bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1116: Neurotensin high affinity receptor 1 is a functional biomarker for lung and breast cancer progression
Authors: Doan Van Kien , Zaïd Sadi Menad Ahmed , Younes Mohamad , Dupouy Sandra , Mourra Najat , De Wever Olivier , Alifano Marco , Gompel Anne , Forgez Patricia 
Published: June 2012

Abstract
Neurotensin (NTS) is a 13 amino acid peptide, exerting hormonal and neurocrine regulation within the gastrointestinal tract to globally facilitate nutriment digestion. NTS action is mainly mediated by the high affinity G protein coupled neurotensin receptor, NTSR1. Abnormal expression of NTSR1 occurs during the early stages of cell transformation in relation with the deregulation of the Wnt/beta catenin pathway. Consequently, the oncogenic effects previously described for NTS in different types of cancer cells could presumably contribute to tumor progression. In order to establish this concept, we observed that NTS and NTSR1 were concomitantly expressed in human breast ductal carcinomas and lung adenocarcinomas. NTSR1 was found to be an independent prognostic marker in lung and breast clinical studies. Cellular models were developed in which NTS or NTSR1 was either abolished by sh-RNA or over-expressed. In experimental tumors using both models, active NTS autocrine or paracrine regulation caused the enhancement of tumor size and metastasis emergence when compared to those having poor expression of NTS or NTSR1. In vitro studies, confirmed that NTS enhancement of cellular growth, adherence, motility and invasion occurred through the activation of PKC, ERK 1/2 pathways, and by interfering with the network of epidermal growth factor tyrosine receptors, as EGFR, HER2, and HER3 expression and activation were increased. The use of NTSR1 specific antagonist and neutralizing NTS antibody confirmed the contribution of NTS in cellular oncogenic effect implicated in each step of cancer progression. Additionally, the activation of metalloprotease induced by NTS contributed to the release to EGF-like ligand. Our results suggest that the activation of the NTSR1 pathway causes an acceleration of the oncogenesis process within preexisting tumors by the up regulation of the three majors epidermal growth factor tyrosine receptors and the formation of autocrine stimulation of the HERs system.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1116. doi:10.1158/1538-7445.AM2011-1116
Abstract 1123: Transforming growth factor α signaling in pancreatic acinar-to-ductal metaplasia
Authors: Liou Geou-Yarh , Storz Peter 
Published: June 2012

Abstract
Pancreatic cancer is the most lethal type of cancer due to its high proliferation, metastasis and resistance to chemotherapy. In pancreatic cancer, pancreatic ductal adenocacinoma (PDAC) is the most common form. Current opinion is that PDAC originates from acinar or centroacinar cells though a process called “acinar-to-ductal metaplasia” (ADM). During ADM, acinar cells undergo a transformation to ductal PanIN (pancreatic intraepithelial neoplasia) cells, which is believed as the first step in PDAC formation. Transforming growth factor α (TGFα) is produced by pancreatic cancer cells and promotes tumor growth. In an ex vivo explant culture system, TGFα transforms murine pancreatic acinar cells into ductal cells. Here we describe a cell signaling pathway that TGFα utilizes to induce acinar-to-ductal transformation. We show that K-ras is downstream of TGFα and is sufficient to drive ADM. We further show the mechanisms that K-ras uses to induce cell structural rearrangement of acinar cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1123. doi:10.1158/1538-7445.AM2011-1123
Abstract 1131: Differential induction of c-fms promoters by TGFβ in cervical cancer and macrophage cell lines
Authors: Kirma Nameer B. , Ganapathy Manonmani , Krishnegowda Naveen K. , De La Garza Elizabeth M. , Tekmal Rajeshwar R. 
Published: June 2012

