloodstream or the lymphatic system. However, the molecular signals responsible for the cancer cells to travel from the primary site to a new location are largely unknown. It has been hypothesized that cancer invasion is similar to leukocyte migration during response of vascular tissue to harmful stimuli. In this process, leukocytes travel through the bloodstream, attach to the vessel endothelium, and migrate through the endothelium to the site of injury. Using leukocyte migration as a model for cancer metastasis it is hypothesized that E-selectin is a major molecular mediator for head and neck squamous cell carcinoma (HNSCC) metastasis. E-selectin is expressed on the surface of vascular endothelial cells and initiates cell-cell interactions by binding to proteins and lipids on the surface of cancer cells that have sialofucosylated carbohydrate epitopes. We have previously shown that HNSCCs bind to E-selectin expressed on stimulated human umbilical vein endothelial cells (HUVECs) under physiological shear stress. Also, it has been shown that glycosphingolipids isolated from HNSCCs support adhesive interactions with E-selectin-transfected Chinese hamster ovary cells. To further reveal the role of sialofucosylated glycosphingolipids in cell-cell interactions, polystyrene microsphere beads were utilized, in an in vitro model of cell adhesion under fluid flow conditions. Polystyrene beads were coated with sialyated non-fucosylated gangliosides (GM1) or sialofucosylated glycosphingolipids from HNSCCs. The expression of glycosphingolipids on the newly coated microspheres was checked by flow cytometry to ensure that the lipids adsorbed to the beads. When coated microspheres were perfused over cytokine-stimulated HUVECs, the microspheres with sialofucosylated glycosphingolipids tethered and rolled on the endothelium similar to HNSCCs, while the microspheres coated with GM1 did not bind to the endothelium. Treatment of the sialofucosylated glycosphingolipid coated microspheres with sialidase or fucosidase also eliminated adhesion of the beads to the endothelium. Our study signifies the importance of the role that glycosphingolipids play in adhesion to endothelial E-selectin under physiological shear stress. Further studies are needed to determine if sialofucosylated glycosphingolipids should be targeted for patients with HNSCCs.
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 5182.
Abstract 5184: Breast cancer cells express glycoprotein and glycolipid ligands for E-selectin
Authors: Shirure Venktesh S. , Burdick Monica M. 
Published: February 2011

Abstract
E-selectin, an adhesion molecule expressed by endothelial cells, has been implicated in various cancer metastatic processes. The hypothesis of the present study is that endothelial E-selectin is involved in the adhesion of breast cancer cells under physiological flow conditions. The characterization of E-selectin ligands expressed by BT-20 and MDA-MB-468 human breast cancer cells was performed. E-selectin ligands were broadly classified into glycoprotein and glycolipid ligands. Purified fractions of glycolipids containing sialic acid residues, known as gangliosides, were found to be E-selectin ligands at wall shear stress of 0.80 dynes/cm2. Immunostaining of breast cancer cells for various proteins known for E-selectin activity on non breast cancer cells revealed that P-selectin glycoprotein ligand-1 (PSGL-1), CD-43, podocalyxin like protein (PCLP), carcinoembryonic antigen (CEA) were absent, but CD44 was expressed by both breast cancer cell lines. Dynamic antigen capture assay at wall shear stress of 0.80 dynes/cm2 indicated that CD44 expressed by breast cancer cells is an E-selectin ligand; however, E-selectin ligand activity of CD44 was weak compared to LS-174T colon carcinoma cells. Efforts were then made to characterize novel glycoprotein ligands using immunoprecipitation and western blotting techniques. BT-20 cells showed presence of protein E-selectin ligands. The characterization of glycans decorating protein E-selectin ligands was performed by immunoprecipitation and western blot staining with various carbohydrate antibodies. In summary breast cancer cells express CD44 and novel glycoproteins as well as glycolipids as E-selectin ligands. Further characterization and identification of novel E-selectin ligands can lead to new diagnostic and prognostic approaches.
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 5184.