bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 529: WISP-1/CCN4 is responsible for mediating the inhibitory effect of Notch-engineered stromal fibroblasts on melanoma growth
Authors: Shao Hongwei , Cai Long , Livingstone Alan S. , Velazquez Omaida C. , Liu Zhao-Jun 
Published: June 2012

Abstract
Purpose. The tumor microenvironment plays a pivotal role in influencing melanoma progression. Fibroblasts are major components of tumor stroma and are critically involved in promoting tumor growth and angiogenesis through secretion of soluble factors, synthesis of extracellular matrix, and direct cell-cell interaction. We aimed to alter the biological activity of stromal fibroblasts by modulating a specific signaling pathway to convert them from promoters to inhibitors of melanoma progression.
Methods. Enforced activation of the Notch pathway was achieved by transducing human dermal fibroblasts with lentiviral vector encoding activated Notch1 (NIC). The effect of NIC-engineered stromal fibroblasts on melanoma growth was tested by the in vivo tumor-fibroblast co-xenografting approach. The soluble factor produced by NIC-engineered fibroblasts was identified by RT2-PCRArray and validated by Western blot analysis. The biological effect of WISP-1 on melanoma cell growth was tested in vitro by MTT. The function of WISP-1/CCN4 in mediating the inhibitory effect of NIC-engineered stromal fibroblasts on melanoma growth was examined through an siRNA-mediated blockade approach and tested by in vitro cell co-culture and animal models of tumor-fibroblast co-xenografting.
Results. NIC-engineered fibroblasts significantly inhibited melanoma growth in vivo by suppressing melanoma cell proliferation and inducing melanoma cell apoptosis. Constitutive activation of Notch1 in fibroblasts up-regulated WISP-1 production. The inhibitory effect of NIC-engineered fibroblasts on melanoma growth was mediated, at least in part, by up-regulating WISP-1 expression, since recombinant WISP-1 was able to inhibit melanoma cell growth in vitro while blockade of WISP-1 production by NIC-engineered fibroblasts liberated their inhibitory effect on melanoma growth in vivo.
Conclusions. Activation of Notch pathway in stromal fibroblasts can suppress melanoma growth, partially through WISP-1. Our study provides a novel approach to target the tumor microenvironment through modulating stromal fibroblasts by manipulating Notch signaling, and highlights WISP-1 as a potential therapeutic target in melanoma.
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 529. doi:10.1158/1538-7445.AM2011-529
Abstract 5291: A preclinical model for investigation of nuclear factor-kappa B inhibitors in ovarian cancer
Authors: Wilson Andrew J. , Lee Hye-Jeong , Oshinko Halina , Yull Fiona , Khabele Dineo 
Published: June 2012

