bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5173: The human homologue of frog (Xenopus laevis) anterior gradient protein promotes metastasis via regulation of cellular adhesion
Authors: Chanda Diptiman , Sawant Anandi , Hensel Jonathan Adam , Reilly Stephanie D. , Siegal Gene P. , Smith Claire , Isayeva Tatyana , Ponnazhagan Selvarangan 
Published: August 2012

Abstract
Our recent studies indicated a significant up-regulation of anterior gradient protein-2 (AGR-2) in bone metastatic human prostate cancer cells, PC3, following growth in bone marrow conditioned medium. Evidence indicates that AGR2 belongs to the family of protein disulfide isomerases and has been linked to intestinal mucus production, tumor growth and metastasis of various adenocarcinomas and poor survival of patients with breast and prostate cancers. Few recent reports have also reported the regulatory elements of AGR2 function, but its specific role(s) in tumorigenesis and metastasis is still unclear. In the present study, we have analyzed the role of AGR2 in cancer progression and metastasis using prostate cancer as a model. Human prostate cancer tissue microarrays and autopsy tissues, obtained from University of Alabama at Birmingham consortiums were immunostained for AGR-2 expression. Results were also confirmed in a spontaneously developing transgenic adenocarcinoma of mouse prostate (TRAMP) model. Further characterization of AGR-2 function was determined in PC3 cells with targeted silencing of AGR-2 expressions for tumor growth and metastases in vitro and in vivo. Results of our study found AGR-2 expression mainly in the prostate luminar epithelial cells, but no difference was observed between normal prostate gland, BPH and early stages of prostate cancer in both human and TRAMP mouse. Significant reduction in AGR-2 expression was observed in grade IV & V prostate cancers. Interestingly, although declining AGR-2 was evident in higher grade prostate tumors, significantly elevated AGR-2 expressions were observed in the metastatic sites of the same individuals. AGR-2-silenced PC3 cells formed tumors in SCID mice similar to control cells whereas their ability to remain attached to various ECM proteins were greatly compromised. Several key integrins, which mediates ECM binding, were also found to be down-regulated in the AGR-2 silenced PC3 cells, suggesting loss of AGR-2 may be associated with their detachment from the primary tumor and initiation of metastasis. AGR-2 is further up-regulated in metastatic sites indicating its necessity for restoration of integrins for attachment in a new microenvironment.
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 5173. doi:1538-7445.AM2012-5173
Abstract 5262: Disruption of alternative and classical NF-kappaB signaling patterns: Connections to branching morphogenesis and mammary tumorigenesis
Authors: Onishko Halina , Barham Whitney , Chen Lianyi , Cheng Dongsheng , Tikhomirov Oleg , Connelly Linda , Blackwell Timothy , Yull Fiona E. 
Published: August 2012

Abstract
NF-kappaB transcription factors including p65 (RelA), RelB, p105/p50, and p100/p52 play roles in mammary development and tumorigenesis. While most studies have focused on classical NF-kappaB signaling (p65/p50), alternative NF-kappaB signaling is elevated in human primary breast tumors and in human breast cancer cell lines. In addition, we have reported that overexpression of p100 within the mouse mammary epithelium during pregnancy and lactation led to ductal thickening and hyperplastic foci. To determine the contribution of alternative NF-kappaB signaling to mammary development and tumorigenesis, we have developed murine transgenic models that enable us to inducibly express activators or inhibitors of classical or alternative NF-kappaB signaling in the mammary epithelium by adding doxycycline to the drinking water of mice. Modulation of both the classical and alternative pathways will enable us to determine the roles that each arm plays independently or synergistically. Using immunoflourescent staining we have identified distinct patterns of expression of the alternative and classical pathways in mammary epithelium, a previously undescribed phenomenon. Classical p65 signaling was found within the luminal cell population and p100/p52 signaling was observed almost exclusively within the basal cell layer. Upon induction of constitutively activated IKK2 or a dominant negative IKBalpha, two regulators of the classical NF-κB pathway, alterations in branching morphogenesis were observed within the developing virgin gland. These branching phenotypes were associated with a break down in the previously observed classical/alternative signaling pattern, as luminal cells were now expressing low levels of p100/p52. Furthermore, this patterning is disrupted during the development of polyoma middle T oncogene induced tumors in which we also observe alternative signaling no longer confined to the basal layer. Ongoing experiments with our newest transgenic model are designed to determine the effects of inducing alternative signaling, through overexpression of p52, within the mammary epithelium. Our models may reveal novel roles for the alternative NF-kappaB pathway in maintaining the basal/luminal structure of mammary epithelial ducts and connect aberrant p100/p52 signaling to tumor progression, potentially identifying a novel therapeutic target.
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 5262. doi:1538-7445.AM2012-5262
Abstract 5263: The APC tumor suppressor controls epithelial polarization and morphogenesis
Authors: Prosperi Jenifer R. , Schwertner Adam , Yang Frank F. , Goss Kathleen H. 
Published: August 2012

