bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2871: JNK1-phosphorylation of Bcl-2 is essential for adenoviral-induced autophagic cell death in glioma cells
Authors: Klein Sarah R. , Piya Sujan , White Erin J. , Jiang Hong , Yung W.K.Alfred , Gomez-Manzano Candelaria , Fueyo Juan 
Published: June 2012

Abstract
Purpose: Delta-24-RGD is a highly selective and potent oncolytic adenovirus that is currently being tested in a clinical trial for patients with malignant gliomas. The mechanism of oncolysis for Delta-24-RGD is defined as autophagic cell death, yet the signal transduction and molecular interactions responsible remain uncharacterized. Methods: Utilizing JNK1- and JNK2-null mouse embryonic fibroblasts, we analyzed the involvement of JNK in Bcl-2 phosphorylation and degradation, and adenoviral-induced autophagy. Mutations at the phosphorylation sites of Bcl-2 were employed to determine which are necessary for release of Beclin 1, degradation of Bcl-2, and induction of autophagy by adenovirus. Results: In this report, we reveal that activation of c-Jun N-terminal kinase 1 (JNK1) is required to initiate and maintain autophagy induced by wild-type and Delta-24-RGD adenoviruses in the host cell. In addition, JNK1-dependent phosphorylation of Bcl-2 at serine 87 (but not serine 70) and subsequent inhibition of Bcl-2:Beclin 1 heterodimerization is necessary for autophagy to occur in infected cells. Upon phosphorylation and release from Beclin 1, Bcl-2 is degraded by the proteosome. Finally, the activation of JNK leads to its translocation to the nucleus and results in the transcription of autophagy-related (ATG) genes for the maintenance of autophagy, as yet undocumented in mammalian cells. Conclusion: Adenoviruses have thus evolved a highly complex mechanism of regulating autophagy which differs from the typical cellular stress response that may be exploited in the treatment of gliomas.
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 2871. doi:10.1158/1538-7445.AM2011-2871
Abstract 2884: Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting leukotriene A4 hydrolase
Authors: Cho Yeon-Yong , Oi Naomi , Jeong Chul-Ho , Nadas Janos , Pugliese Angelo , Bode Ann M. , Dong Zigang 
Published: June 2012

Abstract
Considerable attention has focused on the anticancer effects of red wine. Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a well-known polyphenolic compound found in red wine and recognized as a key substance for cancer chemoprevention. Leukotriene A4 hydrolase (LTA4H) is a bi-functional zinc enzyme that is regarded as a relevant target in certain types of human cancers. Our data indicate that knockdown of LTA4H decreased production of leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of MIA PaCa-2 pancreatic cancer cells. An in silico prediction using a shape-similarity approach suggested that LTA4H might be a potential target of resveratrol. Results showed that resveratrol directly bound to LTA4H in vitro and ex vivo and suppressed proliferation and anchorage-independent growth by inhibiting LTA4H activity in MIA PaCa-2 cells. Importantly, resveratrol exerted stronger inhibitory effects compared to bestatin, a well-known inhibitor of LTA4H activity. The inhibitory effects of resveratrol were reduced in MIA PaCa-2 cells transfected with sh-LTA4H compared with sh-mock transfected cells. Notably, in an in vivo xenograft mouse model, resveratrol suppressed MIA PaCa-2 tumor formation by inhibiting LTA4H activity. These findings suggest that LTA4H is a novel target for the preventive and/or therapeutic effects of resveratrol on pancreatic cancer.
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 2884. doi:10.1158/1538-7445.AM2011-2884
Abstract 2937: The LKB1-STRADα axis regulates vimentin to control cancer cell metastasis
Authors: Kline Erik , Hales Katherine , Marcus Adam I. 
Published: June 2012

