bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 89: Osteopontin-c and osteopontin-b splicing isoforms activate prostate cancer progression features
Authors: Tilli Tatiana M. , Mello Kivvi Duarte De , Accioly Maria Theresa , Faria Paulo Antonio , Gimba Etel Rp 
Published: August 2012

Abstract
Osteopontin (OPN) is one of the proteins overexpressed in prostate cancer (PCa) and is involved in tumorigenesis and metastasis. Alternative splicing of the OPN gene generates three protein splicing isoforms (OPN-SI), designated as OPNa, OPNb and OPNc, which have demonstrated specific roles in different tumor models. However, the roles of each of these isoforms have not been previously characterized in PCa. Our previous study reported that OPN-SI were overexpressed in PCa tissues, strongly associated with PCa occurrence and with tumor cell differentiation. Besides, OPNc was the most upregulated variant. We have also demonstrated that OPNc splicing isoform can contribute for PCa diagnosis and prognosis. Based on these results, the present study aimed to evaluate the putative roles of OPN-SI in PCa biology using in vitro and in vivo functional assays. PC-3 was stably transfected with expression vectors containing OPNa, OPNb and OPNc, as well as empty vector control. PC-3 cells overexpressing each construct were analyzed for in vivo tumor growth and in relation to different aspects mimicking tumor progression, such as cell proliferation, migration, invasion and soft agar colony formation. OPNc and OPNb overexpressing cells significantly activated enhanced xenograft tumor growth and PC-3 proliferation, migration, invasion, and soft agar colony formation, as well as the expression of several cancer related genes. Additionally, we have also shown that some of the OPNc and OPNb-dependent pro-tumorigenic roles are mediated by PI3K/Akt signaling pathway. Inhibition of this pathway by using LY294002 specifically inhibited tumor progression features evoked by OPNc and OPNb overexpression. According to our data, OPNc and OPNb roles on favoring different aspects of PCa progression suggest that these isoforms contribute to the physiopathology of prostate cancer progression and tumorigenesis. Altogether, the data open possibilities of new therapeutic approaches for prostate cancer that selectively downregulate OPNc and OPNb, altering its properties favoring prostate tumor progression.
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 89. doi:1538-7445.AM2012-89
Abstract 890: Interleukin 11: A novel therapeutic target in IL-11Rα expressing sarcomas
Authors: Mancini Monica , Fer Nicole , Perez Victor , Teicher Beverly , Rapisarda Annamaria 
Published: August 2012

Abstract
Interleukin-11 (IL-11) is a member of the IL-6 cytokine family, which mediate signaling via a common signal-transducing gp130 component and a cytokine-specific subunit (IL-11Rβ). Upon binding to the IL-11Rα, a signaling cascade activates several pathways, including JAK kinases, STAT transcription factors (STAT3 and STAT1), MAPK, src-family kinases and PI3K. IL-11 has been implicated in experimental models of chronic inflammation and associated tumorigenesis. Oncomine analysis of publicly available microarray data from patient biopsies showed that IL-11Rα mRNA is expressed in several sarcomas and not in the matched normal tissue counterparts. Surgical resection and cytotoxic chemotherapy are the standard of care for most locally advanced and metastatic sarcomas, the identification of new markers and the development of targeted therapies are needed to increase long-term survival of these patients. Previous studies demonstrated IL-11Rα is expressed in human primary and metastatic osteosarcomas but not in normal bone, suggesting that IL-11Rα is a potential target for sarcoma therapy. We analyzed a panel of 45 human sarcoma cell lines for the expression of IL-11Rα and IL-11. Interestingly, IL-11Rα protein is expressed at high levels in the majority of cell lines examined. In addition, we found that nearly all osteosarcoma, rhabdomyosarcoma, fibrosarcoma and Ewing sarcoma cell lines express high constitutive levels of IL-11 mRNA, indicating that IL-11 autocrine signaling may play a role in these tumor types. Two lentiviral vectors, used for the delivery of shRNA targeting IL-11 in HT-1080, produced an 80-90% decrease in IL-11 mRNA expression when compared to the luciferase control shRNA; however, IL-11 mRNA levels remained significantly high in HT1080 knock-down cells when compared to the constitutive levels of non sarcoma cancer types. Decreasing levels of IL-11 in HT-1080 resulted in a 50% inhibition of cell growth, demonstrating that IL-11 has a role in cell proliferation. Further experiments aimed to assess the expression of IL-11 and IL-11Rβ in xenografts and to explore the role of IL-11 in sarcoma pathogenesis, propagation and response to therapy are ongoing. These data suggest that neutralization of IL-11 or IL-11Rα may be a potential target for the development of cancer therapeutics for sarcomas. Funded by NCI Contract No. HHSN261200800001E.
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 890. doi:1538-7445.AM2012-890
Abstract 891: The chemokine receptor CXCR7 transduces its signal through mTOR: the role of everolimus
Authors: Ieranò Caterina , Caraglia Michele , Bernile Francesca , Antignani Elena , Napolitano Maria , Riccio Anna , Portella Luigi , Penfold Mark E. , Scala Stefania 
Published: August 2012

