bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2302: Analysis of the role of CADM1 in suppression of lung cancer using Cadm1-deficient mice
Authors: Ito Takeshi , Nagata Masayoshi , Kawai Taketo , Sakurai-Yageta Mika , Ito Akihiko , Goto Akiteru , Matsubara Daisuke , Murakami Yoshinori 
Published: August 2015

Abstract
Lung cancer is the leading cause of cancer deaths, and non-small-cell lung cancer (NSCLC) is the most prevalent form of lung cancer. The tumor suppressor gene CADM1/TSLC1 was originally identified in NSCLC. CADM1 encodes an immunoglobulin superfamily cell adhesion molecule. CADM1 is inactivated by deletion and/or promoter methylation of the gene in 40-60% of NSCLC, especially in their advanced stages. Previously we generated conventional Cadm1-deficient mice and found that around 40% of Cadm1-deficient mice spontaneously developed lung adenoma and adenocarcinoma by 15 months of age. To assess the precise role of CADM1 in suppression of lung tumorigenesis, we crossed Cadm1-deficient mice to conditional K-ras-mutant mice, well-established mouse models of lung cancer. The K-ras-mutant mice are shown to develop multiple lung adenocarcinomas by 25 weeks after administration of adenovirus expressing Cre recombinase followed by the activation of oncogenic K-ras. We then analyzed the development of lung tumors in K-ras-mutant (K) mice and K-ras-mutant Cadm1-deficient (KC) mice. Loss of Cadm1 results in enlargement of the size of alveolar tumors (adenomas or adenocarcinomas) as well as higher tumor grades. The most malignant histology of vascular or pleural invasion was only detected in tumors from KC mice. On the other hand, the size of the bronchial tumors was larger in K mice than in KC mice. Immunohistochemical analysis of bronchial marker SOX2 showed that adenomas or adenocarcinomas expressing SOX2 were larger in KC mice, indicating that loss of Cadm1 enhanced the rapid growth of alveolar tumors and thereby impaired the growth of bronchial tumors originated from the common stem cells, bronchio-alveolar stem cells (BASCs). Furthermore, tumors from K mice showed frequent loss of CADM1 expression and the tumors with low expression of CADM1 exhibited more malignant histological features. These results suggest that loss of Cadm1 promotes the malignant progression of alveolar tumor.
Citation Format: Takeshi Ito, Masayoshi Nagata, Taketo Kawai, Mika Sakurai-Yageta, Akihiko Ito, Akiteru Goto, Daisuke Matsubara, Yoshinori Murakami. Analysis of the role of CADM1 in suppression of lung cancer using Cadm1-deficient mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2302. doi:10.1158/1538-7445.AM2015-2302
Abstract 2330: Activation of cancer stem cells by oncogenic K-Ras requires activated Wnt/β-catenin signaling
Authors: Moon Byoung-San , Lee Kug Hwa , Koo Kyounghwa , Choi Kang-Yell 
Published: August 2015

Abstract
Adenomatous polyposis coli (APC) loss-of-function mutations and K-Ras gain-of-function mutations are common abnormalities that occur during the initiation and intermediate adenoma stages of colorectal tumorigenesis, respectively. However, little is known about the role of these mutations in the regulation of cancer stem cells (CSCs) associated with colorectal cancer (CRC) tumorigenesis. We analyzed tissue from CRC patients (n = 49) and observed an association between K-Ras mutations and CSC activation during colorectal tumorigenesis. The oncogenic K-Ras mutations enhanced stemness of CRC cells carrying an APC mutation, as shown by comparisons of sphere formation, transforming potential, and differentiation in vitro and tumor-forming capacity in vivo between isogenic APC mutated CRC cells harboring either wild-type or mutant K-Ras. Moreover, the activation of CSC by K-Ras mutations in CRC required an additional APC mutation, as revealed by the induction of CD44, CD133, and CD166 in intestinal tumor tissues of APCMin/+/K-RasLA2 double-mutant mice, but not in K-RasLA2 mice. Overall, the progression and metastasis of CRC induced by K-Ras mutation occurs by initial activation of CSC by APC loss and further activation of Wnt/β-catenin signaling and subsequent activation of Ras-ERK signaling.
Citation Format: Byoung-San Moon, Kug Hwa Lee, Kyounghwa Koo, Kang-Yell Choi. Activation of cancer stem cells by oncogenic K-Ras requires activated Wnt/β-catenin signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2330. doi:10.1158/1538-7445.AM2015-2330
Abstract 2332: Converging molecular effectors of airway lineage specification and metastasis in lung cancer
Authors: Nguyen Don X. 
Published: August 2015

