bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3829: Chronic stimulation with IL-15/IL-15Rα complexes leads to NK cell dysfunction
Authors: Elpek Kutlu G. , Rubinstein Mark P. , Bellemare-Pelletier Angelique , Goldrath Ananda W. , Turley Shannon J. 
Published: February 2011

Abstract
IL-15/IL-15Rα complexes induce expansion and activation of cytotoxic lymphocytes including NK and CD8 T cells with higher activity compared to IL-15 alone in vivo, and therefore, have therapeutic potential against cancer and chronic infections. Recent studies demonstrated that continuous treatment with IL-15/IL-15Rα complexes improves the survival of tumor bearing mice, however fail to control tumor outgrowth. Given the limited efficacy of long-term cytokine therapy, we sought to investigate the impact of continuous stimulations with IL-15/IL-15Rα complexes on NK and CD8 T cells in tumor-free mice in vivo. Long-term treatment with IL-15/IL-15Rα complexes induced massive expansion of both NK and CD8 T cells. While the functional capacity of CD8 T cells was enhanced after long-term treatments, NK cells exhibited marked defects in activation, IFNγ production, degranulation, and cytotoxicity. In addition, long-term treatment generated a suppressive environment and resulted in marked increase in Treg and CD11c+Gr1+ cell numbers. However, impaired NK cell function was not due to regulatory T cells or various myeloid cell mediated-suppressive factors. Our results have important clinical implications for the design of immunotherapies and vaccines using multiple doses of immunostimulatory agents.
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 3829.
Abstract 3837: PI-3 kinase acts upstream of oncogenic Ras in hematopoietic cells through a cytokine-PLCγ-RasGRP pathway
Authors: Diaz-Flores Ernesto , Goldschmidt Hana , Depeille Philippe , Ng Victor , Roose Jeroen , Shokat Kevan , Braun Benjamin , Shannon Kevin 
Published: February 2011

Abstract
Introduction: KRAS is the most common gain-of-function mutation in human cancer and occur in some myeloid malignancies. Despite extensive data implicating aberrant responsiveness to cytokines in the pathogenesis of myeloid leukemias with hyperactive Ras, the underlying mechanisms are largely unknown. We investigated the biochemical basis of hypersensitivity to granulocyte macrophage colony stimulating factor (GM-CSF), IL-3, and stem cell factor (SCF) in primary cells from Mx1-Cre, KrasG12D mice. Methods: We utilized conventional biochemical techniques, phospho-specific flow cytometry, and small molecule inhibitors to interrogate signaling downstream of the activated GM-CSF and c-Kit receptors. Results: We found that endogenous KrasG12D expression deregulates multiple effectors in primary myeloid lineage cells. Although Ras-GTP levels are markedly elevated in bone marrow cells from KrasG12D mice, these cells only fully activate the Raf/MEK/ERK cascade upon cytokine stimulation. We used a “chemical genetic” strategy to explore the biochemical mechanism linking the activated GM-CSF receptor to oncogenic K-RasG12D and ERK. Surprisingly, inhibitors of type I PI3 kinases (PI-90, PI-103) as well as a p110 γ/α isoform inhibitor (AS605240) interfered with GM-CSF and SCF induced Ras/MAPK activation in wild-type and KrasG12D myeloid cells. These effects of PI3 kinase are mediated through activation of PLC-γ and the RasGRP guanine nucleotide exchange factors. Functional studies confirmed that inhibiting PI3 kinase or PLC-γ blocked KrasG12D-mediated myeloid progenitor colony growth. This PI3 kinase/PLC-γ module also functions downstream of the activated c-kit receptor in lineage- cKit+ Sca1+ (LSK) cells in SCF-induced ERK activation. Conclusions: PI3 kinase, PLC-γ, and RasGRPs function upstream of normal and oncogenic K-Ras to efficiently activate the Raf/MEK/ERK cascade in primary hematopoietic cells. These data infer that PI3 kinase is both an important upstream regulator as well as a major downstream effector of Ras-GTP. Significance: Targeting PI3 kinase in hematologic cancers characterized by hyperactive Ras may have unanticipated biochemical and functional consequences in malignant and normal hematopoietic cells.
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 3837.
Abstract 3844: Targeting macrophages as a novel therapeutic approach for malignant pleural mesothelioma
Authors: Kolhatkar Nikita S. , Johansson Magnus , Barbone Dario , Yagui-Beltran Adam , Bueno Raphael , Sugarbaker David J. , Jablons David M. , Broaddus V. Courtney , Coussens Lisa M. 
Published: February 2011