Abstract
Most women diagnosed with ovarian cancer initially present with metastatic disease characterized by peritoneal implants and ascites. Critical to the distinct clinical pattern of spread of ovarian tumors is activation of a pro-inflammatory process mediated by nuclear factor-kappa B (NF-κB). However, NF-κB inhibitors such as bortezomib have been disappointing in the clinic. Alternative NF-κB inhibitors such as thymoquinone (TQ) and curcumin, both derived from natural products, exhibit promise as potential treatments for ovarian cancer and are well tolerated. Therefore, our goals were to validate a newly developed preclinical model system for NF-κB activity in ovarian cancer cells and test the efficacy of TQ and curcumin in combination with cisplatin, standard therapy for ovarian cancer. Mouse ovarian epithelial cancer cells (ID8) derived from C57BL/6 mice were stably transfected with a fusion reporter that expresses a green fluorescent protein (GFP)/luciferase fusion product under the control of a synthetic NF-κB dependent promoter (ID8-NGL). Tumor necrosis factor-α (TNF-α) stimulated NGL reporter activity approximately 2.5-fold in luciferase assays in ID8-NGL cells, an effect confirmed by bioluminescence imaging of cell monolayers. The specificity of this effect was demonstrated by the ability of the NF-κB inhibitor, TQ, to abrogate TNF-α-stimulation of NF-κB reporter activity. These effects in ID8-NGL cells were confirmed by parallel Western Blot analysis of IκBα phosphorylation (p-IκBα), with TQ markedly inhibiting TNF-α-induction of p-IκBα. Treatment of ID8-NGL cells with TQ and curcumin inhibited NGL reporter activity and inhibited growth in MTT assays in a dose-dependent manner. Furthermore, the combination of TQ or curcumin with cisplatin induced greater inhibitory effects on growth of ID8-NGL cells than either drug alone, indicative of synergistic effects. Finally, we have confirmed ID8-NGL cells transplanted intraperitoneally into C57BL/6 mice form peritoneal tumors and ascites in a similar manner to parental ID8 cells in vivo. This syngeneic model of ovarian cancer progression will allow us to examine in more detail the effects of promising NF-κB inhibitors in combination with platinum therapy in ovarian cancer cells in vitro and in immunocompetent mice in vivo, providing a powerful platform for future preclinical investigation of novel therapeutic agents that target NF-κB in ovarian 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 5291. doi:10.1158/1538-7445.AM2011-5291
Abstract 53: Exploiting heterogeneity to develop better treatment strategies using an evolutionary multiscale mathematical model of tumor-vessel interactions
Authors: Robertson-Tessi Mark , Estrella Veronica C. , Chen Tingan , Lloyd Mark C. , Gillies Robert J. , Gatenby Robert A. , Anderson Alexander R A 
Published: June 2012

Abstract
Tumor heterogeneity in cancer is an observed fact, both genetically and phenotypically. Cell-cell variation is seen in almost all aspects of cancer from early development all the way through to invasion and subsequent metastasis. The tumor microenvironment is also very heterogeneous and dynamic with multiple zones of hypoxia, normoxia, acidosis and necrosis. Central to our understanding of this heterogeneity is how the tumor cells interact with each other and with their microenvironment. Since the microenvironment is modulated by the tumor itself, as well as the surrounding stroma and the vasculature supply, these interactions rapidly become complex. In order to better understand these complex interactions, we have developed an integrated approach utilizing a hybrid multiscale mathematical model in parallel with an experimental murine window chamber model. This study aims to understand the development of the vasculature in response to a growing tumor, the effects of a heterogeneous microenvironment, and how interactions between the tumor and its vasculature modulate tumor progression and treatment resistance. By incorporating phenotypic heterogeneity into the model, a range of tumor phenotypes emerges due to the heterogeneous microenvironment. The response of the tumor to a treatment will depend on the distribution of phenotypes as well as the local conditions. At the same time, treatment will alter the phenotypic distribution and the microenvironment, so that subsequent tumor progression will be profoundly different than it was prior to treatment. By using the spatial and temporal projections of the mathematical model, optimal treatment strategies are derived and classified based on tumor and microenvironmental parameters. One particularly intriguing result is that tumor control, as opposed to eradication, may be more readily achieved by modulation of the tumor heterogeneity via treatment-mediated microenvironmental selection.
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 53. doi:10.1158/1538-7445.AM2011-53
Abstract 5306: 18F-EF5 microPET imaging of treatment response from a novel, hypoxia-selective cytotoxin SN30000 in a human lung cancer xenograft model
Authors: Chitneni Satish K. , Bida Gerald T. , Hay Michael P. , Zalutsky Michael R. , Melcher Thorsten , Wilson William R. , Dewhirst Mark W. 
Published: June 2012