Abstract
Lung adenocarcinoma (LUAD) is a deadly and heterogeneous subtype of non-small cell lung cancer. During LUAD progression, the emergence of alternate epithelial lineage fates in primary tumors correlates with poor outcome. The underlying mechanisms and biological consequences of these phenomena are poorly understood.
Using an integrated approach, we previously examined the molecular relationship between cell differentiation states, lung cancer subtypes, and clinical outcome, to discover a novel role for several lineage-restricted transcription factors in the pathogenesis of LUAD (1). Specifically, we identified the alveolar specification factor, HOPX, as an inhibitor of metastatic progression. Herein we show that down-regulation of its function in a subset of human tumors correlates with DNA hypermethylation, aberrant tumor differentiation, and relapses. HOPX restricts the metastatic potential of LUAD cells, by modulating converging transcriptional programs of airway epithelial differentiation, malignant invasion, and metabolic adaptation in response to the extracellular microenvironment. Mechanistically, HOPX mediates its functions in part through the regulation of previously uncharacterized long-intergenic long non-coding RNAs with potential roles in lung development.
Our findings demonstrate that perturbation of intrinsic cell lineage pathways is a determinant of metastasis in specific lung cancers. The implications of these findings for the origin(s) and treatment of LUAD metastasis will be further discussed.
(1) Cheung, W.K.C., Zhao, M., Liu, Z., Stevens, L.E., Cao, P.D., Fang, J.E., Westbrook, T.F., and Nguyen, D.X. (2013). Cancer Cell, 23 (6): 725-738.
Citation Format: Don X. Nguyen. Converging molecular effectors of airway lineage specification and metastasis in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2332. doi:10.1158/1538-7445.AM2015-2332
Abstract 2336: AD1 promotes astroglial differentiation and depletes glioblastoma stem cells
Authors: Spina Raffaella , Voss Dillon M. , Sloan Andrew , Bar Eli E. 
Published: August 2015

Abstract
Glioblastoma are among the least curable cancers in man, at least in part because of stem-like cellular subpopulations (herein referred to as glioma stem cells, GSC) refractory to current therapies. The cancer stem cell hypothesis suggests that tumor cells are organized in a pyramidal unidirectional differentiation cascade with GSC at the top and functionally defined by the ability to self-renew and initiate tumors identical to the original tumors from which they are derived. GSCs are maintained by both cell intrinsic and micro-environmental factors and conditions. In this study we focused on identifying small molecules which target tumor heterogeneity by promoting differentiation of GSC into less aggressive, more differentiated subpopulations. To this end, we have developed reporter models for astroglial and neuronal differentiation in HSR-GBM1, HSR040622 and HSR040821 tumor-derived, GSC-enriched, neurospheres lines, using lineage-specific reporter constructs. We employed these reporter lines to screen a library of over 700 bioactive small molecules for potential inducers of GSC differentiation. We identified several molecules which significantly induce astroglial differentiation in multiple GSC-enriched lines. In this report, we focus on one of these agents, (AD1 = (Astroglial Differentiation-1), which induces astroglial differentiation by up to 30-fold as compared with DMSO control. Interestingly, the effects of AD-1 appear to be primarily cytostatic rather than cytotoxic. As differentiation should result in reduced self-renewal capacity, we next determined the effect of AD1 on clonogenicity in vitro using the extreme limited dilution assay (ELDA). We found that 48h treatment with AD1 significantly reduced clonogenic capacity of HSR-GBM1, HSR-040622 and HSR-040821 reporter lines by over 90%. To test this in vivo we examined the effect of AD1 on tumor initiation in an intracranial transplantation model. We found that ex vivo treatment with AD1 resulted in a significant increase in the survival of animals as 6 (of 6) animals transplanted with DMSO-treated cells exhibited massively infiltrating tumors while 2 (of 6) of the animals implanted with AD1 treated cells developed tumors, and those began to appear several weeks later. Importantly, the effects of AD1 are likely to be irreversible as cells extracted from tumors maintained reporter expression even after six passages in vitro. Taken together, our results support the therapeutic value of a drug-induced differentiation and define how differentiation affects the GSC compartment in glioma.
Citation Format: Raffaella Spina, Dillon M. Voss, Andrew Sloan, Eli E. Bar. AD1 promotes astroglial differentiation and depletes glioblastoma stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2336. doi:10.1158/1538-7445.AM2015-2336
Abstract 2346: Targeting the tumor immune response for pro-senescence therapy in prostate cancer
Authors: Di Mitri Diletta , Chen JingJing , Alimonti Andrea 
Published: August 2015