Abstract
Lung cancer remains the most lethal form of cancer, and non-small cell lung cancer (NSCLC) patients have a 5-year survival rate of only 15-25%. Metastasis is the major cause of death in nearly all cancer cases. Therefore, determining which genes are altered during cancer invasion and the functional consequences of their alteration will broaden our understanding of metastatic disease and unveil novel targets for anti-metastatic therapies. The pleiotropic tumor suppressor LKB1 is mutated in ∼30% of NSCLC cases and is the third most frequently mutated gene in lung adenocarcinoma. Originally recognized as a regulator of the energy stress pathway and cell cycle signaling, we and others have identified LKB1 and its activating co-factor STRADα as regulators of the lung cancer cell polarity program through the small Rho GTPase cdc42 and its downstream binding partner p21-activated kinase (PAK). We expand these studies and investigate the LKB1-STRADα pathway during the transition from cell polarity to cell motility. We show that when a cancer cell becomes motile, STRADα re-localizes to associate with vimentin intermediate filaments in a motility-dependent manner. Vimentin is specifically overexpressed in invasive human tumors, which also correlates with metastatic disease, poor prognosis, and reduced patient survival. To dissect the mechanistic basis of this observation, we tested the hypothesis that STRADα regulates vimentin function to oversee cancer cell motility. STRADα loss results in aberrant lamellipodia formation, uncoordinated movement, and vimentin bundling. Conversely, STRADα overexpression disassembles the vimentin network with no apparent effect on cell survival. A phospho-proteomic screen in isogenic NSCLC cell lines showed that out of 580 possible proteins the cdc42 GEF, VAV2, demonstrated the greatest loss in phosphorylation upon vimentin depletion. Western blot analysis confirmed that vimentin-depletion decreased phosphorylation of VAV2 at residue Y-142. Dual overexpression of LKB1 and STRADα enhances VAV2 phosphorylation in vimentin-positive cells but not in vimentin-depleted cells. These findings suggest a cell polarity-motility program whereby LKB1-STRADα initiates cell polarity through cdc42-PAK, then STRADα re-localizes to the vimentin cytoskeleton to oversee vimentin dynamics. LKB1-STRADα also regulates VAV2 phosphorylation through vimentin signaling. These results link the LKB1-STRADα tumor suppressor pathway to the lung cancer cell polarity and motility programs, and explain how defects in the LKB1-STRADα alter lung cancer invasion.
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 2937. doi:10.1158/1538-7445.AM2011-2937
Abstract 299: CDK1 and CDK2 activity is a strong predictor of renal cell cancer recurrence
Authors: Hongo Fumiya , Takaha Natsuki , Kimura Yasunori , Nakamura Terukazu , Mikami Kazuya , Nakayama Satoshi , Matsushima Tomoko , Ishihara Hideki , Sakai Toshiyuki , Miki Tsuneharu 
Published: June 2012

Abstract
Background: We established original methods enabling simultaneous analysis of protein expressions and kinase activities of the CDK (cyclin-dependent kinase) molecules in lysate of tumor tissue in a clinical setting (C2P technology, Ishihara et al: Biochim Biophys Acta. 1741; 226-233, 2005). The clinical utility of the technology was first evaluated in breast cancer, and combination analysis of CDK1 and CDK2 activity was shown to be a significant prognostic indicator for relapse (Kim et al: Ann Oncol. 19; 68-72, 2009). The objective of our study is to evaluate the efficacy of CDK1 and CDK2 activity as a prognostic marker in human renal cell carcinoma (RCC).Methods: Surgical specimens were obtained from 125 patients with RCC without metastasis. These patients were selected randomly for this study. Protein expression and kinase activity of CDKs and cyclins were analyzed using a newly developed assay system. The system to measure the CDK specific activity (SA) is named C2Ps (Sysmex, Kobe, Japan). We then examined the specific activities of CDK1 and CDK2 and calculated CDK2/CDK1 ratio in RCC. Also, risk score (RS) was examined as described in previous study (JGH van Nes et al: Br J Cancer. 100; 494-500, 2009). Cut off value was calculated by ROC analysis.Results: 125 cases were tested, though 34 cases were excluded of low sample quality (25 cases) and of assay failure (9 cases). 91 cases were analyzed. They included 68 male and 23 female patients, ranging in age from 19 to 83 years. At a median follow up of 36 months (1-109M), tumor with low CDK2/CDK1 ratio showed significantly better 5-year progression free survival (PFS) than those with high CDK2/CDK1 ratio (88.7% vs 54.7%, P=0.00141). Also, RS enabled the classification of RCCs into high-risk and low-risk groups, patients with tumors classified as low RS showed better PFS than patients with tumors with high RS (88.7% vs 54.7%, P=0.0141).Conclusion: CDK1 specific activity of tumors and the CDK2 specific activity are both associated with recurrence and prognosis. Analysis of cyclin-dependent kinase activity in the clinical setting could be a powerful approach for predicting cancer recurrence and prognosis in RCC after surgery and has potential for use as a routine laboratory test.
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 299. doi:10.1158/1538-7445.AM2011-299
Abstract 3093: Gene regulation induced by constitutive expression of HIF-1α in transgenic mice
Authors: Ide Masaru , Sueoka-Aragane Naoko , Sato Akemi , Nakamura Tomomi , Yokoo Masako , Kimura Shinya , Tanimoto Keiji , Sueoka Eisaburo 
Published: June 2012

