bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3184: TGF-β1 signaling inhibits proliferation but promotes motility with progression to castrate-resistant prostate cancer
Authors: Miles Fayth L. , Sikes Robert A. 
Published: February 2011

Abstract
Transforming growth factor-beta1 (TGF-B1) is a tumor suppressor in normal and early stage prostate cancer (PCa) cells, but exerts pro-tumorigenic effects during progression to metastatic disease, and correlates with poor prognosis. However, the mechanisms whereby TGF-B1 induces pro-metastatic action are uknown. Previously it was reported that the LNCaP cell line was insensitive to TGF-B-mediated growth suppression. Thus we sought to examine the TGF-B1-induced proliferative response of increasingly metastatic, lineage-related LNCaP sublines.
Under reduced serum conditions we show that TGF-B1 inhibits cell proliferation profoundly and promotes apoptosis in castrate-insensitive LNCaP sublines, whereas inhibition of cell proliferation is marginal in LNCaP cells. Growth inhibitory effects and apoptosis are mediated by active TGF-B receptors, TBRII and TBRI, and the downstream Smad2/3 effectors. Knock down of TBRII with a dominant negative construct, as well as inhibition of kinase activity abrogrates these effects. Additionally, we show that TGF-B enhances cytoskeletal rearrangements and increases motility on selected extracellular matrices in metastatic LNCaP sublines.
TGF-B signaling in castrate-resistant PCa cell lines is more robust than in hormonally sensitive clones and leads to selective activation of cell motilty that influences PCa cell metastatic behavior with potential consequences for bone colonization.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 3184.
Abstract 3190: Heparanase modulates Shh and Wnt3a signaling in human medulloblastoma cells
Authors: Ridgway Lon D. , Wetzel Michael E. , Marchetti Dario 
Published: February 2011

Abstract
The pathogenesis of medulloblastoma (MB), the most common and aggressive brain tumor in children, is poorly understood. MB tumors are characterized by a massive expansion of external granule layer cells of the cerebellum in response to Purkinje neurons secreted factors such as Sonic hedgehog (Shh) and Wnt3a. Understanding the modulation of Shh/Wnt signaling is critical to developing new treatments for medulloblastoma. Shh and Wnt3a are involved in the induction of MB cell proliferation, and bind heparan sulfate glycosaminoglycan chains (HS-GAG). HS-GAG are components of syndecans as cell-surface HS proteoglycans (HSPG), important co-receptors involved in the control of signaling by extracellular matrix - based ligands. We hypothesized that Shh/Wnt3a - induced MB cell signaling is mediated by syndecans, altering syndecan carboxy terminal (CT) - associated molecules and downstream targets. We also hypothesized that these events are regulated by heparanase (HPSE), the only functional mammalian endoglycosidase cleaving HS-GAG at intrachain site and widely implicated in cancer metastasis. We compared regulation of Shh/Wnt3a signaling by exogenous HPSE in human MB lines possessing increased invasive abilities (D721 &gt; D556 &gt; D283). We identified GEF-H1, a small GTPase inhibitor, as a new component of syndecan-4 - associated signaling complex. Secondly, we demonstrated that HPSE modulated the expression and localization of GEF-H1, β-catenin, and N-Myc in a Shh/Wnt3a - dependent manner, altering MB cell proliferation. Thirdly, we showed that corresponding, GEF-H1 - regulated, small GTPase (Rac/Rho) activities are stimulated differently among MB lines and promote cell invasiveness. Thus, the HSPG/HPSE axis is implicated in two critical MB cell signaling systems and biological outcomes - proliferation and invasion, and potentially relevant as novel target for treatment of invasive MB.
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 3190.
Abstract 3193: EPHB2 expression parallels malignant behavior in mesothelioma
Authors: Goparaju Chandra M. , Donington Jessica S. , Hirsch Nathalie , Harrington Ryan G. , Pass Harvey I. 
Published: February 2011