Abstract
Mesothelioma is a life-threatening tumor, induced by inhalation of asbestos fibers that is largely resistant to most chemotherapeutic drugs. Using a combination of immunohistochemistry and flow cytometry, we have evaluated both the presence and composition of leukocytes residing in human mesotheliomas, and have found that 1) epithelioid and mixed mesothelioma tumor subtypes contain higher percentages of CD45+ leukocytes than sarcomatous tumors, and 2) macrophages represent the most abundant immune cell subtype in mesothelioms, regardless of type (31 ± 4.6% of total CD45+). Indeed, the percentage of macrophages in mesotheliomas exceeded that found in other thoracic malignancies thus far evaluated (NSCLC cancer, 9%; esophageal, 4%). In view of recent data indicating that macrophages potentiate cancer development in some settings, and that macrophages can be targeted therapeutically to minimize some aspects of tumor progression, we investigated whether macrophages could be targeted to alter the chemosensitivity of human mesotheliomas. To address this question, we adapted a 3-dimensional (3D) spheroid growth model, enabling heterotypic culture of mesotheliomal cells and macrophages. Our data indicate that mesothelioma chemoresistance can be lowered by co-incubation with macrophages. However, the magnitude of the altered response is dependent upon macrophage phenotype. Macrophage phenotype and bioactivity is modulated by TH1 and TH2 cytokine exposure that in turn regulate either an M1 (IFN-γ & LPS) or M2 (IL-4) phenotype. M1-polarized macrophages increased the response of malignant mesothelioma spheroids to pro-apoptotic chemotherapeutic agents, including gemcitabine. Furthermore, our preliminary data indicate that primary human tumor-associated macrophages, isolated from untreated malignant mesotheliomas, exhibit similar pro-apoptotic effects when polarized with M1 cytokines, indicating that cytokine re-polarization of macrophages in mesotheliomas to an M1 phenotype could enhance efficacy of cytotoxic therapy.
This work was supported by grants from the NCI and a DoD Mesothelioma Program grant PR080717 to Broaddus and Coussens
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 3844.
Abstract 3845: The normal breast microenvironment of premenopausal women differentially influences the behavior of breast cancer cells in vitro and in vivo
Authors: Fleming Jodie M. , Miller Tyler C. , Quinones Mariam , Xiao Zhen , Xu Xia , Meyer Matthew J. , Ginsburg Erika , Veenstra Timmothy D. , Vonderhaar Barbara K. 
Published: February 2011