Abstract
Adenomatous polyposis coli (APC) is a multifunctional tumor suppressor that is frequently mutated or lost in most epithelial-derived tumor types, including colorectal, breast and renal cancer. We have previously demonstrated that germline heterozygous Apc mutation disrupts mammary epithelial integrity. In addition, Apc mutation advances polyoma middle T antigen (PyMT)-mediated mammary tumorigenesis. Interestingly, in both of these models, the effect of Apc mutation was independent of Wnt/β-catenin pathway activation. The objective of the present study was to extend these observations to in vitro models and identify the molecular mechanism by which APC exerts its tumor suppressive function through regulation of epithelial polarity and morphogenesis. Using lentiviral-mediated RNA interference, APC was stably suppressed in non-transformed HC11 mammary and MDCK kidney epithelial cells. Although the APC-knockdown cells did not show any significant morphological or growth differences compared to control vector-only or scrambled shRNA-infected cells on plastic, they showed a dramatic multi-layering phenotype when cultured on permeable supports. Moreover, the polarized localization of basolateral markers, such as Dlg and Scrib tumor suppressor proteins, and apical proteins, including MUC1, was severely disrupted. When the cells were cultured under three-dimensional conditions and compared to controls, the APC-knockdown epithelial cells formed enlarged, non-spherical acini and cysts with filled-in lumens, many of which were invasive into the surrounding matrix. Remarkably, in the MDCK APC-knockdown cells, inverted polarity was observed with the apical marker gp135 localized to the periphery of the cysts. Similar to our previous in vivo studies, these polarization defects associated with APC loss did not appear to require activation of the Wnt signaling pathway but likely involve dysregulation of APC-associated cytoskeletal and polarity complex components. These data indicate that APC is a potent regulator of epithelial polarization and morphogenesis and suggest that one mechanism by which APC loss promotes tumorigenesis is by disrupting epithelial architecture to subsequently drive tumor cell growth, survival and invasion.
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 5263. doi:1538-7445.AM2012-5263
Abstract 5270: Evaluation of Cell-able spheroid culture system for culturing patient derived primary tumor cells
Authors: Praveen Kesavan Nair , Streiner Nicole , Vo Martin , Anderes Kenna , Yokota Koichi , Ikeya Takeshi 
Published: August 2012