Abstract
Cellular senescence is a stable growth arrest that constrains cell cycle progression in case proliferation becomes aberrant, thus limiting tumorigenesis. Oncogenic mutations and loss of tumor suppressor genes that cause uncontrolled cell-cycle progression are required events in tumor development. Nevertheless, many of these genetic alterations retain an intrinsic tumor-suppressive potential that gives rise to oncogene-induced senescence and tumor suppressor loss-induced senescence. Interestingly, many evidences support the idea that a strong interplay occurs between senescence, cancer cells, and tumor infiltrating immune populations, thus opening at the possibility to tune such interplay for cancer treatment. Indeed, tumor infiltrating T helper 1 cells can drive senescence in cancers in a cytokine-induced manner, by secreting IFNγ and TNFα in the tumor microenvironment. In addition, we recently described a model where Pten loss induced senescence is hindered in prostate tumor by non-cell-autonomous mechanisms. Our study support a model where tumor-infiltrating CD11b+Gr-1+ myeloid cells paracrinally triggers tumor senescence evasion in the prostate of Pten null mice, eventually promoting tumor progression. These findings we’ll be discussed. Interestingly, we will present new evidences from our lab indicating that M1 macrophages are polarized to the M2 phenotype in both Pten pc-/- and that treatments that interfere with the M1-M2 polarization and switch the skewing to the M1 polarization profile can induce senescence in Pten; Trp53pc-/- invasive prostate cancer tumours thereby arresting tumour progression. These findings open at the possibility that M1 directly control senescence in tumor cells. Finally, we have identified a gene expression signature that distinguishes myeloid infiltration in tumors and can be used as a predictive marker for tumor progression in prostate cancer patients. These evidences we’ll be also discussed.
Citation Format: Diletta Di Mitri, JingJing Chen, Andrea Alimonti. Targeting the tumor immune response for pro-senescence therapy in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2346. doi:10.1158/1538-7445.AM2015-2346
Abstract 2353: Noncanonical NF-κB activation mediates STAT3-stimulated IDO up-regulation in myeloid-derived suppressor cells in breast cancer
Authors: Yu Jinpu , Wang Yue , Li Hui , Ren Xiubao 
Published: August 2015

Abstract
Immunotherapy for cancer treatment is achieved through the activation of competent immune effector cells and the inhibition of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs). While MDSCs have been shown to contribute to breast cancer development, the mechanism underlying MDSCs-mediated immunosuppression is unclear. We have identified a poorly differentiated MDSC subset in breast cancer suppressing T-cell function through signal transducer and activator of transcription (STAT) 3-dependent indoleamine 2,3 dioxygenase (IDO) up-regulation. Here we investigated the mechanisms underlying aberrant expression of IDO in MDSCs. MDSCs were induced by co-culturing human CD33+ myeloid progenitors with MDA-MB-231 breast cancer cells. Increased STAT3 activation in MDSCs was correlated with activation of the noncanonical nuclear factor-κB (NF-κB) pathway, including increased NF-κB-inducing kinase (NIK) protein level, phosphorylation of cytoplasmic inhibitor of NF-κB kinase (IKK) α and p100, and RelB-p52 nuclear translocation. Blocking STAT3 activation with the small molecule inhibitor JSI-124 significantly inhibited the accumulation of NIK and IDO expression in MDSCs. Knock-down of NIK in MDSCs suppressed IDO expression, but not STAT3 activation. RelB-p52 dimers were found to directly bind to the IDO promoter, leading to IDO expression in MDSCs. IL-6 was found to stimulate STAT3-dependent, NF-κB-mediated IDO up-regulation in MDSCs. Furthermore, significant positive correlation between the numbers of pSTAT3+ MDSCs, IDO+ MDSCs, and NIK+ MDSCs was observed in human breast cancers. These results demonstrate a STAT3-NF-κB-IDO pathway in breast cancer-derived MDSCs, which provides insight into understanding immunosuppressive mechanisms of MDSCs in breast cancer.
Citation Format: Jinpu Yu, Yue Wang, Hui Li, Xiubao Ren. Noncanonical NF-κB activation mediates STAT3-stimulated IDO up-regulation in myeloid-derived suppressor cells in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2353. doi:10.1158/1538-7445.AM2015-2353
Abstract 2359: Adrenergic regulation of MCP-1 leads to enhanced macrophage recruitment and ovarian carcinoma growth
Authors: Armaiz-Pena Guillermo N. , Gonzalez-Villasana Vianey , Nagaraja Archana S. , Rodriguez-Aguayo Cristian , Dorniak Piotr , Previs Rebecca , Sadaoui Nouara , Stone Rebecca , Matsuo Koji , Dalton Heather J. , Lutgendorf Susan K. , Sood Anil K. , Lopez-Berestein Gabriel 
Published: August 2015