Abstract
Introduction: Breast cancer studies frequently focus on the role of the tumor microenvironment in the promotion of cancer; however, the influence of the normal breast microenvironment on cancer cells remains relatively unknown. To investigate the role of the normal breast microenvironment on breast cancer cell tumorigenicity, we examined whether extracellular matrix molecules (ECM) derived from pre-menopausal African-American (AA) or Caucasian-American (CA) breast tissue would affect the tumorigenicity of cancer cells in vitro and in vivo. We chose these two populations because of the well-documented predisposition of AA to develop aggressive, highly metastatic breast cancer compared to CA women.
Methods: The effects of primary breast fibroblasts on tumorigenicity were analyzed via real-time PCR arrays and mouse xenograft models. Whole breast-ECM was isolated, analyzed via zymography, and its effects on breast cancer cell aggressiveness were tested in vitro via soft agar and invasion assays, and in vivo via xenograft models. Breast ECM and hormone metabolites were analyzed via mass spectrometry.
Results: Mouse mammary glands humanized with pre-menopausal CA-fibroblasts and injected with primary breast cancer cells developed significantly larger tumors compared to AA-humanized glands. Examination of 164 extracellular matrix (ECM) molecules and cytokines from CA-derived fibroblasts demonstrated a differentially regulated set of ECM proteins and increased cytokine expression. Whole breast-ECM was isolated; invasion and soft agar assays demonstrated that ER-/PR- cells were significantly more aggressive when in contact with AA ECM, as were ER+/PR+ cells with CA ECM. Using zymography, protease activity was comparatively upregulated in CA ECM. In xenograft models, CA ECM significantly increased the tumorigenicity of ER+/PR+ cells and enhanced metastases. Mass spectrometry analysis of ECM proteins showed only 1,759 of ∼8,000 identified were in common. In the AA dataset, proteins associated with breast cancer were primarily related to tumorigenesis/neoplasia, while CA-unique proteins were involved with growth/metastasis. Using a novel mass spectrometry method, 17 biologically-active hormones were measured; estradiol, estriol and 2-methoxyestrone were significantly higher in CA breast tissue.
Conclusions: This study details normal pre-menopausal breast tissue composition, delineates potential mechanisms for breast cancer development, and provides data for further investigation into the role of the microenvironment in cancer disparities.
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 3845.
Abstract 3857: Hedgehog signaling in primary prostate tumors and associated metastases
Authors: Proctor Jennifer , Travaglione Veronica , Deyneko Igor , Read Margaret , Ross Rob , McGovern Karen , Vessella Robert , MacDougall John 
Published: February 2011

Abstract
Malignant activation of the Hedgehog (Hh) pathway is associated with multiple tumor types. The Hh pathway can promote growth of certain cancers via three modes of malignant activation: ligand-dependent signaling either to the tumor cell itself or between the tumor and its microenvironment, and ligand-independent signaling activated by genetic mutations. In certain cancers, tumor-derived Hh ligand signals in a paracrine manner to the stromal cells in the microenvironment that support tumor cell growth. Using a sensitive immunohistochemistry method for detecting Hh ligand, 83 percent of 105 human prostate tumor samples, including lymph and bone metastases from the same patients, were found to express high levels of Sonic Hedgehog (SHh) ligand. LuCaP 23.1 and LuCaP 35v xenografts were derived from lymph node metastasis from patients with prostate cancer. Paracrine Hh signaling is detected in both xenograft models, where the human tumor cells produce Hh ligand and the surrounding stromal cells respond with Hh pathway activation, as measured by Gli1 levels. IPI-926, a novel, small molecule Hh inhibitor that acts by blocking Smoothened, inhibits signaling between the tumor and stromal cells in both castration sensitive and castration resistant tumor models. Inhibition of Hh signaling with IPI-926 was then evaluated as a potential means to reduce growth of prostate cancer tumors and metastases. IPI-926 significantly delays relapse and slows the growth rate of castration resistant primary human prostate tumors post-docetaxel treatment. Additional preclinical studies with IPI-926 in combination with chemotherapy and targeted therapies in castration resistant tumor models are in progress. These pre-clinical results provide a rationale for testing Hh inhibitors in patients with castration resistant prostate 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 3857.
Abstract 3873: Squalene enhanced chemotherapy and radiation therapy sensitivity in mice through the inhibition of DNA damage checkpoint activity
Authors: Nishida Hiroshi , Tatewaki Naoto , Nakajima Yuki , Nakayama-Kawakami Kayoko , Kasai-Eguchi Kiyomi , Anzai Kazunori , Konishi Tetsuya , Ikekawa Nobuo 
Published: February 2011