Abstract
Hypoxia-inducible factor-1α (HIF-1α) has a central role on regulation of various genes under hypoxic condition linked to regulation of angiogenesis, metabolism and tumor development. Expression of HIF-1α was reported in many cancers associated with tumor progression, invasion and metastasis. We reported that constitutive expression of HIF-1α in transgenic mice induced tumors in lymphoid, lung and breast tissues in last this meeting. The incidence of tumors in transgenic mice was up to 90% until 18 months after birth. To clarify the molecular mechanism of lymphomagenesis in the transgenic mice, lymphocyte subsets, gene expression and mitogenic responsiveness on lymphoid tissues were analyzed. Although population of T and B cell subset in spleen, maturation pattern of T cells in thymus, or cell growth rate after treatment with various mitogens were not changed by HIF-1α overexpression, the lymphocytes from transgernic mice showed longer survival than those from wild mice. The lymphocytes also showed resistance for genotoxic stimuli like topoisomerase inhibitors. We next compared gene expression profile on lymphocyte from transgenic mice and wild mice by cDNA microarray and RT-PCR. The expression of over a hundred of genes including HIF-1α itself was altered on T and B cells in transgenic mice. Among them the gene associated with cell survival and cell transformation-related genes were further analyzed by validation study. In this paper, we present the results concerning the role of HIF-1α in lymphoma occurrence, and will discuss the contribution of the transcription factor in human cancer development.
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 3093. doi:10.1158/1538-7445.AM2011-3093
Abstract 3109: Wnt2 secreted by tumor fibroblasts promotes tumor growth and cell motility in esophageal carcinoma
Authors: Guan Xin-Yuan , Fu Li , Zhang Chunyu , Dong Sui Sui , Li Yan , Chen Juan 
Published: June 2012

Abstract
Interaction between neoplastic and stromal cells plays an important role in the tumor progression. Recently, we found that Wnt2 was frequently overexpressed in fibroblasts isolated from tumor tissue (TFs) compared to fibroblasts from non-tumor tissue (NFs) in esophageal squamous cell carcinoma (ESCC). In the present study, we studied the effect of TF-secreted Wnt2 in ESCC development via the tumor-stroma interaction. Quantitative real-time PCR found that Wnt2 expression was about 4 folds higher in the TFs than the NFs. Interestingly, no visible protein expression of WNT2 was detected in all tested ESCC cancer cell lines and clinical ESCC samples. Immunohistochemistry study showed that WNT2(+) cells was were mainly detected in the boundary between stroma and tumor tissue or scattered within tumor tissue. Furthermore, Wnt2-positive ESCC (defined as 5 or more Wnt2(+) cells observed in 200× microscopy field) was detected in 22/51 cases, which was significantly associated with the lymph node metastases (P=0.001), advanced TNM stage (P=0.001) and disease-specific survival (P&lt;0.0001). To further investigate the effect of secreted Wnt2 on ESCC cells, an in vitro Wnt2 secreting system was established using Chinese hamster ovary (CHO) cells and conditioned medium was collected for functional study. Functional assays demonstrated that secreted Wnt2 could promote cell growth and cell migration. Molecular study found that the cell growth promoting effect of Wnt2 was via activating Wnt/β-catenin signaling pathway and subsequently upregulating cyclin D1 and c-myc expression. Wnt2 could also induce epithelial-mesenchymal transition (EMT) and promote cell motility. In conclusion, our data demonstrate that TF-secreted Wnt2 can promote cell growth through activating the canonical Wnt/β-catenin signaling pathway and increase cell motility by inducing EMT in esophageal cancer cells. Further characterization of the effect of Wnt2 secreted by TF on cancer development and progression will reveal the molecular mechanisms of how TF provide cancer cells a suitable microenvironment and find new therapeutic targets for cancer treatment.
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 3109. doi:10.1158/1538-7445.AM2011-3109
Abstract 3112: Host MMP-2 impacts tumor survival in the metastatic bone microenvironment through a TGFβ dependent mechanism
Authors: Thiolloy Sophie , Edwards James , Fingleton Barbara , Rifkin Daniel , Schwartz Herbert S. , Mundy Gregory , Matrisian Lynn M. , Lynch Conor C. 
Published: June 2012

