bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5212: Irradiation-induced uPAR promotes stemness via Wnt/β-catenin signaling in medulloblastoma cells
Authors: Asuthkar Swapna , Gondi Christopher S. , Nalla Arun Kumar , Velpula Kiran Kumar , Gorantla Bharathi , Rao Jasti S. 
Published: August 2012

Abstract
Urokinase plasminogen activator receptor (uPAR) is known to promote invasion, migration and metastasis in cancer cells. In this study, we show that ionizing radiation (IR) induced uPAR has a role in Wnt/β-catenin signaling and mediates induction of cancer stem cells (CSC)-like properties in medulloblastoma cell lines UW228 and D283. We observed that IR induced the expression of uPAR, CSC markers such as CD44 and Msi-1, and activates Wnt/β-catenin signaling molecules. Overexpression of uPAR after IR treatment led to the activation of Wnt signaling, which was demonstrated by an increase in nuclear translocation of β-catenin and β-catenin-Lef/Tcf-mediated transactivation, thereby promoting cancer stemness. Quercetin, a potent Wnt/β-catenin inhibitor suppressed uPAR and uPAR-mediated Wnt/β-catenin activation. Treatment with shRNA specific for uPAR (pU) suppressed the β-catenin-Tcf/Lef-mediated transactivation both in vitro and in vivo. Further, we show that uPAR is physically associated with the Wnt effector molecule β-catenin using immunocytochemistry and immunohistochemistry; these results were confirmed by immunoprecipitation analysis. Most interestingly, we demonstrate for the first time that the localization of uPAR in the nucleus is associated with transcription factors (TF) and their specific response elements. The association of uPAR with β-catenin-Tcf/Lef complex and various other TF involved in neurogenesis during embryonic development and cancer demonstrates the receptor's possible role at generating CSC-like properties in primitive neuroectodermal tumor (PNET) cells of medulloblastoma. Considering all of the data, we conclude that uPAR is a potent activator of stemness, and the targeting of uPAR in combination with radiation has significant therapeutic implications.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5212. doi:1538-7445.AM2012-5212
Abstract 5240: Breast cancer in the metastatic niche: A role for stress-induced dormancy
Authors: Taylor Donald P. , Wells Alan 
Published: August 2012

Abstract
Breast cancer dormancy in the metastatic site allows tumors to avoid clinical detection and evade treatment leading to recurrence after years or decades, with devastating mortality rates. How the aggressive carcinoma cells that initially underwent a cancer-associated Epithelial to Mesenchymal Transition (EMT) from the primary tumor to disseminate and maintain a long-term dormant state in an ectopic site is unknown. We have found that normal parenchymal cells of certain metastatic organs cause a partial reversion of the EMT to a more epithelial phenotype (Mesenchymal to Epithelial Reversion Transition, or MErT). Compared to carcinoma cells in the primary breast tumor, MErT is characterized by increased E-cadherin expression, MAPK and AKT signaling, and chemoresistance. While this phenotype should reflect low proliferation or quiescence, the MErT cells in vitro have heretofore maintained a highly proliferative state. Herein we demonstrate that a pre-stressed hepatic microenvironment allows for EMT cells to increase their MErT phenotype and to become dormant. Our research strategy is to modulate the initial liver stress through biochemical challenges applied to primary rat hepatocytes co-cultured with hepatic resident cells and a human immortalized breast cancer cell line (MDA-MB-231). Biochemical challenges (e.g. TGFβ, TNFα, IL-6, EGF, HGF, and DAMPS) are applied in varying concentrations and incubation periods in order to pre-stress the hepatic culture. In order to maintain hepatic metabolic function we implement a novel 3D perfused micro-well bioreactor. As a secondary aim we explore whether E-cadherin expression is required for metastatic seeding through splenetic injections in immune compromised mice. We aim to uncover novel targets that are not strictly against the cancer cells, but rather, against shared molecular pathways across cancer, parenchymal, and non-parenchymal cells within the hepatic niche. Sustaining and perhaps enhancing the ectopic site resilience may yield therapies directed toward maintaining dormant carcinomas so that secondary EMTs will be blocked and cancer recurrence greatly reduced.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5240. doi:1538-7445.AM2012-5240
Abstract 525: Toll-like receptor-4 mediated cutaneous immune responses augment ultraviolet radiation-induced DNA damage and tumor development
Authors: Ahmad Israr , Guroji Purushotham , Jimenez Hugo , Simanyi Eva , Nagar Anusuiya , Nagar Priyamvada , Yusuf Nabiha 
Published: August 2012