Abstract
Cervical cancer is the second most common gynecological malignancy in the world. An expected 12,200 total new diagnosed cases were estimated by the American Cancer Society for 2010 (Cancer Facts and Figures, 2010). Human papillomavirus infection, a major cause for cervical cancer, results in a persistent and pathological inflammatory response, contributing to establishment of disease and malignant progression. Our previous studies have shown that inflammatory factors, like Cox2, tumor associated macrophages, and cytokines such as macrophage colony-stimulating factor (CSF-1) and transforming growth factor beta (TGFβ) are elevated in cervical carcinomas. The receptors for CSF-1 (encoded by the c-fms oncogene) and TGFβ were also elevated in cervical carcinomas compared to normal cervical tissue. Both CSF-1 and c-fms have been implicated in aggressive gynecological malignancies, including cervical cancer. CSF-1/c-fms signaling is involved in proliferation, differentiation and recruitment of macrophages as well as cancer cell growth. We have previously demonstrated that TGFβ induced the expression of c-fms mRNA in cervical cancer cell lines and macrophage cell line THP-1. Using flow cytometry in this study, we have confirmed induction of c-fms protein at the cell surface due to TGFβ treatment, suggesting that TGFβ may enhance CSF-1 signaling by inducing cell surface expression of its receptor. Our goal was to examine the mechanisms underlying the regulation of c-fms in macrophages, relevant leukocytes associated with inflammation and pro-malignant growth within the tumor microenvironment. Two promoters for the c-fms gene exist, promoter one driving expression in trophoblasts (trophoblast specific promoter) and promoter two driving expression in macrophages (macrophage specific promoter). Consistent with our previous findings, TGFβ induced c-fms expression via MAPK p38 mainly at the trophoblast specific promoter in cervical cancer cells, as shown by the use of the p38 inhibitor SB203580. Our data also suggest that Casein kinase 1 mediates c-fms expression via this promoter in cervical cancer cells. In the macrophage cell line THP-1, p38 mediated the expression of c-fms via both promoters, as demonstrated by using exon specific RT-PCR primer sets. The c-fms mRNA induced at the macrophage specific promoter is the major c-fms transcript in THP-1 cells and is likely to mainly contribute to c-fms expression in these cells. Understanding the regulation of c-fms in macrophages and cervical cancer cells may pave the way to targeting c-fms expression to interrupt aberrant CSF-1 signaling in cervical cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1131. doi:10.1158/1538-7445.AM2011-1131
Abstract 1133: LRIG2 promotes PDGF induced experimental glioma
Authors: Holmlund Camilla , Karlsson Terese , Borota Olivera Casar , Miller Jamie , Baofeng Wang , Zahed Farrah , Sweeney Colleen , Henriksson Roger , Hedman Håkan 
Published: June 2012

Abstract
Leucine-rich and immunoglobulin-like domains protein 2 (LRIG2) is a transmembrane protein, whose expression is associated with poor survival of oligodendroglioma patients. This is in contrast with findings for the homologous protein LRIG1, a negative regulator of growth factor signaling, whose expression is associated with good survival in several different malignancies. Here, we address the role of LRIG2 in an experimental glioma model and its possible regulation of growth factor receptors belonging to the epidermal growth factor receptor (EGFR) and platelet-derived growth factor (PDGF) receptor (PDGFR) families. Gliomas were induced in Ntv-a mice by intracranial injection of PDGFB-expressing RCAS viruses. All injected Lrig2-wild-type mice developed oligodendroglioma-like brain tumors of grade II/III (82%) or glioblastoma-like tumors of grade IV (18%), whereas Lrig2-deficient mice only developed grade II/III tumors (77%) or no detectable tumors (23%). A role for Lrig2 in PDGFR signaling was shown in mouse embryonic fibroblast (MEF) cell lines. MEF cells from Lrig2-deficient mice were less sensitive to PDGFB-induced cell proliferation than MEF cells from wild-type mice. In transfected HEK-293T cells, LRIG2 and LRIG3, in contrast to LRIG1, did not negatively regulate the protein levels of EGFR, ErbB2, PDGFRα, or PDGFRβ. Intriguingly, LRIG2 and LRIG3 instead up-regulated the protein levels of PDGFRα. In summary, we show that LRIG2 promoted the genesis and/or progression of PDGF-induced oligodendroglioma and positively regulated PDGFRα protein levels. This further supports the notion that LRIG proteins play important roles in cancer biology and suggests that LRIG1 and LRIG2/LRIG3 may have opposing functions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1133. doi:10.1158/1538-7445.AM2011-1133
Abstract 1134: ADAM17 promotes glioma cell progression through EGFR-PI3K-AKT activation
Authors: Zheng Xuguang , Jiang Feng , Katakowski Mark , Lu Yong , Chopp Michael 
Published: June 2012