Abstract
Tumor cell microenvironment has significant impact on growth kinetics, cell signaling and response to drug treatments. 3D models are more biologically relevant models compared to 2D models and have gained preference among researchers and drug developers. It is well recognized that primary tumor cell cultures grown in 2D monolayer quickly lose the ability to proliferate while 3D culture conditions on extracellular matrix allows for spheroid formation and proliferation. Cell-able, a novel micropatterned plate has cell adhesion areas in the well bottom where the size and shape of these areas are tightly controlled. Micro-fabrication of the well bottom enables rapid cell attachment and spheroid formation. Cell-able plates are potentially an alternative to culturing cells in 3D without extracellular matrix. We have evaluated spheroid formation, morphology, duration of viability, histopathology and expression of markers in patient-derived primary tumor cells from different tumor types when cultured on Cell-able plates compared to Cultrex extracellular matrix (ECM) coated plates. In addition we have utilized Cell-able plates to grow patient-derived tumor cells and evaluate the anti-proliferative responses to cytotoxic and targeted agents using high content imaging coupled with immunofluorescence characterization enabling subpopulation analysis within the spheroids. Our results indicate that patient-derived tumor cells from multiple indications as well as tumor cell lines can be cultured on Cell-able plates as spheroids that resemble the micro architecture of tumors and are therefore a suitable 3D model. The results of high content imaging analysis suggest that Cell-able plates could be used as a valuable tool in in vitro predictive assay models in oncology drug development.
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 5270. doi:1538-7445.AM2012-5270
Abstract 5275: Biglycan is a specific marker and an autocrine angiogenic factor of tumor endothelial cells
Authors: Yamamoto Kazuyuki , Ohga Noritaka , Hida Yasuhiro , Maishi Nako , Kawamoto Taisuke , Kitayama Kazuko , Akiyama Kosuke , Osawa Takahiro , Kondoh Miyako , Kaga Kichizo , Hirano Satoshi , Shinohara Nobuo , Shindoh Masanobu , Hida Kyoko 
Published: August 2012

Abstract
Tumor angiogenesis is necessary for solid tumor progression and metastasis. Tumor blood vessels are morphologically different from their normal counterparts. We isolated tumor endothelial cells (TECs), demonstrated their abnormalities, compared gene expression profiles of TECs and normal endothelial cells (NECs) by microarray analysis and identified several genes upregulated in TECs. We focused on the gene encoding biglycan, a small leucine-rich repeat proteoglycan. Biglycan is overexpressed in inflammation and fibrosis. However, there has been no report about the expression or the function of biglycan in TEC. In this study, we investigated the expression and the role of biglycan in TECs. Real-time PCR, western blotting and immunocytochemistry revealed higher biglycan expression levels in TECs than in NECs. Furthermore, we confirmed that biglycan was secreted from TECs. Biglycan knockdown inhibited cell migration and tube formation in TECs. TLR2 and TLR4 are the biglycan receptors. TLR2 and TLR4 blocking antibodies suppressed biglycan mediated cell migration and tube formation. We isolated TECs from human renal cell carcinoma tissue and NECs from normal renal tissue in the same patients. TECs and NECs were obtained from six patients. Real-time RT-PCR revealed that the biglycan expression levels were significantly higher in four of the six TEC samples than in the corresponding NEC samples. Furthermore, immunostaining revealed strong biglycan expression in vivo in several human tumor vessels, as in mouse TECs. Biglycan was detected in the sera of cancer patients but was hardly detected in those of healthy volunteers. Biglycan is an autocrine angiogenic factor stimulating tumor endothelial cell migration and tube formation. These findings suggested that biglycan is a novel TEC marker and a target for anti-angiogenic therapy.
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 5275. doi:1538-7445.AM2012-5275
Abstract 5290: Heme oxygenase 1 (HO-1): An auspicious target for state of the art anti-angiogenic therapeutic strategies and new insights in prostate carcinogenesis
Authors: Gueron Geraldine , Ferrando Mercedes , Elguero Belen , Giudice Jimena , Salles Angeles , Labanca Estefania , Jaworsky Felipe , Colombo Lucas , Meiss Roberto , Navone Nora , Siervi Adriana De , Vazquez Elba 
Published: August 2012