Abstract
UV (ultraviolet) B induced DNA damage plays a critical role in development of skin cancer. The molecular basis for this biologic activity resides at least in part from the demonstrated ability of this form of radiant energy to damage DNA, predominantly in the form of cyclobutane pyrimidine dimers (CPD). The purpose of this study was to determine whether toll-like receptor-4 (TLR4) contributed to UV-induced DNA damage responses and cutaneous tumor development. TLR4 deficient and wild type (WT) mice were subjected to a local UVB induced DNA damage regimen consisting of 90 mJ/cm2 UVB radiation. Wild type mice exhibited significant (p&lt;0.05) DNA damage in the form of cyclobutane pyrimidine dimers (CPD), whereas TLR4 deficient mice developed significantly fewer CPD (p&lt;0.05) in their skin and bone marrow dendritic cells (BMDC). The expression of DNA repair gene XPA was significantly less (p&lt;0.05) in skin and BMDC from WT mice than TLR4 deficient mice after UVB exposure. When cytokine levels were compared in these two strains after UVB exposure, BMDC from UV-irradiated TLR4 deficient mice produced significantly more IL-12 and IL-23 cytokines (p&lt;0.05) than BMDC from WT mice. Furthermore, we found that Toll like receptor-4 (TLR4) promoted UVB induced tumor development. We observed that UVB induced skin carcinogenesis was retarded in terms of tumor incidence, and tumor latency, in mice deficient in TLR4 compared to WT mice, whereas significantly greater (p&lt;0.05) numbers of tumors occurred in WT mice. Further, we found that tumor-bearing WT mice produced more IL-17 and IL-10 (p&lt;0.05), whereas TLR4 deficient mice produced more IFN-γ (p&lt;0.05). CD4+CD25+ regulatory T-cells from WT mice produced more IL-10 (p&lt;0.05) than regulatory T-cells from TLR4 deficient mice. There was a significant increase (p&lt;0.05) in Foxp3 expression in skin of WT mice than TLR4 deficient mice. Thus, strategies to inhibit TLR4 may allow us to develop immunopreventive and immunotherapeutic approaches for management of UVB induced cutaneous DNA damage and skin cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 525. doi:1538-7445.AM2012-525
Abstract 5255: Methionine restriction limits prostate tumor cell proliferation
Authors: Allott Emma H. , Tang Xiaohu , Masko Elizabeth M. , Gaines Alexis , Abern Michael R. , Chi Jen-Tsan A. , Freedland Stephen J. 
Published: August 2012

Abstract
Introduction: Methionine restriction has been shown to have growth inhibitory effects in a number of tumor cell lines in vitro. Methionine restriction has previously been demonstrated to slow PC-3 prostate tumor cell growth in vivo, however not at dietary levels tolerable to humans. Up to 90% dietary methionine restriction has been demonstrated to be both tolerable and safe in a preliminary human clinical trial. We hypothesized that 80%-90% methionine restriction could limit prostate tumor cell growth in vitro and in vivo. Methods: We reduced methionine levels by 40%, 80%, 90% and 100% in prostate cancer cell lines in vitro, relative to standard RPMI medium. Cell proliferation and viability were measured using MTS and trypan blue assays, respectively. PC-3 cells were grafted into a xenograft nude mouse model and animals were randomized to standard chow, 80% or 90% methionine restricted diets. Plasma methionine levels were measured before and after the dietary intervention. Tumor volume was measured throughout the study and mice were sacrificed when tumors reached 1000 mm3. Results: Methionine restriction exerted a dose and time-dependent effect on PC-3 tumor cell proliferation and viability in vitro. Methionine restriction of 80% and 90% for a period of 6 days reduced PC-3 tumor cell line proliferation by 20% and 40%, respectively, as measured by MTS assay (p&lt;0.0001). Following 6 days of 80% and 90% methionine restriction, PC-3 cell viability was reduced by 10% and 15%, respectively. We are currently awaiting results from our in vivo study which is underway. Discussion: Methionine restriction slows prostate tumor cell line growth and reduces cell line viability in vitro. Based upon these in vitro results we hypothesize that an 80% - 90% methionine restricted diet will slow tumor growth in vivo, and we await the results of this dietary intervention in mice. Methionine restriction at this clinically relevant level which is tolerable and safe to humans may have the potential to slow tumor growth in prostate cancer patients; however more preliminary studies are needed in order to establish whether 80%-90% methionine restriction actually does slow tumor growth in vivo and if so to understand the mechanisms by which this occurs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5255. doi:1538-7445.AM2012-5255
Abstract 5259: Non-invasive determination of in vivo myeloperoxidase activity in ovarian cancer mouse model
Authors: Papineni Rao V. , Craveiro Vinicius , Pizzonia John , Holmberg Jennie , Mor Gil 
Published: August 2012