Abstract
Everolimus (RAD001, Afinitor) is an mTOR inhibitor FDA-approved for the treatment of patients with advanced clear cell renal cancer (RCC) after failure of treatment with sunitinib or sorafenib, or both drugs. It targets the mammalian target of rapamycin (mTOR) complex inhibiting a serine/threonine kinase regulating PI3K/AKT signaling pathway. Previous evidences demonstrated that the activation of the chemokine receptor CXCR4 involved the mTOR pathway and that CXCR4 was overexpressed in RCC. Recently, also the deorphanized chemokine receptor CXCR7 was described in RCC and defined as an independent prognostic factor. Nevertheless, little is known about the CXCR4-CXCL12-CXCR7-induced signalling. Aim of the study was to investigate if the CXCL12/CXCR4/CXCR7 complex could transduce the signal through mTOR identifying new therapeutic targets. In human renal cancer cells (RXF393, A498) treatment with CXCL12, the CXCR4 and CXCR7 ligand, induced mTOR pathway, as demonstrated through p70S6K and eukaryotic initiation factor 4E binding protein 1 (4E-BP1) induction; the CXCL12 induction is specifically inhibited by AMD3100, a CXCR4 inhibitor, and CCX733, a CXCR7 inhibitor. The inhibition of the mTOR pathway through RAD001 treatment, inhibited CXCL12-induced pERK1/2 and chemotaxis while AMD3100 and CCX733 were not able to inhibit pERK and migration in RXF393 and A498 cell lines suggesting a role of mTOR downstream of CXCR4 and CXCR7. To analyze the CXCR7 transduction pathway the function of p38 kinase, a CXCR7 target, was evaluated. CXCL12 dramatically induced p38 MAPK in cell lines RXF393 and A498 and the p38MAPK induction was specifically inhibited by CCX733, a CXCR7 inhibitory molecule but, interestingly, p38 MAPK is dramatically induced by AMD3100, a CXCR4 antagonist. To further confirm the p38 role downstream of CXCR7, CXCL12 was unable to induce p38 phosphorylation in RXF393 cells CXCR7 siRNA transduced while inhibited by the specific CXCR7 inhibitor CCX733 in RXF393 cells. The treatment with RAD001 in human renal cancer cells inhibited the p38 induction CXCL12-mediated. This is the first evidence demonstrating that p38 is a CXCR7 target in human renal cancer cells and that AMD3100, a specific CXCR4 antagonist, potentiate the CXCL12 activity on CXCR7. Thus the combined inhibition of the three members CXCR4/CXCR7/mTOR is a valid therapeutic strategy to treat RCC inhibiting two cross talking pathways CXCR4-CXCR7 signaling to mTOR.
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 891. doi:1538-7445.AM2012-891
Abstract 893: Anticancer effect and mechanism of prostaglandin E2 receptor EP4 antagonist
Authors: Nonomura Kazuhiko , Miyama Katsuyoshi , Kanazawa Kiyoshi , Okumura Takako , Okumura Yoshiyuki , Oshima Masanobu , Takahashi Satoru , Take Yukinori 
Published: August 2012

