bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2403: Characterization of p53 in transgenic mouse prostate carcinogenesis models
Authors: Spees Colleen K. , Thomas-Ahner Jennifer M. , Tan Hseuh-Li , Yu Jun-Ge , Smolinski Justin B. , Kovalenko Pavlo L. , Fleet James C. , Clinton Steven K. 
Published: June 2012

Abstract
Introduction: Well characterized rodent models of prostate carcinogenesis are critical for the preclinical evaluation of dietary and chemopreventative interventions. p53 signaling is a target for genetic dysregulation in transgenic murine models of prostate cancer. We have examined p53 expression by immunohistochemistry, temporally and spatially in the prostate, as a potential biomarker of efficacy for chemopreventive interventions.
Methods: p53 immunohistochemical staining in wild type mice and two murine models (TRAMP and Rbf/TgAPT121) of prostate carcinogenesis was evaluated. Prostates from male TRAMP (up to 28 wks) and Rbf/TgAPT121 mice (up to 32 wks) were histopathologically evaluated. Normal epithelium, prostatic intraepithelial neoplasia (PIN) and adenocarcinoma was evaluated by p53 (CM5) staining, proliferation index (Ki67) and apoptotic index (ApopTag). Digital image analysis was employed to assist in quantification of biomarkers.
Results: p53 nuclear staining is rare in wild type mouse prostate epithelium. In TRAMP, p53 accumulation is first seen in the nuclei of young mice in areas of hyperprasia and low grade PIN (11%), with greater staining as carcinogenesis progresses through invasive cancers (59%). In the Rbf/TgAPT121 model, a less aggressive model, the PIN can be further subclassified and the percentage of p53 stained epithelial cells in the PIN lesions increases with advanced grade (PIN I: 3%; PIN II: 9%; PIN III: 17%; PIN IV: 30%). p53 staining also correlates with the apoptotic index in the PIN lesions (PIN I: 7%; PIN II: 9%; PIN III: 12%; PIN IV: 13%). Androgen dependency of p53 staining was demonstrated in TRAMP mice, as castration attenuates and repletion of testosterone restores the p53 nuclear staining. p53 staining is predominately located in the basal layer of the glandular epithelium and similar indices were observed in the dorsal and lateral lobes of the prostate.
Conclusions: p53 nuclear staining in TRAMP and Rbf/TgAPT121 models of prostate carcinogenesis increases as a function of lesion grade and stage. The early expression of p53 in murine prostate carcinogenesis is in parallel with other biomarkers of progression, such as proliferation and apoptotic index. p53 staining may serve as an early indicator of effective chemopreventive agent intervention.
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 2403. doi:10.1158/1538-7445.AM2011-2403
Abstract 2407: Decreased inflammation and tumor stage in COX-2 knockout mice in the BBN model of bladder cancer
Authors: Choudhary Shilpa , Hegde Poornima , Pilbeam Carol , Taylor John A. 
Published: June 2012