Abstract
ATM (Ataxia Telangiectasia Mutated) protein kinase plays a crucial role in cellular DNA damage responses. The inhibition of ATM leads to an abolishment of one such signal pathways termed as “checkpoints”. It is expected that the discovery of checkpoint inhibitor will be an effective assistance of anti-cancer therapy. Recent study reported that Wip1, a magnesium dependent protein phosphatase, de-phosphorylates molecules involved DNA damage checkpoint response such ATM (Ser1981). On the other hand, Squalene (SQ) has been thought to assist anti-cancer therapies such as chemo and/or radiation therapy though there is few available data which refer to its detailed mechanisms. We previously showed that SQ enhances the γ-irradiation (IR) sensitivity through the induction of Wip1 in A549 adenocarcinoma cells. It was indicated that IR induced DNA damage checkpoint was abrogated by SQ pre-treatment, and led to the shrinkage of tumor in vivo. Here, we report SQ sensitizes chemotherapy and an advanced radiation therapy, heavy ion (HI) exposure, in mice using allo/xeno-graft model. Mouse Colon-26 and human MKN45 cells (5 × 106 cells/ mouse) were transplanted into Balb/c and SCID mice, respectively. The tumor volumes were estimated by measuring the growing diameters of tumor tissue every day. SQ (200μl, oral administration) was challenged after day-8 and later days. Chemotherapy using DOX (2 mg/kg, i.p.) was conducted in same days with SQ. One-time exposure of HI (Carbon, 290MeV) was performed on the day-8 in NIRS (National Institute of Radiological Sciences, Japan). Marked change of body weight was not observed between the treatments. DOX and HI prevented the tumor growth. SQ itself inhibited tumor growth slightly. The administration of SQ significantly improved the efficacy of DOX and HI on tumor growth. Wip1 protein expression in tumor tissue was detected by western blot analysis, and was elevated by the oral administration of SQ. These results were confirmed in xenograft model using MKN45 cells and SCID mice. Taken together these findings, SQ sensitized chemo/radio therapy through the inhibition of DNA damage checkpoint activity by Wip1. Further in-depth study is required to determine the clinical feasibility of SQ as a sensitizing agent for anti-cancer therapy.
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 3873.
Abstract 3877: An inhibitor-2 complex regulates cell cycle checkpoints in response to DNA damage
Authors: Sun Mianen , Lin Chenghe , Tang Xi , Xu Bo 
Published: February 2011

Abstract
Optimal DNA damage responses such as cell cycle checkpoints are essential for cell survival and prevention of genetic instability. Comprehensive knowledge on the regulation of cell cycle checkpoints will provide molecular insights into tumorigenesis as well as tumor responses to radiation and chemotherapy. The signal transduction network orchestrated by the ATM protein kinase through phosphorylation of downstream targets is critical to activate cell cycle checkpoints in response to ionizing radiation (IR). Among them, Inhibitor 2 (I-2), a regulatory subunit of Protein Phosphatase 1 (PP1), is phosphorylated by ATM on Serine 43 after IR and required for PP1 activation. However, the detailed mechanism of the signaling network involving ATM, PP1 and I-2 has not been elucidated. In the present study, we show that I-2 phosphorylation is required for activation of the S-phase and G2/M checkpoints. We also identified a complex associated with the phosphorylated form of I-2. Several DNA damage responsive proteins such as ATM, Brca1, Cdc7 and Chk2 are presented in the complex. Further, we demonstrate that Brca1 is required for ATM-mediated I-2 phosphorylation and PP1 activation after DNA damage. We find Brca1 is essential for recruiting I-2 to DNA damage sites, and Brca1 interaction with I-2 increases after DNA damage. This DNA damage-induced Brca1/I-2 interaction further lead to I-2/PP1 dissociation, the process required for PP1 activation after DNA damage. Taken together, our results highlighted that a comprehensive pathway mediated by I-2 phosphorylation in response to DNA damage.
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 3877.
Abstract 3878: Perturbations in the AR-cyclin D1 axis controls lethal tumor phenotypes in prostate cancer
Authors: Augello Michael , Burd Craig , Karch Jason , Knudsen Karen 
Published: February 2011

