bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5604: PD-L1 expression identifies a subpopulation of melanoma cells characterized by enhanced invasiveness and aggressiveness
Authors: Brusa Davide , Massi Daniela , Merelli Barbara , Ciano Michela , Audrito Valentina , Serra Sara , Baroni Gianna , Nassini Romina , Minocci Daiana , Cattaneo Laura , Carobbio Alessandra , Deaglio Silvia , Mandala Mario 
Published: May 2015

Abstract
Introduction: Melanoma is one of the most aggressive malignant tumors, and at the metastatic stage is an incurable disease. PD-L1 is a transmembrane molecule that can be expressed by melanoma cells and that has been speculated to play role in inducing immunosuppression by interacting with the PD-1 receptor on T cells. The clinical and biological significance of PD-L1 expression in metastatic melanoma remains partially elusive.
Methods: PD-L1 expression was analyzed by immunohistochemistry using two different antibodies [anti-human B7-H1 monoclonal antibody (clone 5H1) and a rabbit polyclonal AB58810 antibody (Abcam)]. In primary tumors and paired metastases from 83 consecutive melanoma patients treated at a single institution. Protein expression levels were correlated with PD-L1 mRNA, BRAF mutational status and clinical outcome. PD-L1+ and PD-L1- subsets of the A375 cell line were stabilized in vitro and compared using gene expression profiling and functional assays. Results were confirmed in vivo using xenograft models.
Results: PD-L1 membrane positivity was detected in 24/83 (19%) of patients. By multivariate analysis, PD-L1 membrane expression (95% CI 1.48-4.67, P&lt; 0.001), age &gt;57 years [CI 95% 1.20-3.71, P&lt; 0.009] and stage M1c (95% CI 1.01-3.38, P&lt; 0.045) were independent predictors of poor prognosis. PD-L1 expression defined a subset of the A375 cell line characterized by a specific genetic profile. PD-L1+ A375 cells also showed a highly invasive phenotype and enhanced ability to grow in vivo using immunocompromised mouse models.
Conclusions: PD-L1 may be proposed as a novel prognostic marker in metastatic melanoma. Furthermore, it defines a distinct morpho-phenotypic subset of the disease with a specific genetic signature and a different biological behavior. Future studies will tell whether PD-L1 targeting using blocking monoclonal antibodies alone or in combination with other treatments will provide clinical benefit.
Note: This abstract was not presented at the meeting.
Citation Format: Davide Brusa, Daniela Massi, Barbara Merelli, Michela Ciano, Valentina Audrito, Sara Serra, Gianna Baroni, Romina Nassini, Daiana Minocci, Laura Cattaneo, Alessandra Carobbio, Silvia Deaglio, Mario Mandala. PD-L1 expression identifies a subpopulation of melanoma cells characterized by enhanced invasiveness and aggressiveness. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5604. doi:10.1158/1538-7445.AM2014-5604
Abstract 585: WIF1 re-expression in glioblastoma impairs migration through downregulation of the lncRNA MALAT1
Authors: Vassallo Irene , Hamou Marie-France , Hegi Monika E. 
Published: May 2015

Abstract
Glioblastoma is the most aggressive form of human glioma. Despite progress in brain tumor therapy the prognosis remains dismal with a median survival of 15 months. We have recently shown that WIF1, an inhibitor of the WNT pathway, is downregulated in glioblastoma where it functions as strong tumor suppressor gene. Indeed, WIF1 re-expression impairs cell growth, cell migration, induces a senescence-like phenotype, and inhibits tumorigenicity in several orthotopic xenograft models.
To analyse the molecular mechanisms underlying the tumor suppressive functions of WIF1 we developed a TET-on inducible system. Gene expression profiling following WIF1 induction revealed several interesting candidate genes validated in additional cell lines. The gene with strongest downregulation in WIF1-induced cells was MALAT1. MALAT1 is a long non-coding RNA that has been associated with tumor aggressiveness and invasion. Hence, MALAT1 is a plausible candidate, and its downregulation may contribute to the attenuation of malignancy seen in WIF1 expressing cells. Preliminary results show that the expression of a MALAT1 specific short-hairpin drastically reduces the infiltrative capability of glioblastoma cells. Analysis of gene xpression profiles revealed that MALAT1 is overexpressed in glioblastoma as compared to non-tumoral brain. These observations suggest that MALAT1 may contribute to the aggressive phenotype of glioblastoma. Experiments to test the effect of downregulation of MALAT1 in vivo are now ongoing.
The poor prognosis is partially due to the extremely high capability of glioblastoma cells to migrate and to invade the surrounding brain structures, impairing complete surgical resection, hence leading inevitably to recurrence. This provides the rational to further investigate implications of MALAT1 in migration. Understanding the mechanisms of high invasive properties may indeed lead to the identification of new targets for therapy.
Citation Format: Irene Vassallo, Marie-France Hamou, Monika E. Hegi. WIF1 re-expression in glioblastoma impairs migration through downregulation of the lncRNA MALAT1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 585. doi:10.1158/1538-7445.AM2014-585
Abstract 604: Olfactomedin 4 inhibits prostate stem/progenitor cells growth through regulating the hedgehog signaling pathway
Authors: Li Hongzhen , Liu Wenli , Chen Weiping , Zhu Jianqiong , Deng Chu-Xia , Rodgers Griffin P. 
Published: May 2015