Abstract
Introduction and Objective: Prostaglandins (PG) play a critical role in the development of solid tumors. Inhibition of cyclooxygenase-2 (COX-2), the committed step in PG synthesis, has been shown to impair tumor development in the BBN mouse model of bladder cancer. Because inhibitors of COX-2 have been reported to have anti-tumorigenic properties independent of COX-2, we evaluated the impact of gene disruption of COX-2 in the BBN mouse model.
Methods: We used 2 mo old male COX-2 knockout (KO) and wild type (WT) mice in an outbred CD-1 background. Mice were treated with (n=13-14 / group) and without (n=6/group) BBN in drinking water and euthanized after 25-27 wks. Bladders were harvested, weighed, bisected and step sectioned after formalin fixation. H&E stained sections were evaluated for pathologic stage/grade, percent involvement by invasive disease and degree of inflammatory infiltrate(grade 1-3).
Results: All animals receiving BBN had inflammatory changes at the time of euthanasia, with the grade being higher in WT (grade 2-3) than KO mice (grade 1-2). Six WT mice and 3 KO mice receiving BBN died, all within the first 18 wks of study, without gross evidence of tumor. Compared to previous studies with C57Bl/6 mice, tumor development was slower and burden was lower at 25-27 wks. All 7 BBN-treated WT mice had high grade invasive cancer at euthanasia: 6 pT1 and 1 pT3. Out of 11 BBN-treated KO mice at euthanasia, 10 had high grade cancer and 2 had invasive disease: 1 pT0, 6 CIS, 2 pTa (non-invasive) and 2 pT1. Mean bladder weight at euthanasia was elevated only in BBN-treated WT mice. There was a strong correlation between WT genotype and tumor stage by Pearson's R (0.74, p=0.03). The percent of tumor representing invasive disease was 0.31 in COX-2 WT mice vs 0.01 in KO mice (t-test, p=0.002).
Conclusions: Genetic disruption of COX-2 resulted in lower tumor stage and percent invasiveness in the BBN mouse model of bladder cancer. However, most COX-2 KO mice developed high grade disease, indicating disruption of COX-2 was not sufficient to prevent tumorigenesis. Reduced inflammation in the COX-2 KO mice may account for the decreased invasiveness.
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 2407. doi:10.1158/1538-7445.AM2011-2407
Abstract 241: Transcription factor RBP-J-mediated signaling regulates basal cell carcinoma growth
Authors: Yu Mei , Zloty David , Bell Robert H. , Haegert Anne , Carr Nicholas , Shapiro Jerry , Cowan Bryce , Warshawski Larry , McElwee Kevin J. 
Published: June 2012

Abstract
Hair follicles (HF) and basal cell carcinomas (BCCs) can be regarded as ordered and disordered skin appendages respectively. They may utilize similar molecular mechanisms of growth. We examined the similarities and differences in gene expression between BCCs and HFs to define common and unique signaling pathways that distinguish an ordered skin appendage from a disordered skin growth. Nodular BCCs, non-follicular skin epithelium, and HF between the sebaceous gland and bulb region were microdissected and examined using microarrays. Selected genes were validated using quantitative PCR, immunohistochemistry and in vitro studies. Two differentially expressed gene sets were identified by significance analysis of microarray (SAM) in BCC and HF versus skin epithelium respectively. Subsequently, multiple signaling pathway analyses were conducted. The results indicated that Notch and Hedgehog signaling pathways were active in the growth of both HF and BCCs. However, Notch signaling, including tumor suppressor genes NOTCH1, NOTCH2, ligands JAG1, JAG2, signaling inhibitor NUMB, and downstream Notch pathway genes DTX1, DTX2, RBP-J, LFNG, HR, and HES7, all showed significant differential expression in BCCs compared to HF. The data suggests downstream gene expression in the Notch signaling pathway is suppressed in BCCs. We tested the effect of transcription factor RBP-J and found transcription factor RBP-J-mediated signaling suppresses BCC cell growth and induces cell apoptosis in vitro. Our data suggest that RBP-J serves as a tumor suppressor in BCC and BCCs deficient in RBP-J lose tumor repression activity. Modulation of the Notch pathway may be a focus for the development of BCC treatments.
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 241. doi:10.1158/1538-7445.AM2011-241
Abstract 242: The gliogenesis initiation factor Nuclear Factor IB induces differentiation and inhibits growth of glioblastoma
Authors: Stringer Brett W. , Day Bryan W. , Barry Guy , Piper Michael , Jamieson Paul R. , Ensbey Kathleen S. , Charmsaz Sara , Boyd Andrew W. , Richards Linda J. 
Published: June 2012