Abstract
Increased adrenergic signaling is known to promote tumor progression, but the underlying mechanisms remain poorly understood. Tumor associated macrophages (TAMs) are key components of the tumor microenvironment that contribute to pro-inflammatory processes and tumor growth. Recently, it has been reported that patients with higher levels of adrenergic signaling have higher counts of MMP-9-producing TAMs. Here, we examined factors responsible for stress-mediated effects on monocyte/macrophage recruitment into the tumor microenvironment and the resultant effects on tumor growth. Conditioned media from norepinephrine- or epinephrine-treated ADRB positive SKOV3ip1 ovarian cancer cells had significantly increased levels of pro-inflammatory cytokines, such as MCP1, fractalkine, IL6, IL8 and VEGF. MCP1, a key modulator of monocyte/macrophage recruitment, gene and protein levels were significantly increased in vitro after catecholamine exposure, which was mediated by cAMP and PKA, while this effect was abrogated by a beta-blocker. SKOV3ip1 tumor samples from mice, subjected to daily restraint stress, had elevated MCP1 gene and protein expression levels, increased CD14+ cells, and increased infiltration of CD68+ cells. Both, propranolol, a non-specific beta-blocker, and hMCP1 siRNA packaged in DOPC nanoparticles significantly abrogated daily restraint stress-induced tumor growth and inhibited infiltration of CD68+ and F4/80+ cells. Of patient samples evaluated (n = 462), 28% had elevated absolute peripheral blood monocyte (&gt;0.7 × 106/μL) and 43% had high peripheral blood monocytes when measured as the percent of white blood cell content (&gt;8%). Elevated peripheral blood monocytes and increased CD68+ cells (&gt;15/hpf) in samples from ovarian cancer patients were significantly associated with advanced disease and worse overall survival. In summary, increased adrenergic signaling is associated with enhanced macrophage infiltration mediated by tumor cell-derived MCP1 production.
Citation Format: Guillermo N. Armaiz-Pena, Vianey Gonzalez-Villasana, Archana S. Nagaraja, Cristian Rodriguez-Aguayo, Piotr Dorniak, Rebecca Previs, Nouara Sadaoui, Rebecca Stone, Koji Matsuo, Heather J. Dalton, Susan K. Lutgendorf, Anil K. Sood, Gabriel Lopez-Berestein. Adrenergic regulation of MCP-1 leads to enhanced macrophage recruitment and ovarian carcinoma growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2359. doi:10.1158/1538-7445.AM2015-2359
Abstract 2363: Loss of Sparc in p53-null astrocytes alters collagen deposition and promotes macrophage activation and tumor phagocytosis
Authors: Thomas Stacey L. , Schultz Chad R. , Mouzon Ezekiell , Golembieski William A. , Lemke Nancy , Poisson Laila M. , Gutierrez Jorge A. , Cottingham Sandra , Rempel Sandra A. 
Published: August 2015