Abstract
The olfactomedin 4 gene (OLFM4) plays critical tumor suppressor roles in human and murine prostate cancer. We have previously reported that loss or reduce of OLFM4 expression is associated with the progression of human prostate cancer. We further found that loss of Olfm4 leads to prostate neoplastic progression in the Olfm4-knockout mouse model. To study the cellular and molecular mechanisms underlying neoplastic progression of the prostate, we have performed gene chip microarray and quantitative real-time RT-PCR analysis to compare Olfm4 knockout with wild-type mouse prostate. The gene-expression signature of prostate tissues from Olfm4-deficient mice revealed significant changes for genes associated with neoplastic progression. In this study, we further detected that hedgehog signaling-pathway components are up-regulated in Olfm4-knockout mice. Since hedgehog signaling pathways are involved in regulating prostate stem/ progenitor cell proliferation, we performed sphere formation analysis with Olfm4 mutant mouse prostate and found that loss of Olfm4 increased proliferative abilities of prostate stem/progenitor cells. Interestingly, administration of human OLFM4 protein and cyclopamine, a specific inhibitor of Shh-signaling pathway, into the sphere culture media reduced Olfm4-deficient mouse prostate stem/progenitor cell growth.
To extend the observation from the mouse model, we established OLFM4-GFP fusion stably expressing cell clones by using human prostate cancer cell lines PC-3, 22RV1 and DU145. We found significant inhibition of sphere and colony formation in OLFM4 expressing cells compared with vector expressing control cells. The expression levels of Shh signaling pathway components were significantly inhibited in OLFM4 expression cells compared to vector expressing control cells.
To detect whether or not OLFM4 down regulates the Shh signaling pathway through interaction with Shh protein, we performed co-immunopricipitation in 293T and PC-3 OLFM4 stably expressing cells. We found that OLFM4 directly interacts with Shh protein. We then carried out Gli- reporter assay using 293T and prostate cancer cells. We demonstrated that expression of OLFM4 inhibited Gli-reporter activity in a dose-dependent manner.
Taken together, these results suggest that OLFM4 inhibits prostate stem/progenitor cells growth by mediating the Shh signaling pathway through a direct interaction of OLFM4 with Shh protein.
Citation Format: Hongzhen Li, Wenli Liu, Weiping Chen, Jianqiong Zhu, Chu-Xia Deng, Griffin P. Rodgers. Olfactomedin 4 inhibits prostate stem/progenitor cells growth through regulating the hedgehog signaling pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 604. doi:10.1158/1538-7445.AM2014-604
Abstract 679: Glutamine metabolism in MYC-driven antiestrogen resistant breast cancer cells confers metabolic flexibility through the unfolded protein response
Authors: Shajahan-Haq Ayesha N. , Cook Katherine L. , Schwartz-Roberts Jessica L. , Eltayeb Ahreej E. , Demas Diane M. , Warri Anni M. , Hilakivi-Clarke Leena A. , Clarke Robert 
Published: May 2015