Abstract
Introduction: The phylogenetically-conserved vertebrate transcription factor, nuclear factor IB (NFIB), is a key component in the differentiation of astrocytes during the process of gliogenesis in the developing mammalian central nervous system; a process that goes awry following various genetic and epigenetic alterations during the genesis of glioblastoma (GBM), the commonest and most aggressive form of primary human adult brain cancer. We found expression of NFIB to be reduced in GBM compared to normal human brain tissue so investigated what effect increased expression of NFIB had on GBM.
Experimental procedures: Expression of NFIB was investigated by qPCR and western blot in normal human brain tissue, primary GBM surgical specimens and GBM cells lines. The Rembrandt database was interrogated for patient survival data relative to NFIB expression. GBM cell lines were derived from patient tumor tissue, following informed consent, and cultured under serum-free conditions to help preserve the phenotype of the original tumor. GBM cell lines were transfected with HA-tagged Nfib. Glial differentiation marker expression was investigated by qPCR and western blot. Stem/progenitor cell growth was investigated by neurosphere assay and by PKH26 staining. Cell proliferation was measured by MTS assay and Ki67 staining. Cell cycle analysis was performed by PI staining and FACS analysis. Apoptosis was investigated by cleaved caspase staining. Differential gene expression induced by Nfib expression was determined by microarray analysis. In vivo tumorigenicity was investigated using subcutaneous and intracranial xenografts in NOD/SCID mice.
Results: We found NFIB expression in both GBM surgical specimens and GBM cell lines to be reduced relative to normal brain tissue. Reduced NFIB expression was associated with poorer patient survival. Increased expression of Nfib in transfected GBM cell lines induced expression of glial differentiation markers, inhibited cell proliferation, reduced stem/progenitor cell growth, altered cell cycle progression, and inhibited tumor growth in murine models of GBM.
Conclusion: We have identified NFIB as a novel tumor suppressor gene in human GBM.
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 242. doi:10.1158/1538-7445.AM2011-242
Abstract 2426: Differential effects of liver metastatic and brain metastatic subset of murine breast carcinoma cells
Authors: Erin Nuray , Tanrιöver Gamze , Kale Şule , DuymuŞ Özlem 
Published: June 2012

Abstract
Carcinomas are formed by heterogeneous group of cells which differ in their aggressiveness as well as metastatic potential. Understanding the characteristics of cells that form distant metastasis is crucial to design effective treatments. We previously isolated liver metastatic cells (4TLM) formed by 4THMpc murine breast carcinoma using an orthotopic model. Here we observed that 4THMpc cells also generated macroscopic brain metastasis. Cells from brain metastasis were cultured in-vitro and named as 4THM-BM in order to determine differential characteristics of brain metastatic cells from liver metastatic cells. Specifically following features were compared: 1. Metastatic characteristics after mammary pad (MP) injection; 2. The effects of conditioned medium (CM) prepared from ex-plants of primary tumors as well as cancer-associated fibroblasts (CAF) on tumor cell growth. 3. MIP-2 levels found in CM of ex-plants of primary tumors and associated fibroblasts. Methods: 4TLM and 4THM-BM cells (100000 cells /mouse) were inoculated into the right upper MP of 8-10 weeks old female Balb-c mice. Necropsies were performed 25-27 days after injection. CM of ex-plants from primary tumors and surrounding fibroblasts were prepared. Results: Cells that were previously metastasized to liver (4TLM) produced significantly more macroscopic (52.2± 8.5 vs. 16.3 ±2.84 as mean number of nodules per animal) as well as microscopic lung metastasis (12.75 ±4.26 vs. 3.17±1,1 as mean % area involved with metastatic cells per animal) compared to brain metastatic cells (4THM-BM). Similarly number of macroscopic liver metastases was significantly higher (3.4± 0,6 vs. 7,3 ±1,23 as mean number of nodules per animal) in 4TLM injected animals. CM from ex-plants of 4TLM and 4THM-BM primary tumors as well as from corresponding CAF significantly enhanced growth of 4TLM cells but not 4THM-BM cells. MIP-2 levels in CM from ex-plants of CAF were higher from CM of 4TLM and 4THM-BM primary tumors. These results not only demonstrate the heterogeneous nature of the carcinomas but also suggest that cells that metastasize to liver are more aggressive in nature and produce more visceral metastasis. MIP-2, murine equivalent to human IL-8, is involved in angiogenesis as well as inflammation and reported to be highly expressed in metastatic cells. Here we found that both primary tumors formed by metastatic cell lines and associated fibroblasts produce MIP-2 which may contribute to the metastatic behavior.
Study was supported by The Scientific and Technological Research Council of Turkey (TÜBITAK Grant no:109S449).
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 2426. doi:10.1158/1538-7445.AM2011-2426
Abstract 2436: Endothelial integrin α3β1 stabilizes TF antigen/Galectin-3 mediated metastatic cell adhesion to the endothelium
Authors: Glinskii Olga V. , Li Feng , Rittenhouse-Olson Kate , Barchi Joseph , Glinsky Vladislav V. 
Published: June 2012