Abstract
Breast to bone metastases frequently induce a “vicious cycle” in which osteoclast mediated bone resorption and proteolysis results in the release of bone matrix sequestered factors that drive tumor growth. While osteoclasts express numerous proteinases, analysis of human breast to bone metastases unexpectedly revealed that bone forming osteoblasts were consistently positive for the proteinase, MMP-2. In immunocompetent murine models of the lytic tumor-bone microenvironment, we identified that, independent of osteoclast function, osteoblast derived MMP-2 promoted tumor survival by regulating the bioavailability of TGFβ, a factor critical for cell-cell communication in the bone. Collectively, these studies identify a novel interplay between the osteoblast and tumor compartments that is key for tumor survival in the bone microenvironment.
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 3112. doi:10.1158/1538-7445.AM2011-3112
Abstract 3127: Expression and sub-cellular localization of claudin-4 in MCF-7 breast and HEC-1A endometrial cancer cell lines
Authors: Cuevas Maria E. , Sheller Rebecca A. , Holland Andrea C. , Piana Brytanie N. , Todd Maria C. 
Published: June 2012

Abstract
The claudin (CLDN) family consists of 24 tetraspan membrane proteins that are essential for the formation of tight junctions (TJs). Members of the CLDN family display tissue-specific expression and are involved in multiple normal cellular processes. In addition, alterations in CLDN gene expression have been shown to be associated with a variety of cancers. For example, CLDN-3 and CLDN-4 have been found to be upregulated in prostate, ovarian and breast cancer. We have previously shown gross overexpression of CLDN-3 in the breast cancer cell lines MCF-7 and MDA-MB-415. Furthermore, using sequential protein extraction techniques we have consistently observed expression of CLDN-3 in all four subcellular fractions of MCF-7 cells with the bulk of expression in the membrane fraction. CLDN-3 and CLDN-4 genes are located within 50 kb on chromosome 7 and their coordinated regulation has been reported in normal, neoplastic tissues and various cancer cell lines. The present study reports the expression and sub-cellular localization of CLDN-4 in a panel of cancer cell lines using immunoblot analysis. Like CLDN-3, overexpression of claudin-4 was observed in the breast cancer cell lines MCF-7 and MDA-MB-415. In addition, we observed expression of CLDN-3 and CLDN-4 in both endometrial (HEC-1A and RL95-2) and prostate (DU-145) cancer cell lines. Sub-cellular localization analysis of MCF-7 cells demonstrated the expression of CLDN-4 in the membrane, nuclear, cytosolic and to a lesser extent in the cytoskeletal fractions. Currently we are investigating the sub-cellular localization of CLDN-3 and 4 in the endometrial and prostate cancer cell lines described above. Recent studies have shown CLNDs to be involved in signaling to and from TJs, conveying important chemical messages for cell proliferation and differentiation. The presence of CLDN-3 and 4 in the cytosol and nucleus observed in this study may indicate their involvement in cell signaling. Alternatively, their unusual localization may be a characteristic of breast cancer cells.
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 3127. doi:10.1158/1538-7445.AM2011-3127
Abstract 3178: Identification and validation of markers for colon adenoma and adenocarcinoma
Authors: Sewda Kamini , Enkemann Steven , Gillies Robert J. , Morse David L. 
Published: June 2012

