bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4904: Activation of aldehyde dehydrogenase is essential for growth of mesenchymal glioma stem cells.
Authors: Mao Ping , Joshi Kaushal , Li Jian feng , Godlewski Jakub , Mo Xiao kui , Chen Shi yuan , Sobol Robert W. , Nakano Ichiro 
Published: August 2014

Abstract
Emerging evidence has indicated glioma stem cells(GSCs) could be subclassified into two major entities termed as as proneural(PN) GSCs and mesenchymal(MES) GSCs according to their mutually-exclusive gene expression pattern. In this study, we characterize 20 patient-derived GSCs into PN GSCs and MES GSCs based on the unbiased analysis with transcriptome microarray and microRNA profiles. Signaling pathway analysis identified the upregulation of various tumor metabolic pathways in MES GSCs. In particular, the glycolytic pathway containing several aldehyde dehydrogenase (ALDH) genes was significantly enriched in MES GSCs. ALDH activity was elevated in MES GSCs, but not in MES non-GSCs or PN GSCs, and its inhibition attenuated MES GSC growth. Intriguingly, irradiation could induce PN GSC's loss of PN phenotype and a gain of MES phenotype, indicating the irradiation-induced PN-to-MES transformation. Furthermore, selective ALDH inhibitor, DEAB, can partially block irradiation-induced transformation of PN to MES GSCs. Clinically, ALDH immunoreactivity was markedly elevated in malignant gliomas in comparison to low grade gliomas or normal brain tissues. Collectively, our data suggest that two GSC subtypes harboring distinct signaling pathways represent intertumoral glioma heterogeneity, and highlight previously unidentified roles of ALDH-associated metabolic signaling in MES MGs and their GSCs. Blocking the pathways that regulate ALDH activity might providepromising therapeutic approaches for a subset of malignant gliomas with the MES signature.
Citation Format: Ping Mao, Kaushal Joshi, Jian feng Li, Jakub Godlewski, Xiao kui Mo, Shi yuan Chen, Robert W. Sobol, Ichiro Nakano. Activation of aldehyde dehydrogenase is essential for growth of mesenchymal glioma stem 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 4904. doi:10.1158/1538-7445.AM2013-4904
Abstract 4907: Knockdown of MMP-9 inhibits radiation-induced invasive phenotype, angiogenesis and tumor growth in glioma cancer stem cells.
Authors: Chetty Chandramu , Ponnala Shivani , Gujrati Meena , Rao Jasti S. 
Published: August 2014

Abstract
Gliomas contain a small number of treatment-resistant glioma stem cells (GSCs). It is thought that tumor regrowth or recurrence originates from GSCs, thus rendering GSCs an attractive target for novel treatment approaches. GSCs are also resistant to conventional chemotherapy and radiation therapy, and a low dose of ionizing radiation can induce stem cell-like properties in heterogeneous cancer cells. In the present study, an isolated glioma stem cell population exhibited a significant differential expression of MMP-9 and a low dose of irradiation enhanced MMP-9 expression levels. Transfection of GSCs with pMMP-9-Si inhibited radiation-induced MMP-9 activity and protein levels as well as cell proliferation. The sphere de-differentiating and invasive ability of GSCs were also reduced in MMP-9 knockdown cells when compared with mock and pSV controls. MMP-9 knockdown led to the induction of apoptotic cell death as determined by FACS and TUNEL analyses, and caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage. pMMP-9-Si transfection also inhibited radiation-induced angiogenesis in vitro and in vivo in GSCs. Further, pMMP-9-Si treatment inhibited pre-established glioma tumor growth in an intracranial model. In addition, GSC xenograft tissue sections from mice that were treated with MMP-9 siRNA showed reduced expression of VEGF and the angiogenic marker, CD31. Indeed, TUNEL analysis of tumor sections collected from the combination group of pMMP-9-Si and irradiation revealed more apoptotic cells. These results validate the usefulness of targeting MMP-9 and provide a novel perspective in the treatment of the cancer stem cell population with its higher resistance to radiotherapy.
Citation Format: Chandramu Chetty, Shivani Ponnala, Meena Gujrati, Jasti S. Rao. Knockdown of MMP-9 inhibits radiation-induced invasive phenotype, angiogenesis and tumor growth in glioma cancer stem 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 4907. doi:10.1158/1538-7445.AM2013-4907
Abstract 4910: The search for the stem cells of human and canine osteosarcoma: evaluation of stemness markers and sarcosphere formation.