Abstract
Metastatic cell arrest in distant organ microvessels constitutes an essential rate-limiting step in hematogenous cancer metastasis. Previously, in a series of works we demonstrated the importance of interactions between cancer-associated Thomsen-Friedenreich antigen (TF-Ag) and endothelial galectin-3 (Gal-3) in facilitating the initial carbohydrate-mediated tumor cell adhesion to distant organ microvasculature. However, it was unclear which molecules stabilize TF-Ag/Gal-3 mediated adhesion and how these interactions effect subsequent events in a metastatic cascade. Here, the results of a pull down assay using TF-Ag coated gold nanoparticles followed by Western analysis identified endothelial integrin α3β1 being physically associated with TF-Ag/Gal-3 complexes. Blocking α3β1 did not affect the initial tumor cell adhesion to the endothelium, but reduced &gt;10-fold shear force necessary to displace cancer cells stably attached to endothelial monolayers, indicating that α3β1 stabilizes tumor-endothelial cell adhesion initiated by TF-Ag/Gal-3 interactions. Subsequent Quadrupole Time-of-Flight mass spectrometry analysis revealed additional 7 proteins forming a macromolecular complexes with TF-Ag, Gal-3 and α3β1 such as filamin B, talin, IQ motif containing GTPase activating protein 1, vinculin, α actinin 4, zyxin, and T-plastin, all of which map onto focal adhesion pathway. Our data demonstrate an induction of complex signaling pathways downstream of this macromolecular complex facilitating endothelial cell retraction and metastatic cell transendothelial migration. Thus, endothelial α3β1 mobilization downstream of TF-Ag/Gal-3 interactions stabilizes tumor-endothelial cell adhesion, initiates focal adhesion formation, and induces signaling pathways in endothelial cells promoting cancer metastasis.
This work was supported in part by Award Number 1I01BX000609 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development to VVG and AHA National SDG 0830287N to OVG.
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 2436. doi:10.1158/1538-7445.AM2011-2436
Abstract 244: Lung adenocarcinomas show genetic-morphologic correlations in three dimensional culture
Authors: Matsubara Daisuke , Ishikawa Shumpei , Fukayama Masashi , Niki Toshiro 
Published: June 2012

Abstract
EGFR mutation is associated with papillary morphology suggesting a genetic-histologic link. In this study we analyzed the relationship between gene expression, mutation, and morphology on Matrigel. Based on EGFR and MET abnormality combined with gene expression pattern, lung adenocarcinoma could be classified into two groups: Group I (Bronchial epithelial phenotype) with high expressions of CK7, MUC1, TTF-1, and E-cadherin, and Group II (non-Bronchial epithelial phenotype) with high vimentin expression (Matsubara et al, Am J Pathol, 2010). On Matrigel, cell lines formed either round (n=30), grape-like (n=4) or stellate-shaped (n=6) colonies. Most of the Group I cell lines formed round colonies. Most of the cell lines that formed grape-like or stellate-shaped colonies belonged to Group II. Virtually all cell lines with EGFR, HER2, and MET gene abnormality belonged to Group I and formed round colonies. In contrast, KRAS mutants were heterogeneous and formed either round, grape-like or stellate-shaped colonies. All KRAS-mutated Group I cell lines formed round colonies, while KRAS-mutated Group II cell lines frequently formed non-round colonies. Strikingly, non-round colony formation was correlated with loss of LKB1 expression in KRAS mutants. Thus, lung adenocarcinomas show genetic-morphologic correlations in three dimensional culture. The results reinforce the genetic-histologic correlations previously documented in primary tumors.
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 244. doi:10.1158/1538-7445.AM2011-244
Abstract 2440: Inhibition of SDF-1/CXCR4 dependent-metastases by the treatment with metabotropic glutamate receptor 5 (mGluR5) antagonists in oral cancer
Authors: Uchida Daisuke , Kuribayashi Nobuyuki , Tamatani Tetsuya , Nagai Hirokazu , Miyamoto Youji 
Published: June 2012