Abstract
Both the induction of SPARC expression and the loss of the p53 tumor suppressor gene are changes that occur early in glioma development. Therefore, the upregulation of SPARC may cooperate with the loss of p53 to enhance cell survival and inhibit apoptosis during glioma formation. This study determined whether the loss of Sparc in astrocytes that are null for p53 (p53-null/Sparc-null) would result in reduced cell survival and tumor formation and increased tumor immunogenicity in an in vivo xenograft brain tumor model. In vitro, the loss of Sparc in p53-null astrocytes resulted in an increase in cell proliferation (15-33%, p&lt;0.01); however, there was an inhibition of growth in soft agar. Intracranial xenografts of p53-null/Sparc-wt and p53-null/Sparc-null astrocytes were assessed for tumor size, proliferation rate, and SPARC expression. At 7 days post-implantation, Sparc-null astrocytes produced significantly smaller tumors (Wilcoxon rank-sum test p = 0.0091, median = 0.709mm2 for Sparc-wt and 0.240mm2 for Sparc-null) with a significantly lower MIB-1 proliferation index (Wilcoxon rank-sum test p = 0.0345, median = 8.6% for Sparc-wt and 0.4% for Sparc-null). By CD68 and periodic acid Schiff +/- diastase staining of xenograft tumors, it was found that Sparc-null tumors had a massive infiltration of microglia/macrophages with a phagocytic appearance compared to the activated, but non-phagocytic, microglia/macrophages present within the Sparc-wt tumors. The loss of Sparc in astrocytes and the resulting increase in microglia/macrophage activation lead to an alteration in the tumor microenvironment with increased collagen deposition and altered collagen structure at both 7 and 50 days post-implantation as assessed by picrosirius red and polarized light microscopy. Sparc-null tumors had increased collagen deposition with a long fiber structure compared to the small bundles of collagen present in Sparc-wt tumors. Our results indicate that the loss of p53 by deletion/mutation in the early stages of glioma formation may cooperate with the induction of SPARC to potentiate cancer cell survival and escape from immune surveillance.
Citation Format: Stacey L. Thomas, Chad R. Schultz, Ezekiell Mouzon, William A. Golembieski, Nancy Lemke, Laila M. Poisson, Jorge A. Gutierrez, Sandra Cottingham, Sandra A. Rempel. Loss of Sparc in p53-null astrocytes alters collagen deposition and promotes macrophage activation and tumor phagocytosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2363. doi:10.1158/1538-7445.AM2015-2363
Abstract 238: Citrullination of miRNA regulators by PADs: A potential mechanism for the promotion of colitis and colitis-associated colorectal cancer
Authors: Witalison Erin E. , Cui Xiangli , Causey Corey P. , Thompson Paul R. , Hofseth Lorne J. 
Published: August 2015

Abstract
Ulcerative Colitis (UC) is a chronic, relapsing inflammatory bowel disease that affects millions of people worldwide. As a result of DNA damage caused by the chronic inflammatory state of UC, people suffering from UC are at a higher risk of developing colorectal cancer (CRC). Although the cause of UC is still unknown, the protein arginine deiminase (PAD) family of enzymes has been found to be a key component in many human inflammatory diseases and cancer, including UC and CRC. PADs are calcium-dependent enzymes that post-translationally convert positively charged peptidyl-Arginine to neutral peptidyl-Citrulline through a process called ‘citrullination’. In hopes of treating UC and preventing CRC, we developed Chlor-amidine (Cl-amidine), a novel small molecule inhibitor of PADs. Previous results from our group have shown that miR-16, which is often downregulated in cancers, had increased expression levels in mice treated with Cl-amidine. MiR-16 targets (i.e. Cyclin D1 and E1) and colon carcinogenesis were also suppressed in mice treated with Cl-amidine. Our goal is to determine the mechanism(s) by which Cl-amidine targets miR-16 and other tumor suppressor miRNAs. One hypothesis is that Cl-amidine is preventing the citrullination of DNA methyltransferases (DNMTs). Citrullinated DNMTs show hyperactivity, resulting in hypermethylation and subsequent silencing of miRNAs. Evidence suggests that PADs can citrullinate DNMT3A, resulting in ‘methylation-mediated gene silencing’. We predict that this silencing negatively regulates tumor suppressor miRNAs and Cl-amidine treatment will restore these miRNA levels. Initial results suggest citrullination of DNMT3A in our in vitro colon cancer cell line model. Experiments are ongoing to confirm the ability of Cl-amidine to prevent citrullination-induced activation of upstream miRNA regulators. Results from our study will elaborate on the mechanism of action of Cl-amidine and provide further insight into using Cl-amidine as an anti-cancer therapy.
Citation Format: Erin E. Witalison, Xiangli Cui, Corey P. Causey, Paul R. Thompson, Lorne J. Hofseth. Citrullination of miRNA regulators by PADs: A potential mechanism for the promotion of colitis and colitis-associated colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 238. doi:10.1158/1538-7445.AM2015-238