Authors: Yang Ya-Ting , Yuzbasiyan-Gurkan Vilma 
Published: August 2014

Abstract
Osteosarcoma (OS) is the most common primary bone tumor of both humans and dogs. The high recurrence rate, resistance to chemotherapy and radiotherapy indicate that novel approaches to treatment are needed. In various cancers, a small population of cells with capacity for self-renewal, tumor growth and metastasis have been identified and designated cancer stem cells, CSCs. Identification and effective targeting of CSCs are necessary for successful treatment of these cancers. The heterogeneous cell types of OS suggest the involvement of CSCs in OS. In some studies, the ability to form spheres in semi-solid media has been proposed as a characteristic of CSCs and in others, the expression of the general stemness markers such as OCT4 has been proposed as a major phenotype of the CSCs. In this study, we evaluated the sarcosphere forming fraction of two cell lines, D17 and SAOS2, a canine and a human OS cell line, respectively. Both D17 and SAOS2 cells were transfected with an OCT4-YFP (yellow florescent protein) reporter construct. The YFP positive and negative cell fractions were isolated from both cell lines and evaluated for sarcosphere forming ability. In addition, expression of OCT4 and other stemness markers, NANOG and SOX2 were evaluated. All cells were characterized for their tumorigenic potential in vitro, including invasion through Matrigel, as well as for their ability to form sarcospheres. Our data show that OCT4 positive cells were more invasive than negative subsets in both D17 and SAOS2 cell lines. In addition, while both subsets were able to form spheres, OCT4 positive cells formed larger spheres than negative cells. These findings further highlight the heterogeneity of the osteosarcoma tumor cells, and suggest that neither sarcosphere formation nor OCT4 expression are sufficient to define the CSCs in either canine and human OS. Further studies incorporating other markers are ongoing to identify and characterize the CSCs in OS.
Citation Format: Ya-Ting Yang, Vilma Yuzbasiyan-Gurkan. The search for the stem cells of human and canine osteosarcoma: evaluation of stemness markers and sarcosphere formation. [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 4910. doi:10.1158/1538-7445.AM2013-4910
Abstract 4912: MELK-dependent phosphorylation of FOXM1 is essential for mitotic progression of glioma stem cells.
Authors: Joshi Kaushal , Nakano Ichiro 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM) is a life-threatening brain tumor. Accumulating evidence suggests that eradication of glioma stem-like cells (GSCs) in GBM is essential to achieve cure. The transcription factor FOXM1 has recently gained attention as a master regulator for mitotic progression of cancer cells in various organs. Here, we demonstrate that FOXM1 forms a protein complex with the serine/threonine kinase MELK in GSCs, leading to phosphorylation and activation of FOXM1 in a MELK kinase-dependent manner. The MELK-dependent activation of FOXM1 results in an increase of mitotic regulatory genes in GSCs. MELK-driven FOXM1 activation is regulated by the binding and subsequent trans-phosphorylation of FOXM1 by another kinase PLK1 (Polo-like kinase 1). Using neural progenitor cells (NPCs) derived from mouse brains, we found that transgene expression of FOXM1 enhances, while its siRNA-mediated gene silencing diminishes clonal neurosphere formation, suggesting that FOXM1 is required for NPC growth. During tumorigenesis, FOXM1 expression sequentially increases from NPCs, pre-tumorigenic progenitors, and GSCs. As expected, sensitivity of GSCs to pharmacological inhibition of MELK-mediated FOXM1 signaling via the thiazole antibiotic Siomycin A is substantially higher than NPCs. In addition, treatment with the first-line chemotherapy agent for GBM, Temozolomide, paradoxically enriches for both FOXM1 (+) and MELK (+) cells in GBM cell culture, and addition of Siomycin A to Temozolomide treatment to mice harboring GSC-derived intracranial tumors enhances the effects of the latter. Collectively, our data indicate that FOXM1 signaling through its direct interaction with the kinase domain of MELK regulates mitotic key genes in GSCs in a PLK1-dependent manner and thus, this protein complex is a potential therapeutic target for GBM.