Abstract
Introduction: SN30000 (CEN-209) is a structural analogue of the clinically tested hypoxic cell cytotoxin tirapazamine, with improved tumor penetration and increased hypoxic cell kill activity in vitro and in vivo. In this study, we investigated the use of the hypoxia PET imaging agent 18F-EF5 to measure changes in tumor hypoxia before and after treatment with SN30000 in a rat model of human non-small cell lung cancer (H460).
Methods: Xenografts were established by subcutaneous injection of about 5 million H460 cells into the lower hind limb of NIH-RNu nude rats, and after 12-13 days the tumors were used for imaging experiments. Using two groups of animals we studied the changes in hypoxia at early time point (5-6 h) and at about 24 h after intraperitoneal administration of a single dose SN30000 (90 mg/kg body weight) or saline. Each group consisted of two control tumors (saline) and three SN30000 treated tumors. In both pre- and post-treatment scans, animals were scanned for 15-20 min at 2.5 h after i.v. injection 0.7-1.4 mCi of 18F-EF5. After reconstruction, PET images were analyzed by drawing regions of interest (ROI) covering whole tumor tissue and on contralateral leg muscle as background ROI. Standard uptake values (SUV) were calculated from the radioactivity concentration in both tumor and muscle tissue after normalization to the injection dose and body weight of the animal.
Results: All tumors (n=10) showed tumor-to-muscle ratios (2.2 to 3.1) high enough to delineate the tumor from background activity. The SUV values in pre-treatment scans ranged from 0.43 to 0.79. No change in 18F-EF5 uptake was observed when animals were imaged at 5-6 h post-SN30000 therapy (mean SUV 0.59 ± 0.18 vs 0.59 ± 0.08 at baseline). However, tumors when imaged at 24 h after the treatment showed a decrease in tumor accumulation of 18F-EF5 by 19.7% to 54.6% when compared to pre-treatment scans (SUV 0.39 ± 0.12 vs. 0.63 ± 0.09 at baseline, p=0.06). Three out of four control tumors showed a slight increase in SUV in post-treatment scan compared to pre-treatment scan.
Conclusions: The results from this study suggest that SN30000 may reduce hypoxia as measured by 18F-EF5 PET imaging at a later time point (1 day) rather than a few hours after treatment, and suggest potential use of 2-nitroimidazole-based PET imaging as an early response biomarker during clinical development of this compound.
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 5306. doi:10.1158/1538-7445.AM2011-5306
Abstract 5309: Antivascular activities of novel tubulin binding agent BPR0L075
Authors: Liu Xinli , Liu Li , Beck Haley , Hsieh Hsing-Pang , Boreddy Srinivas , Srivastava Sanjay , Mason Ralph P. 
Published: June 2012

Abstract
BPR0L075, 6-methoxy-3-(3′,4′,5′-trimethoxy-benzoyl)-1H-indole, is a novel tubulin binding agent that inhibits tubulin polymerization through binding to the colchicine binding site. We evaluated the antiangiogenic and antivascular properties of BPR0L075 in vitro and in vivo. Human umbilical vein endothelial cells (HUVEC) were treated with BPR0L075, and effects on endothelial cell morphology, migration, and inhibition of tube formation on extracellular matrix were determined in vitro. The BPR0L075 induced inhibition of neovasculature formation was evaluated by rat aortic ring ex vivo assay. Using a validated dynamic bioluminescence imaging method, we assessed acute vascular disrupting effects of BPR0L075 on luciferase-expressing MCF7 human breast mammary fat pad xenografts. The disruption of tumor vascular perfusion after BPR0L075 treatment was confirmed using the perfusion marker Hoechst 33342 and CD31 staining by fluorescence microscopy. Exposure of BPR0L075 (10 nM) inhibits the endothelial cell migration (within 24 hr) and tube formation on Matrigel (3-6 hr). BPR0L075 treatment also blocked angiogenesis in rat aortic ring assay. A single dose of BPR0L075 induced rapid temporary tumor vascular shutdown evidenced by rapid and reproducible decrease of light emission from luciferase-expressing breast tumors. Histological staining using Hoechst dye and anti-CD31 antibody revealed a time-dependent reduction of tumor perfusion after 2, 4, and 24h of BPR0L075 treatment. Taken together, our results show that the novel tubulin-binding agent BPR0L075 alters endothelial cell tubule formation, prevents cell migration, and inhibits the formation of neovessels. These properties of BPR0L075 may ultimately contribute to the loss of tumor blood vessel integrity causing rapid tumor vascular shutdown in experimental breast 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 5309. doi:10.1158/1538-7445.AM2011-5309
Abstract 5313: Real-time video imaging of protease expression in vivo
Authors: Lee Seulki , Zhu Lei , Mansfield James R. , Chen Xiaoyuan 
Published: June 2012