Abstract
Myeloperoxidase (MPO) is an inflammatory heme protein present in myeloid cells- neutrophils, microglia, and macrophages. The enzyme activity of MPO utilizes hydrogen peroxide in the process of reactive oxygen species generation. Myeloperoxidase has been suggested recently as a likely marker in ovarian carcinoma. This relationship between the MPO and ovarian cancer however was deduced primarily from data obtained from in vitro studies using cancer cell lines and from immunostaining of ovarian carcinoma paraffin blocks. Therefore, a real-time determination of in vivo MPO activity in the tumor and during the progression of ovarian cancer will be valuable to assess the role of innate immune process in ovarian cancer progression, in cancer treatment, and the proper management of current therapies. Here, we developed non invasive methodologies to determine the MPO activity in intraperitoneal ovarian cancer tumor mouse model. Tri-modal non invasive imaging of the metastatic ovarian cancer in athymic mice model were performed to obtain fluorescence, luminescence, and X-ray images at different time points during the progression of the intraperitoneal tumor metastasis. Progression of the tumor metastasis was monitored using fluorescence; simultaneously MPO activity was obtained by luminescence imaging. The MPO activity was detected by i.p injection of Luminol (5-amino-2,3-dihydro-1,4-phthalazine-dione) in physiological buffered saline (5 mg / 25gm mice). Luminol a redox-sensitive compound emits blue luminescence upon exposure to oxidizing agents, and in vivo, and has been established to have unique specificity to MPO activity. The fluorescence and luminescence images were overlaid on planar X-ray images for anatomical coregistration. The results show a robust increase in MPO activity in the mouse with the tumor development as compared to the control mice of the same cohort. Increase in MPO activity as a result of neutrophil activation was observed in the early phase of the ovarian cancer progression, and this increase subsides in the latter stages. However, the lumiscence signal intensities vary between the tumors, and near negligible MPO activity was observed in some tumors indicating a differential tumor microenvironment within the mouse. Further, the activity is far greater, at least in the initial stages, at the lung, nasal and other distal regions when compared to the intraperitoneal tumors. These real-time monitoring methodologies of MPO activity by in vivo imaging will greatly enhance the understanding of the tumor microenvironment during ovarian cancer progression, and contribute significantly in the development of better cancer treatments.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5259. doi:1538-7445.AM2012-5259
Abstract 5320: Sonic hedgehog in non-small cell lung cancer lymph node metastasis; ROS and PI3kinase/Akt signaling pathway
Authors: Cheon Seungwoo , Kang Myounghee , Kang Hanna , Kim Junglim , An Hyunsuk , Kim Hyunkoo , Yoo Younga , Kim Junsuk , Oh Sangcheul 
Published: August 2012