Abstract
Molecular studies reveal that over-expression of cyclooxygenase-2 (COX-2) is a prominent feature of premalignant and malignant neoplasms. The increased COX-2-mediated prostaglandin-E2 (PGE2) production has a strong association with various cancers, by promoting cell survival, cell growth, migration, invasion, angiogenesis, and immunotolerance. The use of COX-2 selective inhibitors has shown promise in the prevention and treatment of various cancers, however, the chronic use of COX-2 inhibitors is associated with an increased risk of cardiovascular adverse effects. Therefore, there is an urgent need to further understanding of the downstream mechanisms by which PGE2 promotes tumorigenesis and more effective strategies for the treatment of cancer. There are four PGE2 receptors, i.e., EP1, EP2, EP3, and EP4, involved in the pharmacology of PGE2. Accumulating evidences suggest that EP4 is the responsible receptor for PGE2 / COX-2-mediated tumorigenic signals in cancer cells and cancer microenvironment. On the other hands, signals from other prostaglandin receptors, e.g. IP and EP1, are reported to inhibit cancer proliferation or metastasis. These evidences suggest that selective blockade of EP4 would offer anti-cancer efficacy and safety advantages over COX-2 inhibition as cancer therapy. We have developed novel plural EP4 antagonists, with pA2 values of nanomolar range which are selective against other EP receptors. EP4 antagonists inhibited the PGE2-dependent productions of key molecules for cancer promotion i.e. VEGF, IL-23, and IL-6 in macrophages, dendritic cells, and PBMC, respectively. At the same time EP4 antagonist reversed PGE2 -induced TNFα and IL-12 suppression in human whole blood. As a consequence, EP4 antagonists exhibited anti-cancer activity in lung, GI, and prostate cancer models. These results indicate that selective EP4 antagonists show anti-cancer effect mediated by multifaceted mechanisms, and represent an attractive medicine for anti-cancer 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 893. doi:1538-7445.AM2012-893
Abstract 900: Caveolin-1 silencing arrests the proliferation of glioblastoma cells by inhibition of STAT3 signalling
Authors: Gasperi-Campani Anna , Pancotti Fabia , Roncuzzi Laura 
Published: August 2012

Abstract
Caveolin-1 is an essential structural constituent of caveolae implicated in mitogenic signalling, oncogenesis, angiogenesis, neurodegenerative diseases and senescence. Its role as a tumor suppressor gene or as a tumor promoter seems to strictly depend on cell type and tumor stage/grade. The high expression of caveolin-1 in some tumors in vivo is associated with increased tumor aggressiveness, metastatic potential and suppression of apoptosis. In the present study we investigated the role of Caveolin-1 in human glioblastoma cells proliferation, in which we found cav-1 expressed at high levels (A172, CRS-A2, LI). Results show that siRNA-mediated down-regulation of Cav-1 caused stable arrest of proliferation in each cell line. A marked reduction of cyclin D1 and of CDK4 expression was evident in the cells transfected with Cav-1 siRNA and consequently of phosphoRb. Furthermore, a significant decrease of the expression of Src and p38α and of their down-stream effector STAT3 was evident. Together, these findings indicate that Cav-1 silencing induces an arrest of tumor cells proliferation in vitro by a new inhibitory pathway in glioblastoma multiforme, the most aggressive of the primary central nervous system tumors, and provide new insights into the molecular mechanisms underlying the pro-survival and tumor-promoting functions of Cav-1. Grants from MIUR (RFO, PRIN), Roberto Pallotti's Legacy for Cancer Research, Cornelia Pallotti's Legacy for Cancer Research, University of Bologna, Italy
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 900. doi:1538-7445.AM2012-900
Abstract 901: Mitotic kinase inhibitors synergize with PI3K and Akt inhibitors in a novel model of anaplastic thyroid carcinomas
Authors: Russo Marika A. , Cristofano Antonio Di 
Published: August 2012

