bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C37: BMAL1 depletion represses growth of mesothelioma through induction of mitotic catastrophe
Authors: Elshazley Momen H.K.A. , Hasegawa Yoshinor , Sato Mitsuo , Hase Tetsunari , Yoshida Kenya , Toyokuni Shinya , Seikido Yoshitaka , Yokoi Kohei , Usami Noriyasu , Kondo Masashi 
Published: June 2012

Abstract
Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm arising from the mesothelial cells lining the pleura. Asbestos exposure is considered the most important carcinogenic factor that has been mentioned in relation to MPM. Although the incidence of MPM continues to increase, it remains resistant to the currently available therapeutic modalities. Thus, identification of more efficient therapeutics based on its molecular abnormalities is highly recommended. Recently, a genome-wide expression analysis showed deregulation of the circadian rhythm pathway in MPM, including overexpression of BMAL1, a central player in the circadian clock machinery. In this study we explored the consequences of targeting BMAL1 in MPM. This was accomplished by genetic knockdown of BMAL1 with small interference RNA (siRNA) and short hairpin lentiviral expression system. The majority of MPM cell lines expressed higher levels of BMAL1 than the nontumorigenic mesothelial cell line (Met-5A). Immunohistochemical analysis revealed that BMAL1 is constitutively expressed in the cytoplasm with granular pattern in a subset of clinical MPM specimens. Long-term depletion of BMAL1 induced senescence and downregulation of IL-8 and BcL-2 in ACC-MESO-1-cells. Notably, RNAi-mediated knockdown of BMAL1 resulted in suppression of cell growth and induction of apoptosis in MPM cell lines with limited consequences in Met5A. Moreover, ACC-MESO-1 cells, which expressed the highest level of BMAL1, underwent drastic morphological changes including micronucleation, multiple nuclei, and increased cellular volume. Consistently, cell cycle profiling revealed substantial increase in apoptotic and polyploidy cells with concomitant decrease in Wee1, cyclin B, p21, and increase in cleaved caspase 3 and cyclin E proteins by Western blot analysis. Taken together, these results suggest that mitotic catastrophe could be the main cause of cells death in ACC-MESO-1 cells after BMAL1 knockdown. BMAL1 plays an important role in MPM and serves as an attractive therapeutic target for MPM with high therapeutic index.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C37.
Abstract C5: Surface profiles of colorectal cancer cells and inflammatory lymphocytes correlate with blood neutrophil/lymphocyte ratios
Authors: Zhou Jerry , Belov Larissa , Clarke Stephen J. , Christopherson Richard I. 
Published: June 2012

Abstract
Background: Half of the patients diagnosed with colorectal cancer (CRC) relapse and succumb to systemic disease within 5 years. In most hospitals, multidisciplinary postoperative care focuses on identifying histo- and clinicopathological tumour characteristics. Adjuvant therapy based on these standardized staging systems has resulted in mixed success; as few as 10–20% of patients may benefit. The clinical course for individual patients remains unpredictable, with prognostic heterogeneity for patients with same-stage tumours. Single biomarkers have limited utility; patterns or profiles of biomarkers will be required to predict post-surgical disease progression and patient prognosis. Local inflammation may have a negative or positive effect upon cancer development; for example, neutrophils may mediate tumor angiogenesis. A high neutrophil to lymphocyte ratio (NLR) in the peripheral blood has been associated with poorer patient survival and response to chemotherapy (Chua et al., 2011). We have developed a new system for sub-classification of CRC based upon extensive surface profiles and these results have been correlated with the NLR.
Methods: The DotScan CRC antibody microarray captures live cells on immobilized antibodies against 122 surface CD antigens. Fresh surgical CRC samples (69) with corresponding normal intestinal mucosa were disaggregated to produce viable single cell suspensions that were captured on microarrays. Binding dot patterns were recorded for subsets of cells labeled with fluorescent antibodies. Epithelial cell adhesion molecule (EpCAM) labeled CRC cells; CD3 labeled tumour-infiltrating T-lymphocytes (TILs). Differential white blood cell counts and NLRs were obtained for each patient from hematology reports.
Results: Statistical analysis showed significant immunophenotypic differences between CRC and control mucosal cell populations. Unsupervised hierarchical clustering of these data identified several patient sub-groups based on EpCAM (CRC cells) and CD3 (TILs) profiles. Differentially expressed CD antigens were recognized between groups of patients with low, medium or high NLRs. The DotScan CRC microarray may provide disease signatures for distinguishing patients with good and poor prognosis, and an alternative to current pathology CRC staging systems.
Chua W, Charles KA, Baracos VE, Clarke SJ (2011) Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. Br J Cancer 104:1288–1295.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C5.
Abstract C60: IGF-1 signaling enhances mitochondrial activity and biogenesis in cancer cells independently of the glycolytic phenotype
Authors: Favre Cedric , Zhdanov Alexander , Papkovsky Dmitri , O'Connor Rosemary 
Published: June 2012