Abstract
Most new drug candidates generated during in vitro screening turn out to be invalid after time-consuming and costly testing in animal models. Therefore, there is an urgent need for development of noninvasive, real-time, sensitive, and cost-effective tools with high throughput for monitoring and early detection of drug efficacy in vivo.
Proteases are known as exceptionally critical signaling proteins that are involved in numerous processes such as cancers. Considerable efforts have been made to identify the role of certain proteases in given biological processes and to screen specific molecules that can regulate protease expression. Most experimental methods are based on the use of protease reporters or molecular beacons. Moreover, they are limited to in vitro applications.
To date, protease-activatable probes have already emerged as powerful tools for in vivo imaging because of their potential to offer high specificity and lower background. However, current activatable probes strive to image protease activity and effects in real-time. Although major improvements have been made, such as the conjugation of macromolecules to improve in vivo stability, these probes still suffer in sensitivity and specificity. In addition, conventional protease activatable probes typically take about 24 hours to activate fully, impeding real-time imaging and high throughput in in vivo applications. Here, we report a simple methodology to improve real-time imaging of protease activity by in vivo activatable probes by balancing competing needs for stability and sensitivity in applications where there are high target-to-background signal ratios.
We demonstrate the first true real-time in vivo video imaging of extracellular protease expression using an ultrafast-acting and extended-use activatable probe. This simple, one-step technique is capable of boosting fluorescent signals upon target protease cleavage as early as 30 minutes from injection in a small animal model and is able to sustain the strong fluorescent signal up to 24 hours. Using this method, we video imaged the expression and inhibition of matrix metalloproteinases (MMPs) in a MMPs-positive SCC-7 tumor-bearing mouse model. The current platform can be universally applied to any target protease of interest with a known peptide substrate and is adaptable to a wide range of real-time imaging applications with high throughputs such as for in vivo drug screening, examinations of the therapeutic efficacy of drugs, and monitoring of disease onset and development in animal models.
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 5313. doi:10.1158/1538-7445.AM2011-5313
Abstract 5317: Non-invasive dynamic bioluminescence imaging of tumor functional vascular changes during antiangiogenic therapy in conscious mice
Authors: Schnell Christian R. , Orsini Vanessa , Barbé Stéphanie , Arnal Samuel , Cozens Robert 
Published: June 2012

Abstract
Bioluminescence imaging has been used for several years in oncology research to quantify tumor growth and metastatic spread rather than functional physiological effects.
Two recent publications have highlighted the use of non-invasive dynamic bioluminescence imaging (DBLI) in isofluran anesthetized mice to assess vascular changes in subcutaneous xenografts (1) and orthotopic implanted tumors (2) post-treatment.
We have previously reported that anesthesia impairs bioluminescence signal intensity (3) and may in turn profoundly affect interpretation of compound activity based on BLI (4).
Thus, we decided to investigate DBLI for non-invasive, longitudinal and quantitative monitoring of functional vascular changes (tumor perfusion, blood volume, vascular flow) in conscious mice during antiangiogenic therapy. Subcutaneous xenografts (HCT116 colorectal, U87MG glioblastoma and SJSA-1 osteosarcoma) were treated with a blocking antibody to vascular endothelial growth factor receptor 2 (DC101) and repeatedly examined at bi-weekly intervals.
Our results have clearly demonstrated that in all tested models, tumor growth was significantly inhibited (T/C: 0.33, 0.52 and 0.53 for HCT116, U87MG and SJSA-1, respectively) after treatment with DC101 when compared to control. DBLI analysis revealed an initial increase in vascular flow (Day 2 to 3) followed by a gradual decrease after a 2-wk therapy, suggesting early and long-term effects on functional tumor vasculature. Notably, this pattern was more pronounced in highly vascularized (SJSA-1) when compared with less well vascularized (HCT116) tumors. Lastly, very similar decreased microvessel density (MVD) was noted by histological immuno-fluorescence staining following chronic treatment with DC101 in all three tumor models.
In conclusion, DBLI measurements in conscious tumor bearing mice offer an optimal and reliable approach for non-invasive functional tumor vessel assessment without the confounding effects of anesthesia. It can be foreseen that with future development of more efficient light-emitting enzyme/substrate systems and the improvement of detection devices it will be possible to increase the sensitivity of this technique allowing the measurement of weaker bioluminescence signals and extending spatial resolution.
References:
[1] Zhao et al. FASEB J. 22, 2445-2451 (2008).
[2] Sun et al. Neurosurgery 66, 751-757 (2010).
[3] Schnell et al. AACR meeting (2009), Tumor Biology, Abstract 4006.
[4] Schnell et al. EORTC meeting (2010), Animal models, Abstract 261.
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 5317. doi:10.1158/1538-7445.AM2011-5317
Abstract 5327: In vivo fluorescence imaging of solid tumor-bisphosphonate interaction
Authors: Papineni Rao V. , Udayakumar Thirupandiyur , Ahmed Mansoor , Pizzonia John , Pollack Alan 
Published: June 2012