Abstract
Sonic hedgehog signaling pathway plays an important role in the metastasis of various organs. Recently, we found that increased shh producing cells correlate with enhanced migration, invasiveness and increased lymphangiogenesis in Non-small-cell lung cancer (NSCLC), but the mechanism is unknown. In this study, we investigated the function of shh pathway in human NSCLC. We performed immunohistochemistry on lung tumor biopsies and the result showed the expressions of shh, Gli1, VEGF-D and LYVE1 were enhanced in lymph node metastasis specimens compared to lymph node negative lung cancer specimens. We also investigated the role of shh signaling in the invasiveness and the motility of NSCLC. We found that Shh N-terminal peptide (N-shh) enhanced cell motility and invasiveness in NSCLC, and this process was inhibited by AAD-cyclopamine (SMO inhibitor). We observed that the mRNA expressions of shh, Gli1, VEGF-D and LYVE1 were enhanced by N-shh treatment, whereas no increase of these factors was observed when KAAD-Cyclopamine (a Shh signaling inhibitor) was treated together. In addition, we confirmed that Shh-induced lymphangiogenesis and motility/invasiveness of NSCLC are also reduced by LY294002, PI-3 Kinase/Akt inhibitor meaning that shh pathway and PI-3 Kinase/Akt are strongly related. Thus, we investigated the functional relationship between Shh and Akt signaling in the metastatic progression in NSCLC. Phosphorylation of Akt was enhanced by N-Shh, but regulated by KAAD-cyclopamine or LY294002. We further analyzed the effects of shh signaling in vitro by stimulating a HMVEC with N-shh and we observed N-shh enhanced the tube formation on matrigel, but the enhancement was inhibited upon cyclopamine or LY294002 treatment. The ROS production was increased in shh-overexpressing cells. These results indicate that shh signaling pathway can contribute to ROS generation enhancing the metastatic and lymphangiogenetic potential of tumor cells. Our findings suggest that Shh-Akt signaling processes through ROS and the activation of these pathway increases the metastatic potential of non-small cell lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5320. doi:1538-7445.AM2012-5320
Abstract 5321: Tyrosine kinase activation by the metastasis promoting protein S100A4
Authors: Grotterød Ida , Boye Kjetil , Mælandsmo Gunhild Mari 
Published: August 2012

Abstract
S100A4 is a protein linked to increased invasion and metastatic potential of cancer cells and the significance of S100A4 as a prognostic marker has been reported for different tumor types. It has no enzymatic activity and exerts its functions through interaction with other proteins, both intracellularly and in the extracellular space. Many functions and biological effects of S100A4 have been elucidated, but the detailed knowledge on receptor(s) affected and signaling pathways induced are not completely revealed. Induction of metastasis resembles changes occurring during epithelial-to-mesenchymal transition (EMT) and it has been suggested that several of the metastases promoting properties of S100A4 is caused by involvement in this process. In a previous study we identified a set of 136 genes affected by extracellular S100A4. Induced expression of some of these genes was validated and found to be dependent on NF-κB signaling. In the osteosarcoma cell line used, S100A4 activated NF-κB through IKK and IκBα phosphorylation, and the induced signal transduction was found independent of the previously suggested S100-receptor RAGE (receptor for advanced glycation end products). In the present study, tyrosine kinase arrays (PamGene) were utilized to screen for substrates phosphorylated by S100A4-activated kinases. Comparing levels of substrate phosphorylation, S100A4 stimulation significantly affected 32 substrates, including EGFR and PDGFR. EGFR and PDGFR phosphorylation has been validated using western immunoblotting and immunoprecipitation. The EGFR inhibitors AG 1478 and gefitinib reduced the level of basal and S100A4-induced EGFR phosphorylation. Interestingly, reduced levels of S100A4-induced IκBα phosphorylation and NF-κB activation were also observed. The mechanisms of EGFR activation are under further investigation. Of particular interest, EGFR could be activated by ligands cleaved from the cell membrane in a process involving ADAM activity, referred to as ectodomain shedding. Thus, we are in the process of testing the effect of ADAM inhibitors in our cell system and characterize the expression of specific ADAMs. Insight into the signaling mechanisms induced by S100A4 is important to understand how this protein is involved in the biological processes constituting the metastatic cascade and will provide valuable information for identification of novel therapeutic targets.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5321. doi:1538-7445.AM2012-5321
Abstract 5323: Fractalkine receptor CX3CR1 regulates peritoneal dissemination of ovarian carcinoma
Authors: Barbolina Maria V. , Xie Jia , Burdette Joanna E. 
Published: August 2012