Citation Format: Kaushal Joshi, Ichiro Nakano. MELK-dependent phosphorylation of FOXM1 is essential for mitotic progression of glioma stem 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 4912. doi:10.1158/1538-7445.AM2013-4912
Abstract 4917: CD44 standard form expression in human ovarian carcinoma is correlated with disease progression but not prognosis.
Authors: Zhang Jing , Chang Bin , Liu Jinsong 
Published: August 2014

Abstract
Single-chain glycoprotein CD44 is a major cell surface receptor for hyaluronan and mediates epithelial cell adhesion by its involvement in cell-cell and cell-matrix interactions. Recently, CD44 has been identified as a biomarker of cancer stem cells in many malignancies, including ovarian carcinoma. However, its clinical significance in human ovarian carcinoma has been controversial until recently. The aim of our current study was to clarify the clinical role of CD44 expression in ovarian carcinoma. Immunohistochemical staining of 483 human primary ovarian carcinoma, and 27 paired primary and recurrent ovarian carcinoma samples for CD44 standard form (CD44s) was performed using tissue microarray. The associations between CD44s expression and clinical factors (diagnosis, tumor grade, International Federation of Gynecology and Obstetrics stage, and response to chemotherapy) and overall and disease-free survivals were analyzed. We observed CD44s expression in 38.1% of the ovarian carcinoma samples. Results of Fisher's exact test suggested that CD44s expression was associated with high-grade carcinoma (P = 0.013), especially high-grade serous carcinoma (P = 0.037); International Federation of Gynecology and Obstetrics stage (III-IV, P &lt; 0.001); age at diagnosis less than 60 years old (P = 0.011); and transitional cell carcinoma (P = 0.039). However, CD44s expression was not associated with overall survival (P = 0.529) or disease-free survival (P = 0.035) by the log-rank test. Moreover, there was no statistical difference in CD44s expression between the primary and recurrent epithelial ovarian carcinomas. Our results showed that CD44s expression is correlated with tumor progression but not prognosis.
Citation Format: Jing Zhang, Bin Chang, Jinsong Liu. CD44 standard form expression in human ovarian carcinoma is correlated with disease progression but not prognosis. [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 4917. doi:10.1158/1538-7445.AM2013-4917
Abstract 4936: Ableson kinases negatively regulate invadopodia function and invasion in head and neck squamous cell carcinoma by inhibiting an HB-EGF autocrine loop.
Authors: Hayes Karen E. , Walk Elyse L. , Ammer Amanda G. , Kelley Laura C. , Martin Karen H. , Weed Scott A. 
Published: August 2014

Abstract
Head and neck squamous cell carcinoma (HNSCC) has a proclivity for locoregional invasion. HNSCC mediates invasion in part through invadopodia-based proteolysis of the extracellular matrix (ECM). Activation of Src, Erk1/2, Abl and Arg downstream of epidermal growth factor receptor (EGFR) modulates invadopodia activity through phosphorylation of the actin regulatory protein cortactin. In MDA-MB-231 breast cancer cells, Abl and Arg function downstream of Src to phosphorylate cortactin, promoting invadopodia ECM degradation activity and thus assigning a pro-invasive role for Ableson kinases. We report that Abl kinases have an opposite, negative regulatory role in HNSCC where they suppress invadopodia and tumor invasion. Impairment of Abl expression or Abl kinase activity with imatinib mesylate enhanced HNSCC matrix degradation and 3D collagen invasion, functions that were impaired in MDA-MB-231. HNSCC lines with elevated EGFR and Src activation did not contain increased Abl or Arg kinase activity, suggesting Src could bypass Abl/Arg to phosphorylate cortactin and promote invadopodia ECM degradation. Src transformed Abl-/-/Arg-/- fibroblasts produced ECM degrading invadopodia containing pY421 cortactin, indicating that Abl/Arg are dispensable for invadopodia function in this system. Imatinib treated HNSCC cells had increased EGFR, Erk1/2 and Src activation, enhancing cortactin pY421 and pS405/418 required for invadopodia function. Imatinib stimulated shedding of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) from HNSCC cells, where soluble HB-EGF enhanced invadopodia ECM degradation in HNSCC but not in MDA-MB-231. HNSCC cells treated with therapeutic inhibitors of the EGFR invadopodia pathway indicated that EGFR and Src are required for invadopodia function. Collectively our results indicate that Abl kinases negatively regulate HNSCC invasive processes through suppression of an HB-EGF autocrine loop responsible for activating an EGFR-Src-cortactin cascade, in contrast to the invasion promoting functions of Abl kinases in breast and other cancer types. Our results provide mechanistic support for recent failed HNSCC clinical trials utilizing imatinib.