Abstract
Prostate cancer (PCa) is a leading cause of death among males. Angiogenesis is critical during tumor initiation and progression. The arrival of anti-angiogenic agents as cancer treatments joining the ranks of surgery, chemotherapy and radiotherapy has been a source of renewed hope. Heme oxygenase-1 (HO-1) counteracts oxidative and inflammatory damage. It has become increasingly clear that in addition to its effect on blocking proliferation, invasion and migration, other mechanisms including a direct effect on angiogenic factors may account for its anti-tumoral role in PCa. To further assess its properties, we investigated its potentiality to modulate PCa associated-angiogenesis. In the present study, we identified in PCa cells a set of inflammatory and pro-angiogenic genes down-regulated in response to HO-1 overexpression, in particular VEGFA, VEGFC, HIF1α, KDR and α5β1 integrin. Our results indicated also that HO-1 counteracts oxidative imbalance reducing ROS levels. An in vivo angiogenic assay showed that intradermal inoculation of PC3 cells stable transfected with HO-1 (PC3HO-1) generated tumours less vascularised than controls, with decreased microvessel density and reduced CD34 and MMP9 positive staining. Interestingly, longer term grown PC3HO-1 xenografts displayed reduced neovascularization with the subsequent down-regulation of VEGFR2 expression. Furthermore, using immunofluorescence and structured illumination microscopy we visualized NFκB retention in cytoplasm and demonstrated a higher rate of co-localization with HO-1 under HO-1 over-expression. These observations correlated with repressed nuclear factor κB (NF-κB)-mediated transcription from an NF-κB responsive luciferase reporter construct, induced accumulation of IκB and decreased IKK mRNA levels under HO-1 modulation. These evidences strongly suggest that HO-1 may regulate angiogenesis through this pathway. Taken together, these data supports an unprecedented role of HO-1, challenging the angiogenic-switch in prostate carcinogenesis outlining a rationale for its development as an anticancer target in PCa.
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 5290. doi:1538-7445.AM2012-5290
Abstract 5383: Evaluation of immune response in preclinical settings
Authors: Mignard Caroline , Bichat Francis , Serin Guillaume , Duchamp Olivier , Mirjolet Jean-François 
Published: August 2012

Abstract
Among all new strategies against cancer, the treatments with vaccines, biologics, antibodies, antibody fragments, and other immunological modulators are promising. All of them aim to be more targeted, more effective, and less toxic than other therapies. In order to be developed and accurately evaluated, these immunological related therapies need appropriated preclinical models and relevant immunological readouts. Most of these immunological readouts should be analyzed in vitro, in vivo and ex vivo. A panel of tools from rodents to the bench was evaluated toward the modulation of the immune system by new therapies. All these protocols were developed and validated properly to evaluate these new immunology related cancer therapies. In immunocompetent mice, the immune cells were studied for their cell surface activation markers detection, induction of proliferative phenotype, antigen-specific T lymphocyte detection, secretion of soluble mediators such as cytokines … using FACS phenotyping, cytometric bead assay (CBA) or Luminex multiplex technologies and ELISPOT. In immunodeficient mice, the reconstitution of the mature human immune system with PBMC or naïve human immune system using hematopoietic stem cells were used to evaluate the modulation of those immune cells by therapies through human cytokine release, onset of graft versus host disease. Among other examples, characterization of antibody function (Fab and Fc mediated activities), quantification of the existence and function of antigen-specific T cell clones, phenotyping study of immune cells for activation markers as well as multiplex assays to understand the cytokines network, differentiation of hematopoietic cells by colony formation unit will be described. All of them will be presented in the context either of rodent syngenic model or humanized mouse model. All results, integrative data and examples will be presented in the poster.
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 5383. doi:1538-7445.AM2012-5383
Abstract 5390: Anti-IL10-R1 monoclonal antibody with concomitant bacillus calmette-Guérin (BCG) prevents metastatic bladder cancer in an in vivo mouse model
Authors: Askeland Eric , Newton Mark , Bockholt Nathan , Knudson Matthew , Henning Jonathan , Wang Xu , Askeland Ryan , Weady Peter , Smith George , Eisenbraun Michael , Fraser James , O'Donnell Michael , Luo Yi 
Published: August 2012