Abstract
Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to any therapeutic approach. We have generated a mouse model in which the simultaneous selective activation of the PI3K pathway and inactivation of p53 in the thyroid epithelial cells leads to the development of ATCs. These tumors display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion and distant metastases. Expression profiling of the murine ATCs reveals a significant overlap with genes found deregulated in human ATC, including genes involved in mitosis control, such as Aurora kinase A (AURKA), its co-activator TPX2, and Polo like kinase-1 (PLK1). These proteins are crucial driving forces for normal mitotic spindle formation, centrosome maturation and separation, and their overexpression has been demonstrated in a wide range of tumors. MLN8237 (AURKA inhibitor), TAK960 and GSK461364 (PLK1 inhibitors) are a promising new generation of anti-mitotic agents. We show that these molecules inhibit cell proliferation and induce cell death in mouse ATC-derived cell lines and in the human ATC cell lines CAL62 and C643. A dose-dependent decrease in the degree of chromosome alignment and spindle bipolarity during mitosis is observed after the treatments, together with a change in mitotic index indicated by the decrease of the mitotic marker pHisH3. FACS analysis reveals a G2/M phase arrest followed by apoptosis. Furthermore, small molecule inhibitors of PI3K or AKT potently synergize with these anti-mitotic compounds. Taken together these data suggest that AURKA and PLK1 inhibitors are promising therapeutic agents against undifferentiated thyroid carcinoma cells, and that concurrent inhibition of key driver pathways is a viable option to increase efficacy in this otherwise invariably lethal cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 901. doi:1538-7445.AM2012-901
Abstract 905: Mirk/Dyrk1B mediates cell survival and G0/G1 phase of cell cycle via interacting with MAPK/ERK pathway in human cancer cells
Authors: Gao Jingchun 
Published: August 2012

Abstract
Minibrain-related kinase (Mirk) known as the dual specificity tyrosine-phosphorylation-regulated kinase (Dyrk) 1B is a serine/threonine kinase. Our recent studies have also demonstrated that knockdown of Mirk by small interfering RNA (siRNA) resulted in reduction of viable cells and cell apoptosis in both ovarian cancer and non-small cell lung cancer (NSCLC) cell lines. Furthermore, it has been reported that Mirk/Dyrk1B can be negatively regulated by mitogenic-activated protein (MAP) / extracellular signal-regulated kinase (ERK) kinase signaling. In this study, we demonstrated the widely overexpressed Mirk protein in variant cell lines of both human ovarian cancer and NSCLC was correlated with the levels of activated ERK examined by western blot analysis. Interestingly, knockdown of Mirk by siRNA in those ovarian cancer cells (OVCAR3, OVCAR10, OVCAR1063, MDAH2774), and NSCLC cells (H292, H441, H1299, PC9) led to increased cell number and cells from G0/G1 into S phase of cell cycle accompanied by up-regulated activation of ERK and its upstream signals, increased cyclin D1, reduced p27, and no evidence of cleaved PARP which are not consistent with our previous findings in the other cell lines. We hypothesized that the increased activation of ERK after Mirk siRNA treatment may block the anti-proliferative effects of Mirk siRNA in some lines or may counterbalance cell loss through apoptosis in human cancer. To examine this further in both OVCAR3 and H292 cells, the increase in cell proliferation induced by Mirk siRNA could be blocked by the MEK inhibitor U0126 in a dose-dependent manner. MEK inhibition abrogated the activation of ERK and subsequent changes in cell cycle proteins (cyclin D1, p27) induced by Mirk knockdown. Combined Mirk siRNA and U0126 induced cell apoptosis in both OVCAR3 and H292 cells. In summary, Mirk may mediate cell survival and G0/G1 phase of cell cycle via interacting with MAPK/ERK pathway in human cancer cells.
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 905. doi:1538-7445.AM2012-905
Abstract 908: Differential role of JAK1/2-STAT3 pathway in drug response and survival of oncogenic Kras colorectal cancer
Authors: Kalimutho Murugan , Allen Wendy , Dunne Philip , Longley Daniel , Johnston Patrick , Schaeybroeck Sandra Van 
Published: August 2012