Citation Format: Karen E. Hayes, Elyse L. Walk, Amanda G. Ammer, Laura C. Kelley, Karen H. Martin, Scott A. Weed. Ableson kinases negatively regulate invadopodia function and invasion in head and neck squamous cell carcinoma by inhibiting an HB-EGF autocrine loop. [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 4936. doi:10.1158/1538-7445.AM2013-4936
Abstract 4939: MicroRNA-375 regulates tumor invasion and metastasis phenotypes and is associated with poor outcome in head and neck squamous cell carcinoma.
Authors: Jimenez Lizandra , Harris Thomas , Kawachi Nicole , Belbin Thomas , Schlecht Nicolas , Lim Jihyeon , Angeletti Ruth , Prystowsky Michael B. , Childs Geoffrey , Segall Jeffrey 
Published: August 2014

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a highly invasive cancer, with a five-year survival rate of around 50%. Our goal is to improve patient outcome through understanding the mechanisms determining HNSCC invasiveness. Our research group identified miR-375 as the most consistently down-regulated miRNA in tumor samples when compared to paired normal samples. Patients in the lowest quartile of miR-375 expression had significantly decreased disease-specific survival, increase incidence of loco-regional recurrence and distant metastasis. The highly significant association of lower miR-375 expression in patients with poor prognosis and distant metastasis led us to investigate the mechanism by which miR-375 expression causes alterations to the invasive properties of HNSCC. Stable transductant cell lines with increased expression of miR-375 have been generated from two oral cavity cell lines, UMSCC1 and UMSCC47, utilizing lentiviral constructs driving expression of the miR-375 precursor. We have not seen a significant change in proliferation rate for either of the miR-375 expressing lines compared to the empty vector control expressing lines. We have observed diminished invasion properties in vitro correlates with increased miR-375 expression. We have also identified that miR-375 expression in HNSCC result in impaired chemotactic migration properties and suppressed matrix degradation properties. To identify proteins regulated by miR-375, we are utilizing stable isotope labeling of cells in cell culture (SILAC) to identify candidate miRNA target proteins to identify differentially expressed proteins in control and miR-375 over-expressing lines. Candidate target proteins will be validated as targets of miR-375 and tested for involvement in the diminished invasive properties of HNSCC as a result of miR-375 expression. In conclusion, miR-375 represents a potential prognostic marker of poor outcome and metastasis in HNSCC and may function by suppressing the expression of genes and proteins which are involved in the invasive properties of HNSCC.
Citation Format: Lizandra Jimenez, Thomas Harris, Nicole Kawachi, Thomas Belbin, Nicolas Schlecht, Jihyeon Lim, Ruth Angeletti, Michael B. Prystowsky, Geoffrey Childs, Jeffrey Segall. MicroRNA-375 regulates tumor invasion and metastasis phenotypes and is associated with poor outcome in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4939. doi:10.1158/1538-7445.AM2013-4939
Abstract 495: Immune response to XAGE-1b (GAGED2a) in NSCLC patients and its clinical relevance.
Authors: Ohue Yoshihiro , Kurose Koji , Eikawa Shingo , Mizote Yu , Matsumoto Hirofumi , Isobe Midori , Uenaka Akiko , Fukuda Minoru , Nakayama Eiichi , Oka Mikio 
Published: August 2014

Abstract
BACKGROUND:XAGE-1bis a cancer/testis (CT) antigen expressed highly in non-small cell lung cancer (NSCLC) with restricted expressiononly in testis in normal tissues. In this study, we investigated correlation of intensity of humoral and cellular immune responses against XAGE-1b and itsclinical relevance in NSCLC patients.
MATERIALS AND METHODS:Peripheral bloodwas obtained from NSCLC patients who visited Kawasaki Medical School Hospital between 2005 and 2012 under written informed consent. Antibody response to XAGE-1bwas analyzed by ELISA using synthesized XAGE-1b protein. CD4 and CD8 T-cell responses were examined by IFN-γ ELISA and/or IFN-γcapture assay by FACS using 12-mer or 16-merXAGE-1b-overlapping peptides (OLPs) spanning the entire XAGE-1b (GAGED2a) protein.