Abstract
Bisphosphonates are used for the osteoporosis and in palliative cancer related bone pain management. A role in the cancer cell proliferation and metastases prevention has been proposed. Here, we determined the possibility of utilizing NIR dye conjugated bisphosphonate drug as a potential theragnostic agent. Alendronate was conjugated to water soluble, near-infrared tricarbocyanine, cyclic enamine-functionalized dye, and the imaging probe was used for the purpose. Near-infrared (NIR) fluorescence imaging of both LNCaP cells in cell culture and grown orthotopically in nude mice indicate NIR-bisphosphonate binding. Both in vivo and ex vivo NIRF image analysis of 4 nmol of NIR conjugate delivery show substantial tumor residence time and routine biodistribution to areas of high metabolic bone activity. We present here early evidence of NIR-bisphosphonate analog as a potential diagnostic tool.
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 5327. doi:10.1158/1538-7445.AM2011-5327
Abstract 5330: Leukemia initiating cells are frequent and oligoclonal in de novo resistant ALL
Authors: Bornhauser Beat , Schmitz Maike , Breithaupt Petra , Scheidegger Nastassja , Mirkowska Paulina , Meissner Barbara , Bonapace Laura , Tchinda Joelle , Cario Gunnar , Schrauder Andre , Stanulla Martin , Schrappe Martin , Jean-Pierre Bourquin 
Published: June 2012

Abstract
Xenotransplantation of primary leukemia cells constitutes an attractive strategy to model disease for translational research, but the consequences of selective pressure on leukemia cells need to be clarified. Here we evaluate the phenotypic and genetic stability of primograft samples that were established by xenotransplantation of ALL cells from a group of patients with very high-risk precursor B-cell ALL, characterized by the persistence of minimal residual disease (VHR-ALL by MRD) after an intensive induction and consolidation therapy. Phenotypic properties remained unchanged, with concordant immunophenotypes in 9-10/10 leukemia-associated markers after up to 5 passages in Nod/scidIL2Rgammanull (NSG) mice and with stable drug response profiles in vitro on bone marrow stroma co-cultures. In 4/6 cases, 100 unsorted ALL cells were sufficient to reconstitute the leukemia. From up to 5 recurrent copy number abnormalities (CNA) detected in diagnostic samples, most were maintained in primografts. Changes in CNAs upon transplantation in NSG mice were few with 0-2 new lesions per case, mostly occurring during the first xenotransplantation. At the single cell level, the pattern of deletions in the CDKN2A/B locus revealed distinct subsets of ALL cells, which could reproducibly be tracked in primografts. These results provide unequivocal data for the existence of clonally closely related but distinct subsets of leukemia initiating cells in ALL, which has important implications for the use of this model for translational research.
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 5330. doi:10.1158/1538-7445.AM2011-5330