Abstract
Colorectal cancer (CRC) is the second leading cause of cancer related deaths in the United States and Europe. The early detection and diagnosis of dysplastic and early neoplastic colonic lesions will improve survival and make possible curative treatments. Currently, this is best done with colonoscopy, which is expensive and requires a cathartic bowel prep that has led to low compliance. The goal of this study is to develop targeted molecular imaging agents for the early detection of colon cancer via targeted and potentially prepless colonography using CT or MRI contrast. Such agents can also be used to improve detection of lesions for removal during traditional colonoscopy. By gene expression profiling of DNA microarray data from patient samples of colon adenoma (n =39), adenocarcinoma (n = 432), inflammatory bowel disease (IBD) (n = 16) and unaffected gastrointestinal (GI) tract tissues (normal colon, n = 178 and other gastrointestinal tissues n = 32), we have identified 6 potential cell-surface targets that are highly expressed in colon adenomas and adenocarcinomas relative to unaffected GI tissues: TLR4, LY6G6D, GRM8, GPR56, SLCO1B3 and CLDN1. None of these markers alone cover 100% of the colon adenoma and adenocarcinoma samples surveyed, although combinations did. Nearly all (99.7%) of the adenoma and adenocarcinoma samples express at least one of the three markers TLR4, LY6G6D and CLDN1. One tumor did not express any of these markers. CSF3R and SLC6A14 are expressed exclusively in IBD, which is a risk factor for colon cancer. DNA microarray expression data for colon tumor cell lines (DIFI, SW-620, SW-480, HT-29, COLO-205, KM12, KM12S, HCT116, and HCT115) were also analyzed, and SW-620 and SW-480 cell lines were identified as expressing TLR4, LY6G6D, GPR56 and CLDN1. COLO-205 cells highly express GRM8 and KM12 cells express SLCO1B3. GPR56 and CLDN1 were broadly expressed amongst all cell lines. Validation of these markers for protein expression in patient tissue samples by immunohistochemistry is underway. Molecular imaging agents against validated targets are being developed for the potentially prepless and non-invasive detection of colon adenomas and adenocarcinomas using molecular colonography.
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 3178. doi:10.1158/1538-7445.AM2011-3178
Abstract 3285: Ang-2-VEGF CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 function mediates potent anti-tumoral and anti-angiogenic efficacy
Authors: Thomas Markus , Scheuer Werner , Regula Jörg Thomas , Bähner Monika , Schanzer Jürgen Michael , Croasdale Rebecca , Gassner Christian , Georges Guy , Kettenberger Hubert , Dürr Harald , Imhof-Jung Sabine , Schwaiger Manfred , Stubenrauch Kay-Gunnar , Weidner Michael K. , Schäfer Wolfgang , Klein Christian 
Published: June 2012

Abstract
VEGF-A blockade has been validated clinically as a treatment for human cancers. Angiopoietin-2 (Ang-2) expression has been shown to function as a key regulator of blood vessel remodeling and tumor angiogenesis. In tumors Ang-2 is up-regulated and a bad prognostic factor. Recent data demonstrated that Ang-2 inhibitors, both as a single agent or in combination with chemo- or anti-VEGF therapy mediate anti-tumoral effects.
We have recently described a novel generic method for the production of bivalent bispecific human IgG1 antibodies (CrossMabs) based on the crossover of the CH1 and CL domains within the Fab region of one half of a bispecific antibody combined with the knobs-into-holes technology to enforce heterodimerization of the Fc portion. Subsequently, we have applied the CrossMab technology for the generation of a bispecific antibody recognizing VEGF-A with one arm based on bevacizumab and recognizing Ang-2 with the other arm based on LC06, a highly Ang-2 selective human IgG1 antibody. The Ang-2-VEGF CrossMAb could be produced with good yields and purity by eukaryotic.
Surface Plasmon resonance studies showed that the two different arms of the Ang-2-VEGF CrossMab retained their antigen binding affinity for VEGF-A and Ang-2 and interfered with VEGF-induced HUVEC proliferation and Ang-2 induced Tie2-phosphorylation in a similar manner than the parental antibodies. Crossmab showed very potent tumor growth inhibition in orthotopic (KPL-4) and in subcutaneous xenograft tumors (Colo205). In the orthotopic KPL-4 and the s.c. Colo205 xenograft we observed a strong inhibition of angiogenesis by ex vivo analysis. In the VEGF-induced cornea pocket assay Crossmab resulted in a complete shutdown of angiogenesis.
We have generated a bispecific human IgG1 antibody blocking VEGF-A and Ang-2 function simultaneously. Our data indicate that the Ang-2-VEGF CrossMab mediates potent anti-tumoral, anti-metastatic and anti-angiogenic efficacy and represents a promising therapeutic agent for the therapy of cancer.
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 3285. doi:10.1158/1538-7445.AM2011-3285