Abstract
Androgen receptor (AR) signaling is critical to prostate cancer development. It has been well established that AR activation promotes lethal tumor phenotypes including proliferation, survival, invasion, and therapeutic resistance. However, mechanisms by which AR promotes these phenotypes are poorly understood. Previous reports assessing cellular proliferation revealed that the AR-cyclin D1a axis plays a significant role in controlling the response to androgen. While activated AR induces cyclin D1a through mTOR mediated mechanisms, accumulated cyclin D1a serves a negative feedback control function, through the ability of the cyclin to bind and suppress further AR signaling. Importantly, this process is frequently abrogated in human prostate cancer through an alternative splicing event that results in production of cyclin D1b. Cyclin D1b is deficient in its ability to regulate AR, and has been shown in other model systems to harbor significant oncogenic activity. Importantly, we have demonstrated that nearly 1/3 of a large cohort of primary prostate cancer tumors exclusively express cyclin D1b. Thus, it is imperative to determine the molecular and cellular consequence of the alternative splicing event in prostate cancer. Endogenous D-cyclins were eliminated using hormone ablation; subsequent viral-mediated reintroduction of cyclins D1a or D1b allowed for unbiased comparison of cyclin function in the presence and absence of androgen. Gene expression profiling confirmed that D1b is unable to manage AR activity. Concordantly, alteration of androgen-sensitive genes was observed, in particular those associated with migration and invasion. In vitro manipulation of the D1 splicing event confirmed these results. Subsequent modeling of cyclin D1b function revealed that cyclin D1b confers a specific anchorage independence and migration phenotype to AR-positive prostate cancer cells. Thus, these data provide the first evidence that perturbation in the AR-cyclin D1 axis controls lethal tumor phenotypes.
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 3878.
Abstract 3896: Non-canonical regulation of the Hedgehog mediator GLI1 by c-MYC in Burkitt lymphoma cells
Authors: Yoon Joon Won , Xu Ke , Iannaccone Philip M. , Walterhouse David O. 
Published: February 2011

Abstract
Aberrant activation of the oncogene GLI1, a key mediator of the Hedgehog (HH) signaling pathway, is observed in a wide variety of human cancers. Although HH plays a major role in GLI1 transcription and activation via Patched (PTCH) and Smoothened (SMO), there is increasing evidence suggesting that other pathways also regulate GLI1 expression. A recent study suggested that upregulation of c-MYC by the EWS/FLI1 fusion protein in Ewing Sarcoma may play a role in upregulating GLI1. To determine the role of c-MYC in the regulation of GLI1 and whether c-MYC regulates GLI1 independently of the HH signaling pathway, we initiated studies in Burkitt lymphoma cells, which constitutively overexpress c-MYC due to a chromosomal translocation. Using RT-PCR, we showed that BL1647, BL1648, BL2392 and BL2625 Burkitt lymphoma cell lines express c-MYC and HH pathway components, including PTCH1, SMO, and GLI1. Using Western blot analysis, we showed that GLI1 protein levels varied among the different cell lines. We demonstrated a sequence-specific interaction between c-MYC protein and E-boxes in the GLI1 promoter with chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays (EMSA). This interaction resulted in transcriptional activation of a luciferase reporter gene in NIH3T3 and HeLa cells. Treating Burkitt lymphoma cells with the c-MYC inhibitor 10058-F4 downregulated GLI1 mRNA and protein and reduced cell viability as measured by MTT assays. In contrast, inhibition of HH-signaling by cyclopamine did not affect GLI1 expression in Burkitt lymphoma cells and only reduced viability of cells when used at high concentrations, possibly representing non-specific cytotoxic effects. Inhibition of GLI1 by GANT61 suggests that GLI1 functions as an anti-apoptotic factor as measured by Caspase3/7 activity in Burkitt lymphoma cells. Collectively, our data provide evidence that c-MYC may function independently of the HH pathway in Burkitt lymphoma to directly regulate GLI1 in a non-canonical manner and support an anti-apoptotic role for GLI1 in Burkitt lymphoma.
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 3896.