Abstract
Antiestrogens are used to treat estrogen receptor positive (ER+) breast tumors that constitute 70% of all breast cancer cases. Unfortunately, acquired resistance to antiestrogen therapy remains a critical clinical obstacle. Here we show that human breast cancer cells and rat mammary tumors that have acquired resistance to antiestrogens express increased levels of MYC, a major regulator of both glutamine and glucose. Glutamine metabolism and glucose uptake were elevated in ER+ antiestrogen resistant cells (LCC9) compared with sensitive cells (LCC1). Inhibition of MYC, with siRNA or small molecule inhibitor, reduced cell viability and uptake of both glutamine and glucose in resistant cells. In resistant cells, MYC expression controlled protein levels of glutamine, glutamate and glucose transporters as well as GLUL and GLS, two enzymes that promote glutamate-glutamine inter-conversion. Increased MYC function in resistant cells correlated with increased cellular sensitivity to deprivation of, and also inhibitors of, both glutamine and glucose. While apoptosis eliminated all resistant cells in glucose-only conditions beyond 72 h, in glutamine-only conditions, the unfolded protein response (UPR) via GRP78-IRE1α and activating JNK and increased CHOP, induced apoptosis in majority of the cells but promoted survival in some. The antiestrogen faslodex (FAS; ICI 182,780) significantly reduced glucose uptake in antiestrogen resistant cells compared with sensitive cells. Thus, our findings reveal unique roles for MYC in promoting metabolic flexibility in and promoting survival in antiestrogen resistant breast cancer cells via the UPR. Targeting glutamine and glucose metabolism pathways, therefore, may provide novel strategies in treating endocrine resistant breast cancers.
Citation Format: Ayesha N. Shajahan-Haq, Katherine L. Cook, Jessica L. Schwartz-Roberts, Ahreej E. Eltayeb, Diane M. Demas, Anni M. Warri, Leena A. Hilakivi-Clarke, Robert Clarke. Glutamine metabolism in MYC-driven antiestrogen resistant breast cancer cells confers metabolic flexibility through the unfolded protein response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 679. doi:10.1158/1538-7445.AM2014-679
Abstract 724: Systemic injection of fiber-redesigned oncolytic adenovirus eliminates tumors in vivo
Authors: Miura Yoshiaki , Sato Mizuho , Davydova Julia , Yamamoto Masato 
Published: May 2015

Abstract
Adenovirus (Ad) has been used as a platform of oncolytic viral agents. Unlike loco-regional therapy, systemic application of cancer gene therapy mandates different level of selectivity of gene delivery. Lack of tumor selectivity at the stage of infection has hampered the in vivo efficacy of systemic therapy. The controlled vector distribution and cancer selective transduction would overcome the obstacles for systemic delivery and enable efficient systemic treatment of cancer.
AdML-VTIN was identified as a mesothelin (MSLN) targeted Ad by screening of high-diversity (109-level) Ad fiber mutant library. This AB-loop-redesigned Ad yielded a potent and selective infectivity to MSLN-positive pancreatic cancer (Panc-1) in vitro.
In the examination of in vivo selectivity and anti-tumor effect, the intra-tumor injection of AdML-VTIN showed significant anti-tumor effect against Panc-1 tumors, and about half of the tumor disappeared. Contrarily, the same virus showed no anti-tumor effect in MiaPaCa-2 (MSLN-negative). Viral DNA quantitation supported the selective viral replication only in Panc-1.
We compared organ distribution after intravenous injection to the nude mice with subcutaneous Panc-1 xenograft among AdML-VTIN, AdML-5WT (wild type Ad5 fiber), and AdML-GERS (against PC-3, prostate cancer cell). The liver sequestration of both AB-loop redesigned Ads were more than one order of magnitude lower than that with AdML-5WT at 1hr and 48 hrs after injection. At day 7, the viral copy number of AdML-VTIN in the tumor was more than 3 orders of magnitude higher that those with AdML-5WT.
Next, systemic therapeutic effect was examined with same condition of vector distribution. In only VTIN group, tumor volume was significantly decreased, and about one-third of the tumor was eliminated at 15 days after the injection even though viral amount was pretty low (109vp/mouse).
In this study, systemic injection of the AB-loop redesigned oncolytic Ad with VTIN motif that was identified by Ad library screening showed remarkable anti-tumor effect in spite of low viral amount. This new oncolytic Ad enabling systemic therapy may embody efficient treatment for pancreatic cancers which are mostly found with spread or metastatic lesions.
Citation Format: Yoshiaki Miura, Mizuho Sato, Julia Davydova, Masato Yamamoto. Systemic injection of fiber-redesigned oncolytic adenovirus eliminates tumors in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 724. doi:10.1158/1538-7445.AM2014-724
Abstract 729: Norleual a hepatocyte growth factor/c-Met inhibitor blocks malignant phenotypes in cancerous cells
Authors: Kawas Leen H. , Church Kevin J. , Lange Malte , Mcmicheal Michelle , Yamamoto Brent , Harding Joseph W. 
Published: May 2015