Abstract
Background & Objective: A disintegrin and metalloproteinase-17 (ADAM17) is involved in proteolytic ectodomain shedding of several membrane-bound growth factors and cytokines. The expression and activity of ADAM17 increase under some pathological conditions such as stroke and cancer. ADAM17 promotes neural progenitor cell migration and contributes to stroke-induced neurogenesis after stroke and breast cancer growth and invasion. In the present study, we sought to elucidate whether ADAM17 contributes to glioma progression and its mechanisms.
Experimental Approaches: We examined the role of ADAM17 in the proliferation, invasion, and tube formation of human glioma cells (U87) in vitro and tumor growth in vivo. Stable transfection of the U87 cell line with either a plasmid for over-expression of human ADAM17, or a siRNA to ADAM17 was employed in this study to establish high or low ADAM17 expression in glioma cells, respectively. For study of mechanism, the ADAM17 inhibitor TAPI-2 and the PI3K-AKT inhibitor LY294002 were used to counteract high ADAM17 expression or the activated PI3K-AKT pathway. Proliferation of glioma cells were tested by MTT Cell Proliferation Assay, Bromodeoxyuridine incorporation assay, growth curve, and sulforhodamine B assay. Matrigel invasion assays were used to assess the ability of U87 cells to penetrate the Extra Cellular Matrix. A Matrigel tube formation assay was performed to test capillary tube formation ability. EGFR-PI3K-Akt pathway activation in U87 cells under different ADAM17 expression levels were tested by Western blot
Results: Our data show that ADAM17 promotes the U87 malignant phenotype by increased proliferation, invasion, angiogenesis and in vivo tumor growth. TGF-α, VEGF secretion and VEGF expression was increasing by ADAM17 and counteracted by ADAM17 siRNA, TAPI-2, and LY294002 in U87 cells. ADAM17 activated, whereas ADAM17 siRNA, TAPI-2, and LY294002 deactivated the EGFR-PI3K-AKT signal pathway, which correlated with U87 cell malignant phenotype changes.
Conclusion: This study suggests ADAM17 contributes to glioma progression through activation of the EGFR-PI3K-AKT signal pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1134. doi:10.1158/1538-7445.AM2011-1134
Abstract 1135: PPAPDC1B isoform 2, a new candidate oncogene within the 8p11-12 amplicon induces a proliferative advantage in breast cancer
Authors: Liu Gang , Yang Zeng-Quan , Ethier Stephen P. 
Published: June 2012