Abstract
Purpose: Erythropoietin-producing hepatocellular (EPH) receptors and their Ephrin (EFN) ligands are members of the transmembrane receptor tyrosine kinase (RTK) family. EPHB2 is a RTK, promotes uncontrolled cell growth, migration and tumor progression. Preliminary gene array data indicate EPHB2 overexpression in malignant pleural mesothelioma (MPM). Here, we aim to verify EPHB2 overexpression in MPM tumors and cell lines and hypothesize that EPHB2 silencing decreases malignant behavior in MPM cell lines.
Methods: EPHB2 mRNA expression was evaluated by RT-PCR in eight MPM and three benign mesothelial cell lines, and seven pairs of MPM tumors and matched normal tissue. Functional significance of EPHB2 was evaluated by transfecting EPHB2-shRNA and empty vector controls into two MPM cell lines, HP-1 and H2595. Expression of EPHB2, BCL2L1, survivin, Caspase2, Caspase8, matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) were evaluated by RT-PCR following silencing. Pooled populations of transfected cells were evaluated in scratch closure, cell proliferation by CellTitre BlueTM, MatrigelTM Invasion and colorimetric TUNELTM apoptotic assays. Comparisons were made between EPHB2 silenced and control cell lines.
Results: EPHB2 was overexpressed in all MPM cell lines, but not in the benign mesothelial cell lines and in all tumors compared to matched normal tissue. Targeted knockdown of EPHB2 in MPM cell lines reduced its expression and subsequently reduced MMP-2, VEGF, BCL2L1 and survivin expression, and increased Caspase2 and Caspase8 expression. Inhibition of EPHB2 significantly decreased scratch closure, proliferation and invasion compared to the controls, and significantly increased apoptotic cells, likely related to Caspase2 and Caspase8 mediated cell death.
Conclusion: Silencing of EPHB2 reduced the malignant behavior in MPM cell lines. EPHB2 appears to play an important role in MPM pathogenesis and could potentially serve as a novel therapeutic target for MPM treatment.Results of Functional AssaysAssayHP-1 ControlHP-1 EPHB2shRNAp ValueH2595 ControlH2595 EPHB2shRNAp ValueScratch Assay (% closure)69.237.6&lt;0.00556.945.7&lt;0.03Cell Proliferation Assay (OD value)9.56.4&lt;0.058.75.7&lt;0.05Matrigel Invasion Assay (cells invaded)14678&lt;0.0057643&lt;0.005TUNEL Apoptotic Assay (% apoptotic cells)074n/a088.5n/a
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 3193.
Abstract 3207: Telomerase inhibition affects fludarabine sensitivity in quiescent primary chronic lymphocytic leukemia lymphocytes
Authors: Shawi May , Amrein Lilian , Gryaznov Sergei , Autexier Chantal , Aloyz Raquel 
Published: February 2011

Abstract
B- Cell chronic leukemia (CLL) is the most common leukemia in adults. It is clinically very heterogeneous and has a highly variable clinical course. Telomere length and telomerase activity have been shown to be excellent prognostic factors in CLL. Moreover, telomere maintenance is deficient in CLL lymphocytes. These studies have prompted the assessment of the telomerase inhibitor GRN163L in a phase I-II clinical trial in CLL and lymphomas. Here we report that telomerase activity is not required for the survival of quiescent primary CLL lymphocytes. In contrast telomerase activity seems to be required for the survival of quiescent primary CLL lymphocytes after treatment with fludarabine (FLU) in vitro. Furthermore, the effect of fludarabine on telomerase activity was associated with the basal expression of the telomere shelterin protein TRF2. In summary, our results suggest that GRN163L in combination with FLU may be useful to decrease the tumor burden in CLL. To our knowledge this is the first report assessing the effect of telomerase inhibition in combination with a chemotherapeutic agent in non-stimulated primary CLL lymphocytes.
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 3207.
Abstract 3229: Biomarker validation for a rare malignancy in a mouse model
Authors: Servais Elliot L. , Colovos Christos , Suzuki Kei , Rodriguez Luis , Sima Cami , Rusch Valerie W. , Sadelain Michel , Adusumilli Prasad S. 
Published: February 2011