Abstract
Previously, we identified a metastasis-candidate gene, metabotropic glutamate receptor (mGluR)-5 by using an oral cancer cell line, B88-SDF-1, which have an autocrine stromal cell-derived factor (SDF)-1/CXCR4 system and distant metastatic potentials in vivo. In this study, we examined the effect of mGluR5 antagonists on the SDF-1/CXCR4 dependent-metastases in oral cancer. We used 2 kinds of mGluR5-specific antagonists, 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP). These antagonists did not affect the growth of B88-SDF-1 cells, but did inhibit the enhanced-migration of the cells. Under these conditions, actin polymerization and pseudopodia formation were also inhibited by the treatment with MPEP and MTEP. In order to confirm the drug toxicities, these antagonists were intraperitoneally injected into wild-type mice for 4 weeks. All the mice injected with MPEP (5 mg/kg) and MTEP (5 mg/kg) did not show side effects, such as hematotoxicity, allergic reaction and body weight loss. When the B88-SDF-1 cells were transplanted into the vein of nude mice, these antagonists significantly inhibited the lung metastases of the cells. These results suggested that blockade of mGluR5, using antagonists such as MPEP and MTEP, may be effective at preventing metastasis in patients with CXCR4-related oral 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 2440. doi:10.1158/1538-7445.AM2011-2440
Abstract 2447: Novel TLR4-Nanog stemness pathway in liver cancer stem cells confers resistance to TGF-β-mediated tumor suppression through YAP1 and IGF2BP3-AKT-mTOR
Authors: Machida Keigo , Chen Chia-Lin , Kashiwabara Claudine , Liu Jian-Chang , Feldman Douglas , Hyeongnam Jeong Joseph , Tsukamoto Hidekazu 
Published: June 2012

Abstract
Cancer stem cells (CSCs) confer resistance to chemotherapy and are associated with metastatic hepatocellular carcinoma (HCC) commonly observed in hepatitis C virus (HCV)-infected patients with alcohol abuse. We recently identified pluripotency marker Nanog is induced by Toll-like receptor 4 (TLR4) signal activated by alcohol-associated endotoxemia in CD133+/CD49f+ CSCs from liver cancers in HCV Ns5a transgenic mice fed alcohol. We propose the novel oncogenic TLR4 signaling reciprocally regulates tumor suppressive TGF-β pathway. Molecular mechanisms for the genesis of CSCs through TLR4 signaling and defective TGF-β pathway, however, are unknown. CD133+/CD49f+ CSCs were isolated from liver tumors of alcohol-fed HCV Ns5a Tg mice. Lentiviral cDNA library were established from the CSCs for screening genes responsible for defective TGF-β signaling. GFP-labeled CSCs were injected in nude or NOG mice with or without genetic manipulation of TGF-β signaling components or newly identified genes to monitor tumor growth. Interactions of proteins encoded by identified genes with TGF-β pathway components were examined. Here we demonstrate TLR4/Nanog-dependent CSCs are indeed defective in TGF-β signaling. Functional oncogene screening of a cDNA library identified the organ size control pathway target Yap1 and AKT activator Igf2bp3 as Nanog-dependent genes that inhibit TGF-β signaling in CSCs through Yap1/Smad7/Smad3 association and suppressed Smad3 phospho-activation due to AKT-mTOR pathway, respectively. Silencing of both Yap1 and Igf2bp3 restores TGF-β signaling, inhibits pluripotency gene expression, and sensitizes CSCs to autophagy and cell death by the conventional chemotherapy (rapamycin and sorafenib). Therefore, a combined therapy targeting both YAP1 and AKT-mTOR pathways to restore TGF-β pathway should improve therapeutic efficacy for HCC.
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 2447. doi:10.1158/1538-7445.AM2011-2447