RESULTS: Antibody positive frequencies of total 362 NSCLC, 220 lung adenocarcinoma and 85 lung squamous cell carcinoma patients were 8.8% (32/362), 12.7% (28/220) and 1.2% (1/85), respectively. With antibody positive NSCLC patients, the patients showing high, intermediate and low antibody response was 7, 20 and 5, respectively. The frequency of XAGE-1b-reactive CD4 T-cells in patients showing high, intermediate and low antibody response was 5.5 ±2.1 x 10−5, 1.5 ±0.7 x 10−5 and &lt; 1.1 x 10−5, respectively. The frequency of XAGE-1b-reactive CD8 T-cells was 6.9 ±1.6 x 10−6, 4.6 ±1.6 x 10−6 and &lt; 1.1 x 10−6, respectively. The frequency of cytotoxic CD8 T-cells in IFN-γ secreting CD8 T-cells in response to XAGE-1b-peptide-pulsed autologous EBV-B cells in patients showing high and intermediate antibody responses was 59.0% and 4.8%, respectively.We evaluated overall survival (OS) time with 120 stage IIIB/IV lung adenocarcinoma patients. Median OS were 32.3 and 14.4 months in antibody-positive and negative patients(P-.039). There was no significant differencewith 1-year survival rate in antibody-positive (68.7%) and negative (55.6%)patients, but was significant with 3-year survival rate in 34.8% and 14.1% respectively. Furthermore, univariate and multivariable analyses showed XAGE-1b antibody response was independent prognostic factor.
CONCLUSION:Our findings indicate that CT antigen XAGE-1b is highly immunogenic in NSCLC patients inducing antibody, and CD4 and CD8 T-cell responses and the immune response against XAGE-1b is beneficial for prognosis.
Citation Format: Yoshihiro Ohue, Koji Kurose, Shingo Eikawa, Yu Mizote, Hirofumi Matsumoto, Midori Isobe, Akiko Uenaka, Minoru Fukuda, Eiichi Nakayama, Mikio Oka. Immune response to XAGE-1b (GAGED2a) in NSCLC patients and its clinical relevance. [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 495. doi:10.1158/1538-7445.AM2013-495
Abstract 4953: Stromal endosialin modulates the proinflammatory tumor microenvironment and is crucial for the growth of orthotopic pancreatic tumors.
Authors: Christian Sven , Sivanandam Vijaysahankar , Strerath Michael , Apeler Heiner , Hess-Stumpp Holger , Augustin Hellmut G. 
Published: August 2014

Abstract
Endosialin (CD248), a transmembrane protein expressed in stromal fibroblasts and activated pericytes during embryonic development, is expressed in human carcinomas. Although its function is unknown, due to its highly specific expression pattern endosialin represents a promising anti-tumor target. To unravel the role of endosialin during tumor progression and metastasis, we employed systematic loss-of-function approaches in stromal fibroblasts in vitro as well as in subcutaneous and orthotopic tumors in vivo. These experiments revealed an important role of endosialin in regulating fibroblast proliferation and in orchestrating an inflammatory response by modulating the secretion of inflammatory cytokines (IL6) in stromal fibroblasts. The proinflammatory environment created by activated fibroblasts is thought to support tumor growth and metastasis in vivo. Experiments in endosialin-deficient mice confirmed an important role of endosialin in tumor progression in highly stroma-recruiting orthotopic pancreatic tumor models. Finally, lung metastases were dramatically decreased in endosialin-deficient mice supporting a role of a proinflammatory tumor stroma in tumor dissemination. Taken together, our experiments identify endosialin as an important modulator of stromal responses that are crucial for tumor progression and metastasis. Endosialin may therefore represent a novel target for development of anticancer therapies for solid tumors.
Citation Format: Sven Christian, Vijaysahankar Sivanandam, Michael Strerath, Heiner Apeler, Holger Hess-Stumpp, Hellmut G. Augustin. Stromal endosialin modulates the proinflammatory tumor microenvironment and is crucial for the growth of orthotopic pancreatic tumors. [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 4953. doi:10.1158/1538-7445.AM2013-4953