Abstract
Purpose:
Malignant pleural mesothelioma (MPM) is a rare malignancy often diagnosed at an advanced stage. Clinical validation of a biomarker that would allow for earlier diagnosis as well as detection of recurrence following therapy is limited by the rarity of the tumor. Soluble mesothelin-related peptide (SMRP), which can be detected in patients’ serum, is a cleavage product of mesothelin, a tumor-associated cell surface protein over-expressed in &gt;80% of MPMs. The purpose of this study is to validate the pharmacodynamics of SMRP as a tumor biomarker of prognosis and therapy response using a clinically and pathologically relevant orthotopic xenograft model of MPM.
Experimental Design:
Orthotopic MPM xenograft mice (athymic nude and SCID-beige) were established by direct pleural injection of human mesothelioma cells (MSTO-211H) retrovirally transduced to stably express mesothelin and the GFP-Firefly Luciferase fusion gene. Quantitative bioluminescence imaging (BLI) and MRI were used to serially monitor tumor burden and progression and were correlated with serum SMRP levels (Mesomark® ELISA assay). Kaplan-Meier survival analyses were performed following xenografting of mesothelin and non-mesothelin expressing tumors. The utility of SMRP as a biomarker of therapeutic response was validated by treating MPM mice with either: (a) Cisplatin (4mg/kg IP weekly), (b) thoracic radiation (20Gy total in 5 fractions), (c) combination chemoradiation, or (d) no treatment and correlating serial SMRP levels to survival and BLI signal.
Results:
MPM cells secreting SMRP demonstrated increased invasion and migration in vitro as assessed by the modified Boyden Chamber assay compared to cells without SMRP secretion, 124 vs 48 cells per high-powered field (p&lt;0.0001) and 49 vs 32 cells (p=0.017), respectively. In MPM xenograft mice, increasing SMRP levels correlated with tumor progression by quantitative BLI (spearman r=0.89, p=0.04) and decreased survival (p=0.001). SMRP demonstrated improved sensitivity for detecting early MPM tumors compared to MRI. SMRP levels significantly decreased following treatment versus control mice (p=0.03) and were predictive of survival (hazard ratio = 4.5, 95%CI 1.53-13.1). In addition, SMRP detected tumor recurrence following treatment earlier than MRI.
Conclusions:
We have shown that a serum biomarker of tumor progression and therapy response can be successfully studied in a clinically relevant animal model. To our knowledge, this is the first report utilizing BLI as a reproducible tool, in conjunction with an orthotopic animal model, to quantitatively assess pleural tumor burden and biomarker pharmacodynamics.
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 3229.
Abstract 3263: Acceleration of mammary tumorigenesis by PDK1 and peroxisome proliferator-activated receptorδ
Authors: Pollock Claire B. , Yin Yuzhi , Yuan Hongyan , Zeng Xiao , King Sruthi , Kopelovich Levy , Glazer Robert I. 
Published: February 2011