Abstract
The primary purpose of this study was to demonstrate that the hepatocyte growth factor (HGF) antagonist norleual is capable of attenuating the cellular responses of cancer cells to HGF. The angiotensin IV analog norleual [Nle-Tyr-Ile-ψ-(CH2-NH2)3-4-His-Pro-Phe] exhibits structural homology with the hinge (linker) region of HGF and acts to block HGF dimerization, a process required for its activation. Norleual competitively inhibited the binding of a H3-Hinge peptide sequence to the HGF, and binds directly to HGF with a Ki = 3.6x10-12M. Predictably, norleulal is able to block the cellular responses due to HGF activation in multiple cell types at concentrations in the picomolar range including HGF/c-Met sensitive pancreatic cancer cells. Norleual's ability to inhibit the growth and survival of several cell lines including pancreatic cancer cells was evaluated using viability testing and cell sorting tags to identify living, dead and apoptotic cells. HGF/c-Met activation increases the invasive potential of the pancreatic cancer cells, which provides a mechanistic basis for the ability of c-Met to support pancreatic tumor metastasis. In this regard norleual as an HGF antagonist was able to block the migration and invasion of cancer cells through collagen gels in a transwell chamber. Over-activation of the growth factor system HGF/c-Met is a critical contributor to cancer's ability to disseminate rapidly and its refractoriness to standard chemotherapy. Norleual, which is a representative of a “first-in-class” group of molecules that blocks the activation step of HGF, represent a novel therapeutic approach to the treatment of HGF/Met sensitive cancers including pancreatic cancer.
Citation Format: Leen H. Kawas, Kevin J. Church, Malte Lange, Michelle Mcmicheal, Brent Yamamoto, Joseph W. Harding. Norleual a hepatocyte growth factor/c-Met inhibitor blocks malignant phenotypes in cancerous cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 729. doi:10.1158/1538-7445.AM2014-729
Abstract 741: Combined inhibition of MDM2 and MEK for KRAS mutant non-small cell lung cancer
Authors: Hata Aaron N. , Archibald Hannah L. , Gomez-Caraballo Maria D. , DeBussche Laurent R. , Sidhu Sukhvinder , Watters James , Engelman Jeffrey A. 
Published: May 2015

Abstract
There are currently no effective targeted therapies for KRAS mutant NSCLC. Combination drug strategies that target downstream pathways activated by mutant KRAS are currently being investigated, however efficacy may be limited by inability to induce a sufficient apoptotic response. MDM-2 (murine double minute 2) is a ubiquitin ligase that negatively regulates p53 function by promoting its degradation. Inhibitors of the MDM2-p53 interaction lead to p53 activation and transcription of genes promoting cell cycle arrest and apoptosis. We investigated the efficacy of combined MEK and MDM2 inhibition for KRAS mutant NSCLC. In KRAS mutant NSCLC cell lines with wild-type p53, pimasertib (MEKi) and SAR405838 (MDM-2i) led to upregulation of BIM and PUMA respectively. Induction of apoptosis and cell cycle arrest correlated with in vitro efficacy, and the combination exhibited marked in vivo activity against KRAS mutant p53 wild-type NSCLC xenograft tumors. These studies provide rationale for future clinical investigation of combined MEK and MDM-2 inhibition for KRAS mutant NSCLC.
Citation Format: Aaron N. Hata, Hannah L. Archibald, Maria D. Gomez-Caraballo, Laurent R. DeBussche, Sukhvinder Sidhu, James Watters, Jeffrey A. Engelman. Combined inhibition of MDM2 and MEK for KRAS mutant non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 741. doi:10.1158/1538-7445.AM2014-741
Abstract 9: An angiogenic function for E-cadherin in ovarian cancer
Authors: Tang Maggie Kei Shuen , Wong Alice Sze Tsai 
Published: May 2015