Abstract
Mutations in the Kras proto-oncogene are found in 40%-45% of colorectal cancer (CRC) patients and confer resistance to EGFR monoclonal antibody (mAb) therapies. The identification of druggable targets uniquely required by KrasMT CRC tumours has the potential to fill a gap in the therapeutic armamentarium of advanced CRC. We carried out microarray profiling of isogenic Kras wild type (WT) and mutant (MT) in vivo CRC models, KrasMT/WT primary colon tumours, pre-treatment metastatic CRC liver biopsies and drug resistant and sensitive CRC cell lines. We have used systems biology approach incorporating pathway analyses of the microarray data followed by siRNA screening to identify novel targets/pathways which are critical for the survival of KrasMT tumours, both basally and following chemotherapy treatment. We found that JAK1/2-STAT3 signaling was essential for the survival of KrasMT CRC cells. Moreover, suppression of JAK1/2-STAT3 activity using RNAi or small molecule inhibitors resulted in more potent increase in apoptosis in KrasMT CRC cells. In addition, treatment with chemotherapy and MEK1/2 inhibition resulted in significant increases in JAK2 and STAT3 activity and this was associated with strong increase in apoptosis when JAK1/2-STAT3 RNAi or small molecule inhibitors were combined with chemotherapy and MEK1/2 inhibition, especially in KrasMT cells. Moreover, we found that these effects were not drug- or cell line-specific. Collectively, using a systems biology approach, we have identified an essential role of JAK1/2-STAT3 signalling in survival of KrasMT CRC models. These findings support the further clinical investigation of JAK/STAT3 inhibitors in conjunction with chemotherapy or MEK inhibition in KrasMT CRC tumours.
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 908. doi:1538-7445.AM2012-908
Abstract 911: Vemurafenib FDG-PET preclinical imaging outcomes across BRAF V600E mutant and resistant tumors
Authors: Baudy Andreas R. , Dogan Taner , Flores Judith E. , Hoeflich Klaus P. , Su Fei , van Bruggen Nicholas , Williams Simon P. 
Published: August 2012

Abstract
The BRAF inhibitor vemurafenib (marketed as zelboraf) has recently been FDA approved for the treatment of metastatic melanoma in patients harboring BRAF V600 mutations. PET imaging will be essential for guiding therapy in terms of gauging initial drug response, monitoring for disease relapse, and evaluating combination treatments in clinical trials. Herein, we assess 18F-FDG uptake across V600E mutant and vemurafenib resistant cells. We find that vemurafenib is equally effective at reducing FDG uptake in cell lines harboring either heterozygous or homozygous V600E BRAF but is ineffective in cells with acquired resistance or BRAF WT cells. Combination treatment with MEK inhibitor GDC-0973 results in a highly significant enhancement of efficacy across all twenty lines tested. We show that FDG uptake is driven by Glut-1, and that the membrane localization of the transporter paralleled with drug efficacy. Interestingly, we find that vemurafenib induced increased FDG uptake in cells harboring RAS mutations, as well as in tumors that have acquired vemurafenib drug resistance. Hexokinase II, CRAF, KSR and p-MEK protein levels in sensitive and drug resistant tumors were all associated with decreased measurements of FDG uptake in vivo. Overall, we have demonstrated that FDG PET imaging should be effective at monitoring the efficacy of vemurafenib in V600E melanoma mutants and that any detected increases in tumor uptake will likely be an indication of drug resistance.
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 911. doi:1538-7445.AM2012-911