Abstract
The 3-phosphoinositide-dependant kinase-1 (PDK1) is a master regulator of least 23 members of the AGC protein kinase family, including protein kinase B (PKB/Akt). Genetic alterations which activate PI3K/AKT signaling are common in cancer, and elevated expression of PDK1 has been detected in various cancer types, including breast cancer. To assess the effect of PDK1 over-expression in mammary gland function and tumorigenesis, transgenic mice were generated that express PDK1 in the mammary epithelium under the control of the MMTV promoter. PDK1 over-expression resulted in increased pT308Akt and pS9GSK3β and PPARδ expression, but did not affect the phosphorylation of other targets, such as RSK2, S6K and BAD. Transgenic mice exhibited a moderate acceleration of tumor induction by progestin/DMBA in comparison to wild-type mice, and GW501516 treatment accelerated tumorigenesis in both transgenic and wild-type animals. GW501516 promoted the formation of highly keratinized squamous cell carcinomas in both PDK1 transgenic and wild-type mice, and exhibited a profile of elevated pT308Akt and PPARδ expression. Treatment of wild-type mice with PPARδ agonist GW501516 alone increased PDK1 and pT308Akt expression in mammary epithelium. Thus, MMTV-PDK1 mice provide a model in which PDK1 enhances mammary carcinogenesis through activation of Akt and PPARδ to elicit a cooperative effect in promoting tumorigenesis.
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 3263.
Abstract 3269: Calpain knockdown in human breast carcinoma cells reduced xenograft tumor growth rates and inhibited in vitro cell migration and proliferation
Authors: Hu Jing H. , Elliott Bruce , Greer Peter A. 
Published: February 2011

Abstract
Ubiquitously expressed µ- and m-calpain are calcium dependent intracellular cysteine proteases that have been implicated in the regulation of cell proliferation, survival, apoptosis, migration, and invasion. Stable expression and proteolytic activity of the µ- and m-calpain catalytic subunits (encoded by capn1 and capn2 genes, respectively) requires a common regulatory subunit encoded by the capn4/capns1 gene; thus both µ- and m-calpain activities can be blocked by genetic knockout or knockdown of capn4 expression. Calpain is also regulated by an endogenously expressed inhibitor peptide, calpastain.
We screened a panel of human breast cancer and normal epithelial cell lines for expression of calpain and calpastatin. µ- and m-calpain and calpastatin were abundantly expressed in MDA-MB-231, SKBR3, T47D, and MCF-7 breast cancer lines, as well as the normal human breast epithelial cell line MCF-10A.
A stably expressed lentivirally encoded shRNA directed against the capn4 transcript was used to effectively knockdown µ- and m-calpain expression and activity in MDA-MB-231 breast cancer cells. This correlated with attenuated proliferation, migration and invasion, but resistance to anoikis. Biochemical analysis also suggests a role for calpain in the regulation of focal adhesion complex proteins such FAK, PTP-1B, talin and F-actin.
Finally, knockdown of calpain in MDA-MB-231 cells significantly reduced their ability to form tumors when orthotopically injected into the mammary fat pads of nude mice. These observations provide direct genetic evidence that calpain plays a pro-tumorigenic role in the MDA-MB-231 breast cancer cell model system.
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 3269.
Abstract 3271: The RNA binding protein HuR controls angiogenesis in triple negative breast cancer
Authors: Atasoy Ulus , Gubin Matthew , Calaluce Bob , Davis Wade , Magee Joseph , Strouse Connie , Shaw Daniel , Hoffman Timothy , Rold Tammy 
Published: February 2011