Abstract
The loss of E-cadherin, a cell-cell adhesion molecule, is a well-established marker for metastasis of cancer. Although E-cadherin is synthesized as a transmembrane molecule, it can be cleaved of the ectodomain and released in a soluble form (sE-cad), and this accounts a key mechanism for a rapid reduction of functional E-cadherin at the cell surface. Yet, very little is known about how this important protein dictates the metastasis of these tumors. In ovarian cancer, a highly metastatic tumor that is rapidly lethal, sE-cad is highly expressed in the serum and metastatic ascites of ovarian carcinoma patients. Despite many studies focused on the role of E-cadherin loss in weakening cell-cell adhesion, whether sE-cad has biological activity in itself remain virtually unknown. Here we show for the first time that sE-cad can transduce angiogenic signals. sE-cad was also present in the culture supernatant of ovarian cancer lines. sE-cad of supernatant and a recombinant sE-cad-Fc chimera potently stimulated the migration of, permeability, and tubulogenesis by human umbilical vein endothelial cells in vitro. sE-cad also promoted functional neovascularization in a Matrigel implant model in vivo. These effects could be reversed by neutralizing anti-sE-cad, confirming that the effects were sE-cad specific. In addition, we found that sE-cad bound to VE-cadherin, an effect mediated through the phosphatidylinositol 3-kinase/Akt-β-catenin pathway. These results unravel a new and important piece to the complex biology of tumor angiogenesis and metastasis, and provide insights of novel mechanisms regulating angiogenesis (This study was supported by RGC grant HKU781013).
Citation Format: Maggie Kei Shuen Tang, Alice Sze Tsai Wong. An angiogenic function for E-cadherin in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 9. doi:10.1158/1538-7445.AM2014-9
Abstract 983: Intratumor heterogeneity in non-small cell lung cancer inferred by multi-region exome sequencing
Authors: Bruin Elza D. , McGranahan Nicholas , Yates Lucy , Jamal-Hanjani Mariam , Salm Max , Mitter Richard , Shafi Seema , Murugaesu Nirupa , Rowan Andrew , Gerlinger Marco , Wedge David , Horswell Stuart , Varela Ignacio , Tom Warren , Parikh Chaitali , Harkins Timothy , Lee Clarence , Matthews Nik , Stewart Aengus , Campbell Peter , Swanton Charles 
Published: May 2015

Abstract
Lung cancer is the most common cancer worldwide, and a leading cause of cancer-related death. Despite improvements in molecular diagnosis and targeted therapies, the 5-years overall survival remains poor. To obtain a better insight into the genetic architecture of the most common type of lung cancer, non-small lung cancer (NSCLC), we performed multi-region DNA sequencing on 7 resected NSCLC samples.
Ultra-deep sequencing of a comprehensive cancer gene panel and whole-exome sequencing revealed intratumor heterogeneity in all samples, with several putative tumor driver mutations present in some but not all regions of a tumor. Phylogenetic tree analyses based on non-synonymous mutations revealed a branched evolution pattern in all tumors. An adenosquamous tumor showed striking intratumor heterogeneity, with only a third of all non-synonymous mutations shared across all tumor regions, and clear separation of adenocarcinoma and squamous cell carcinoma tumor regions in the remaining two-third of the mutations. Our multi-region exome sequencing data also revealed regional differences in DNA copy number alterations. Some tumors, relatively homogeneous in terms of mutations, displayed high levels of intratumor heterogeneity in terms of DNA copy number changes, indicating the presence of distinct patterns of intratumor heterogeneity that might contribute to disease progression in different tumours.
Overall, our multi-region deep exome sequencing data revealed intratumor heterogeneity in NSCLC, demonstrating branched evolution, both in terms of non-synoymous mutations and DNA copy number alterations, which has important implications for our understanding of the clonal evolution of NSCLC.
Citation Format: Elza De Bruin, Nicholas McGranahan, Lucy Yates, Mariam Jamal-Hanjani, Max Salm, Richard Mitter, Seema Shafi, Nirupa Murugaesu, Andrew Rowan, Marco Gerlinger, David Wedge, Stuart Horswell, Ignacio Varela, Warren Tom, Chaitali Parikh, Timothy Harkins, Clarence Lee, Nik Matthews, Aengus Stewart, Peter Campbell, Charles Swanton. Intratumor heterogeneity in non-small cell lung cancer inferred by multi-region exome sequencing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 983. doi:10.1158/1538-7445.AM2014-983