Abstract
The 8p11-12 genomic region is amplified in about 10-15% of human breast cancer and may be associated with poor prognosis. Earlier, we used genomic analysis of copy number and gene expression to perform a detailed analysis of the 8p11-12 amplicon for identifying candidate oncogenes in breast cancer. We identified phosphatidic acid phosphatase type 2 domain containing 1B (PPAPDC1B) as one of the candidate oncogenes based on statistical analysis of copy number increase and over expression.
Recently, fine-mapping of this locus, and the updated human genomic database has shown there may be more than 3 splicing variants of PPAPDC1B. We measured the expression status of all 3 individual PPAPDC1B isoforms in breast cancer cell lines by real-time quantitative RT-PCR and western blot. Interestingly, the short splicing variant /isoform2 is the dominant over-expressed form in SUM44 and SUM52 breast cancer cell lines that harbor the 8p11-12 amplicon.
The PPAPDC1B gene encodes a novel type of transmembrane phosphatidate phosphatase with an acid-PPc domain with broad lipid phosphate substrate specificity. This suggests that PPAPDC1B may play a role in cell signaling and lipid metabolism. The PPAPDC1B isoform 2 is predicted to have an inactive acid-PPc domain due to truncation of mRNA.
To address the question of whether PPAPDC1B possesses transforming properties, and to functionally characterize the different isoforms, we established lentiviral expression constructs of full-length PPAPDC1B as well as the short isoform. MCF10A cells were infected with equalized viral titer of lentiviral vectors and assayed for alterations in growth rates, colony formation and growth factor-independent proliferation. Cell proliferation assays indicated that over expression of PPAPDC1B isoform 2 enhanced cell proliferation more dramatically than full-length PPAPDC1B. Furthermore, colony formation assay showed that MCF10A cells over expressing PPAPDC1B isoform 2 formed large highly proliferative colonies compared with control cells. All of the isoforms of PPAPDC1B could induce insulin-like growth factor-independence in MCF-10A cells, but not independence of EGF. Thus, our data suggest that PPAPDC1B isoform 2 is a candidate oncogene from the 8p11 region that can induce a proliferative advantage in subset of breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1135. doi:10.1158/1538-7445.AM2011-1135
Abstract 1138: Breast cancer-derived mutations abolish Na+/H+ exchanger regulatory factor 1 inhibition of platelet-derived growth factor signaling
Authors: Cheng Shan , Li Yang , Feng Duiping , Yang Ying , Yang Longyan , Zhou Yunying , Xiong Ying , Sun Licui , Jiang Wenguo , He Junqi 
Published: June 2012

Abstract
Na+/H+ exchanger regulatory factor 1 (NHERF1, also known as EBP50) is a scaffold protein known to interact with a number of target proteins, including cancer-related proteins such as phosphatase and tensin homolog deleted on chromosome 10 (PTEN), neurofibromatosis 2, spleen tyrosine kinase, platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and β-catenin. This suggests a possible function of NHERF1 as a negative tumor regulator. Several lines of evidence have suggested that NHERF1 is involved in carcinogenesis. However, the mechanisms by which NHERF1 plays a role in breast cancer have not yet been clearly defined. Three point mutations in nherf1 (K172N, R180W, and D301V) were recently identified in breast cancer cell lines or primary breast tumors. To gain more insight into the functional properties of NHERF1, wild-type (wt) and cancer-derived nherf1 mutations were introduced into a human non-small cell lung cancer cell line, SKMES-1. NHERF1-wt overexpression suppressed the malignant phenotypic characteristics of SKMES-1 cells, including cell proliferation, migration, and invasion. Three nherf1 mutations led to complete or partial loss of NHERF1 functions by affecting the formation of PTEN/NHERF1/PDGFRβ complex, attenuating NHERF1-mediated inhibition of PDGF-induced AKT and ERK activation, and abolishing the tumor suppressor effects mediated by NHERF1-wt. These results provide the first evidence of the functional consequences and signaling properties of breast cancer-derived nherf1 mutations, and suggest that these nherf1 mutations might play a causal role in tumor development and progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1138. doi:10.1158/1538-7445.AM2011-1138
Abstract 1140: C/ebp beta represses Arf induction by tgf-beta2
Authors: Zheng Yanbin , Chu Patricia , Skapek Stephen X. 
Published: June 2012