Abstract
Introduction: Induction of Th1 immunity is required for effective intravesical BCG immunotherapy of bladder cancer. IL-10 down-regulates the Th1 response and is associated with BCG failure. We previously demonstrated that blocking IL-10 receptor (IL-10R) by systemic administration of anti-IL-10R1 mAb enhanced intravesical BCG (living Pasteur strain) treatment of bladder cancer in an orthotopic mouse model. Here we investigated the effect of anti-IL-10R1 mAb on clinically used BCG (lyophilized TICE strain) for induction of anti-bladder cancer immunity. Methods: Splenocytes were incubated with BCG alone or plus control IgG or ant-IL-10R1 mAb for 24 hours, followed by ELISA analysis of IFN-γ production. Bladder RNA was extracted after 6 treatments (twice weekly) with intravesical (i.b.) BCG plus intraperitoneal (i.p.) control IgG or anti-IL-10R1 mAb, followed by qPCR analysis of IFN-γ mRNA expression. Three groups of 20 mice were inoculated with luciferase-expressing MB49 bladder cancer cells and treated with i.b. PBS plus i.p. PBS (Group 1), i.b. BCG plus i.p. control IgG (Group 2), or i.b. BCG plus i.p. anti-IL-10R1 mAb (Group 3) 2x/wk for 6 total treatments. Mice were monitored weekly using IVIS luminescence and followed for 76 days. A bioluminesence cutoff of 5X104 p/s was used to establish the presence of bladder cancer. At animal death bladders were collected, weighed and processed for histological analysis. In suspected cases of metastatic disease the affected organs were also collected for histological analysis. Results: BCG plus anti-IL-10R1 mAb induced increased IFN-γ production by splenocytes in a dose-dependent manner. BCG plus anti-IL-10R1 mAb substantially increased IFN-γ mRNA. Eleven, 17 and 9 mice from Groups 1, 2 and 3, respectively, developed bladder cancer. One mouse in Group 2 and 2 mice in Group 3 showed cancer regression. 36%, 53% and 0% of Groups 1, 2 and 3 developed metastatic bladder cancer, respectively (p=0.020). While bladder weights for the groups were different, the differences did not reach statistical significance. Conclusions: Anti-IL-10R1 mAb enhances BCG-induced Th1 immune responses both in vitro and in vivo. Intravesical BCG plus anti-IL-10R1 mAb shows statistical significance in preventing metastasis of bladder cancer in an orthotopic bladder tumor mouse model. Anti-IL-10R1 mAb may prove useful in clinical practice for the prevention of metastatic bladder cancer in high-risk patients.
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 5390. doi:1538-7445.AM2012-5390
Abstract 5399: S100A9 drives MDSC migration and contributes to tumor progression by inhibiting the immune response
Authors: Condamine Thomas , Cheng Pingyan , Youn Je-In , Ortiz Myrna L. , Vogl Thomas , Roth Johannes , Gabrilovich Dmitry I. 
Published: August 2012

Abstract
S100A9 is a pro-inflammatory molecule, secreted by myeloid cells, which has been reported to recruit leukocytes to the sites of inflammation or tumors. We have previously found that up-regulation of S100A9 expression in myeloid progenitor cells in cancer resulted in inhibition of DC differentiation and promotion of expansion of myeloid-derived suppressor cells (MDSC). It remained unclear how S100A9 could regulate MDSC expansion and function. In this study we evaluated the effects of secreted (extracellular) vs intracellular S100A9 on MDSC. Recombinant S100A9 or S100A8 proteins separately or as heterodimers did not promote MDSC expansion from hematopoietic progenitor cells (HPC), or affect their suppressive activity. However, recombinant proteins had a strong chemotactic effect on MDSC. Interestingly, this effect on immature myeloid cells isolated from naïve tumor-free mice was substantially lower. To study intracellular activity of S100A9 we used S100A9 transgenic (Tg) and knockout (KO) mice. Mice were injected with several different weakly and strongly immunogeneic tumors. As expected Tg mice had increased expansion of MDSC and KO mice had substantially reduced number of these cells. Different levels of MDSC did not affect the growth of weakly immunogeneic tumors. In contrast, overexpression of S100A9 in mice lead to significantly accelerated growth of immunogenic tumors. Lack of S100A9 resulted in fast rejection of immunogeneic tumors. Our data indicate that extracellular and intracellular S100A9 had different signalling in myeloid cells and apparently affect different aspects of their function. S100A9 over-expression, in vivo, inhibits the immune response, most likely by promoting MDSC accumulation and/or suppressive activity. Our data suggest that targeting of S100A9 in cancer can be an attractive therapeutic option.
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 5399. doi:1538-7445.AM2012-5399