Abstract
Epithelial ovarian carcinoma (EOC) is the deadliest gynecologic malignancy largely due to the metastatic disease. EOC metastases spread by shedding the malignant cells off of the ovarian surface and seeding tissues and organs of the peritoneal cavity. Currently used therapies, a combination of chemotherapy and surgery, fail to keep most patients in the remission. Mechanistic understanding of the biology of EOC metastasis will facilitate development of new therapeutic approaches. Our previous data demonstrated that fractalkine receptor (CX3CR1) is expressed by EOC cells and can support cell migration and proliferation. Moreover, our previous data suggested that CX3CR1-positive EOC cells can adhere to the CX3CL1-postive peritoneal mesothelial cells in in vitro assay. Thus, we hypothesized that CX3CL1/CX3CR1 axis could be important for peritoneal dissemination of metastatic EOC. To test this hypothesis, we performed short-term ex vivo and in vivo adhesion assay, as well as long-term metastasis formation assay. Expression of CX3CR1 in EOC cells was downregulated in SKOV-3 using shRNA. Both CX3CR1 shRNA-expressing and scrambled shRNA-expressing EOC cells were seeded atop of mouse peritoneum and omentum tissues in the ex vivo assay and allowed to adhere for up to 24 h. CX3CR1 shRNA-expressing and scrambled shRNA-expressing EOC cells were intraperitoneally injected into abdomens of athymic nude mice for 4 h following sacrifice of the animals and examination of the peritoneal organs and tissues for green fluorescence. Data analysis has demonstrated that downregulation of CX3CR1 in EOC cells led to a significant decrease of adhesion in these assays. Furthermore, parental SKOV-3 as well as CX3CR1 shRNA-, scrambled shRNA-, and vector shRNA-expressing cells were intraperitoneally injected into athymic nude mice and allowed to form metastasis for 10 weeks. As a result, we observed very small omental metastatic lesions in three out of six animals injected with CX3CR1 shRNA-expressing cells. In opposite, all of the control groups developed gross intraperitoneal metastasis in many organs and tissues. Our data suggest that CX3CR1 may be one of the key factors that determine peritoneal dissemination of EOC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5323. doi:1538-7445.AM2012-5323
Abstract 5330: Androgen independent promotion of prostate cancer cell invasion by HOXB13-mediated zinc regulation
Authors: Kim Young-Rang , Kim In-Je , Kang Taek Won , Choi Chan , Kim Min Soo , Nam Kwang Il , Jung Chaeyong 
Published: August 2012

Abstract
A healthy prostate maintains the high level of zinc while intracellular zinc is diminished during prostate cancer (PCa) developments. However, down-regulation of intracellular zinc in PCa are not fully understood, particularly in development of hormone refractory PCa (HRPC). Our previous studies showed that HOXB13 was overexpressed in HRPC. In our attempt to profile androgen-independent HOXB13 target genes in LNCaP PCa cells by DNA microarray, most strikingly regulated gene was ZnTs, a group of zinc output transporters. HOXB13 drove PCa cells to decrease intracellular zinc concentration. In the absence of androgen, HOXB13 dramatically promoted NF-κB-mediated signaling by reduction of inhibitor of NF-κB alpha (IκBα) and correspondingly stimulated nuclear translocation of RelA/p65. HOXB13-mediated NF-κB activation was nearly eliminated by suppression of ZnT4. At the same time, prostate tumors strongly indicated inverse correlation of HOXB13 and IκBα expression. Correspondingly, HOXB13 stimulated an invasive property of LNCaP cells, which can be negated by suppression of ZnT4 in an androgen-free environment. Taken together, these results demonstrate that HOXB13 promoted PCa cell invasion in an androgen-deprived condition by decreasing intracellular zinc concentration to further stimulate NF-κB-mediated transactivation, indicating that HOXB13 overexpression contributes to the malignant biological behavior of HRPC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5330. doi:1538-7445.AM2012-5330