Abstract
Arf is a bona fide tumor suppressor that regulates cell proliferation through p53-dependent and -independent mechanisms. Recent studies show that Arf also has physiological functions in addition to tumor repression. Our group reported that the Arf promoter is strictly controlled during development and Tgf-beta2 is required for Arf promoter activation at several sites in the developing mouse. In a cell culture-based model, Arf induction by Tgf-beta depends on Smads 2/3 and p38 MAPK. But the transcription factors influenced by these signaling pathways are not yet clear. Using a candidate-gene approach, we have identified C/ebp beta as a negative Arf regulator, modified by Tgf-beta 2. The ability of Tgf-beta2 to increase p19Arf expression in wild-type mouse embryo fibroblasts (MEFs) and Arf promoter activity in Arf lacZ/lacZ MEFs correlated with repression of C/ebp beta. Pre-incubation of MEFs with SB431542, a Tgf-beta type I receptor inhibitor, blocked C/ebp beta repression and Arf induction. Retrovirus-mediated ectopic C/ebp beta blocked Arf induction by Tgf-beta2 in Arf lacZ/lacZ and wild-type MEFs. Similarly, RNAi-driven knock-down of C/ebp beta augmented Arf promoter activation by Tgf-beta2. Chromatin immunoprecipitation revealed that C/ebp beta binding to the Arf promoter after Arf promoter is initially activated by Tgf-beta2, and the binding dropped at 48 hours, when Arf expression was significantly induced. In summary, our results indicate that C/ebp beta is modified by and contributes to Arf regulation by Tgf-beta2. In contrast, the p38 MAPK inhibitor SB203580 did not influence C/ebp beta levels but still interfered with Arf induction. We are currently exploring the importance of C/ebp beta in Arf regulation by other signals and in other cell types, and investigating its importance in vivo in the developing mouse.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1140. doi:10.1158/1538-7445.AM2011-1140
Abstract 1141: p19Arf represses Pdgfrβ-driven pericyte proliferation in vivo
Authors: Widau Ryan C. , Zelivianskaia Anna , Skapek Stephen X. 
Published: June 2012

Abstract
p19Arf, encoded by the mouse Arf gene, is a critical tumor suppressor with roles regulating cell cycle arrest in embryo development and suppressing oncogenesis. Previous studies established that p19Arf controls pericyte-like cells in the hyaloid vascular system (HVS) in the primary vitreous of the developing eye. Arf-deficient mice have hyperplasic expansion of pericytes in the vitreous, a developmental defect driven by excessive Pdgfrβ signaling. We have used complementary studies of cultured cells and mouse embryos to further explore the functional interactions between p19Arf and Pdgfrβ. To address whether Pdgfrβ acts as a mitogenic or a survival factor in the Arf-deficient mouse eye, we quantified cell proliferation and apoptosis at 13.5 days post coitum (dpc) in ArfGFP/GFP embryos that had or lacked Pdgfrβ. Cell proliferation, measured by BrdU incorporation, was increased by two-fold in the vitreous in the presence of Pdgfrβ. The presence or absence of Pdgfrβ did not change the small number of apoptotic cells in the vitreous of the eye. To explore mechanisms by which Arf expression impeded Pdgfrβ signaling, we used the 10T1/2 pericyte-like cell culture model to show that retroviral expression of p19Arf significantly repressed Pdgfrβ protein. Conversely, shRNA-mediated knockdown of p19Arf enhanced Pdgfrβ in serial-passaged mouse embryo fibroblasts (MEFs). In vivo measurements of Arf mRNA extracted from vitreous samples isolated by laser capture microdissection (LCM) from mouse embryos at 13.5 dpc demonstrated increased Pdgfrβ mRNA in Arf-deficient embryos as compared to wild-type. To confirm that p19Arf repressed Pdgfrβ transcription, we demonstrated that both mature and primary Pdgfrβ RNA transcripts were repressed in 10T1/2 cells. Co-transfection of p19Arf with a luciferase reporter plasmid driven by the Pdgfrβ promoter demonstrated that a 1.6kb segment of DNA conferred Arf-dependent regulation. Chromatin immunoprecipitation (ChIP) showed that p19Arf reduced RNA Pol II binding to the proximal Pdgfrβ promoter. Overall our data show that, in the absence of Arf, Pdgfrβ drives excess proliferation in cells that would normally express Arf in the developing eye. p19Arf acts to repress Pdgfrβ transcription, in part by blocking RNA Pol II binding to the proximal Pdgfrβ promoter. We are currently using additional ChIP assays to identify how the presence or absence of Arf influences the binding of several transcription factors known or suspected of regulating Pdgfrβ expression, and we are exploring the importance of the Arf-Pdgfrβ pathway deregulation in cancer models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1141. doi:10.1158/1538-7445.AM2011-1141