Abstract
Due to the poor correlation between steady state mRNA levels and protein products, traditional microarray analysis may miss many genes which are regulated primarily at the level of mRNA stability and translation. Posttranscriptional gene regulation mediated by microRNAs and RNA binding proteins (RBPs) is being recognized as an important form of gene regulation. The elav (embryonic lethal abnormal vision) family of RBPs, are paraneoplastic antigens, over-expressed in a variety of malignancies, including breast cancer. Antibodies against elav family members are believed to be cancer-protective. The elav family binds to the AU-rich elements (AREs) found in the 3’ untranslated regions (UTRs) of many early-response genes, including proto-oncogenes and cell cycle regulators. HuR, the ubiquitously expressed family member, has been described to play a role in cancer progression by stabilizing and translationally up regulating expression of its target mRNAs. Elevated levels of cytoplasmic HuR directly correlate with increased invasiveness of malignancy and poor prognosis for many cancers, including those of the breast. HuR has been described to positively control the expression of multiple genes in the acquired capabilities model, such as VEGF and HIF1α. Hence, it has been suggested that HuR may serve as a tumor maintenance gene which allows for cancers to proliferate. Therefore, it is of interest to discover in vivo HuR targets, as these genes may play vital roles in transformed cells. We have developed methods called RNA immunoprecipitations applied to microarrays, RIP-Chip. We used RIP-Chip to identify distinct subsets of HuR associated mRNAs in MDA-MB-231 and MCF-7 breast cancer cell lines and validated several novel targets. To further investigate the role of HuR in triple negative breast cancer, we over expressed HuR in MDA-MB-231 cells, which results in accelerated growth and alterations in cell cycle kinetics. Surprisingly, when employed in orthotopic mouse models of cancer, HuR over expression significantly inhibited growth of triple negative tumors by 90%. Putative mechanisms appear to be anti-angiogenic, as HuR over expression increases anti-angiogenic factors, but surprisingly, also down regulates pro-angiogenic factors such as VEGF. These results are highly significant because they implicate HuR as a master regulator of angiogenesis in triple negative breast cancer tumor formation and suggest potentially novel treatment methods for this aggressive form of breast cancer.
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 3271.
Abstract 3290: Overexpression of Aurora B kinase is correlated with vascular invasion and metastasis of human hepatocellular carcinoma
Authors: Lin Zhong-Zhe , Jeng Yung-Ming , Hu Fu-Chang , Pan Hung-Wei , Tsao Hsin-Wei , Hsu Hey-Chi , Cheng Ann-Lii 
Published: February 2011

Abstract
Background:
We previously demonstrated that Aurora B overexpression correlated well with higher histology grade and more advanced stage of hepatocellular carcinoma (HCC). In this study, we sought to analyze the association between Aurora B overexpression and vascular invasion/metastasis of HCC, as well as the potential of AZD1152, a novel and selective Aurora B kinase inhibitor in preventing vascular invasion and metastasis of HCC.
Method:
Aurora B mRNA levels were measured in HCC and paired non-tumorous liver tissues by reverse transcription-PCR. One hundred and sixty surgically resected, primary unifocal HCCs were selected for this study. Vascular invasion was determined by pathologic examination. All 160 patients had been followed for more than 5 years or until death. Forty-nine patients developed extrahepatic tumor metastasis. Multivariate analysis was conducted to determine the significance of Aurora B overexpression on vascular invasion and metastasis of HCC. The effects of AZD1152 on tumor invasiveness were tested in Huh-7 and HA-27T HCC cell lines by migration and invasion assays.
Results:
Overexpression of Aurora B was found in 98 of the 160 (61%) primary HCC. Univariate analysis showed that vascular invasion and metastasis were both associated with younger age (≤ 55 years, P = 0.027 and P = 0.003, respectively), high α-fetoprotein levels (&gt; 200 ng/mL, P &lt; 0.001 and P = 0.008), large tumor size (&gt; 5 cm, P &lt; 0.001 and P &lt; 0.001), higher tumor grade (grade III-IV, P &lt; 0.001 and P = 0.025), as well as Aurora B overexpression (P &lt; 0.001 and P &lt; 0.001). Multivariate analysis confirmed that Aurora B overexpression was an independent risk factor associated with vascular invasion (odds ratio, 2.659; P = 0.0183) and metastasis (odds ratio, 4.195; P = 0.0027). AZD1152, 5-125 nM, induced dose-dependent inhibition on migration and invasion in Huh-7 and HA-27T cells.
Conclusions:
Overexpression of Aurora B correlates well with vascular invasion and metastasis of HCC. Inhibition of Aurora B kinase by small molecular inhibitors may suppress invasion and metastasis of HCC.
Grant support:
Grant NSC96-2628-B-002-054-MY3 from the National Science Council (Taiwan), Grant DOH97-TD-B-111-001 from the Department of Health (Taiwan), and Grant NSC98-3112-B-075A-001 from the National Science Council (Taiwan).
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 3290.