Abstract
Cancer cells exhibit increases glycolytic rates and glucose transport to facilitate adaptation to the high energy demand imposed by increased proliferation rates and their often hypoxic environment. Moreover, this is often accompanied by reduced mitochondrial activity due to the accumulation of mtDNA mutations. Since there is close coordination of glycolysis and mitochondrial respiration, cancer cells may be particularly sensitive to pharmacological agents that increase mitochondrial activity.
We recently identified a mitochondrial UTP transporter, PNC1, whose expression is induced by IGF-1 in an Akt-mTOR-dependant manner in transformed cells. PNC1 is a conserved orthologue of a yeast UTP carrier that is essential for maintenance of mtDNA replication and transcription and thereby mitochondrial biogenesis and activity. Suppression of PNC1 leads to increased mitochondrial ROS production, acquisition of an invasive phenotype, and mitochondrial biogenesis in cancer cells. Overexpression of PNC1 suppresses ROS production, mitochondrial biogenesis and protects from TGF-beta-induced epithelial-mesenchymal transition (EMT). The function of IGF-1-regulated PNC1 in cancer cells lead us to hypothesize that the IGF-1 signaling pathway may directly influence mitochondrial activity in cancer cells even in the presence of a switch to the glycolytic phenotype. Here we show that IGF-I stimulation increases mitochondrial mass in both normal cells and several cancer cell lines. The increased mitochondrial mass correlates with an increase in both mitochondrial protein and mRNA levels. This increase in mitochondrial biogenesis is also accompanied by increased oxygen consumption and ATP production. Furthermore, we show that the increase in both mitochondrial biogenesis and mitochondrial activity is due to IGF-1-mediated activation of a ROS-AMPK-PGC1 alpha signaling pathway.
We conclude that mitochondrial activity and biogenesis in cancer cells is enhanced by the IGF-1 signaling pathway. Thus, attenuation of growth factor signaling may lead to accumulation of mtDNA damage and the consequent effects of increased ROS production on cancer cell phenotype.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C60.
Abstract C69: Ontogenetic switches in activity and location of multidrug efflux transporters during embryonic development
Authors: Hamdoun Amro , Campanale Joseph , Gokirmak Tufan , Shipp Lauren , Whalen Kristen 
Published: June 2012

Abstract
Multidrug resistance, mediated by ATP binding cassette (ABC) transporters, is a major obstacle to the treatment of metastatic cancer. This phenomenon has eluded treatment by direct pharmacological inhibition of the multidrug transporters responsible for resistance. An alternative strategy could be to control drug resistance by targeting the cellular regulation of insertion and retrieval of transporters from the plasma membrane. However, the pleiomorphic nature of cancer cells and tumors complicates the identification of core machinery involved in regulation of transporter dynamics. Embryos have natural, rapid switches in multidrug efflux activity, coincident with the normal reorganization of cell surfaces at fertilization and at epithelial to mesenchymal transitions.
We are focusing on two major changes in surface organization and transport activity occurring during the first 24 hours of sea urchin development. As basal deuterostomes, the branch of evolution leading to vertebrates, sea urchins provide a tractable system in which core machinery regulating multidrug efflux transporters can be manipulated and characterized. The first occurs at fertilization and involves the activation of transport by shortrange, actin-dependent translocation of ABCB1a (aka P-gp, MDR1). Super-resolution fluorescence microscopy reveals that transporters move to the to the distal tips of microvilli, possibly to overcome diffusive limits in the boundary layer between microvilli. The second switch in activity is a selective downregulation of multidrug efflux transport that occurs in germline progenitors of these animals and results in long-term reduction of transport. It is mediated by endocytosis of the proteins in those cells coincident with changes in apicobasal cell polarity. We are currently investigating the sequence of events that leads to pump retrieval in these cells. The implications of this work are new insights into the molecular switches that govern acquisition and loss of transporter-mediated drug resistance during differentiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C69.
Abstract IA10: How the p53 pathway controls the response to chemotherapy
Authors: Lane David P. , Brown Chris , Khoo Kian Hoe , Goh Amanda , Lin Guo , Liew Hoe Peng , Verma Chandra , Cheok Chit Fang 
Published: June 2012

Abstract
Intensive drug discovery activity in both the commercial and academic sector has produced a number of small molecules that can potently regulate the p53 pathway in vivo and in vitro. The availability of these tools along with precise genetic models is allowing a re-examination of the role of the p53 response in Chemotherapy and Radiotherapy. Some chemotherapeutic agents such as actinomycin D have been found to act in an extraordinarily p53 specific manner, while others, such as doxorubicin, while still activating the p53 response actually kill cancer cells by largely p53 independent mechanism. Indeed the p53 response can reduce their effectiveness by inducing a p21 dependant cell cycle arrest. The temporal sequence and kinetics of drug action have a dramatic effect on outcome when p53 activating small molecules such as Nutlin are combined with chemotherapeutic drugs. We have synthesized new p53 activating molecules using peptide stapling methods and generated Zebra fish and mouse models to study the p53 response in normal tissues. These studies suggest that the p53 response is constitutively activated at a low level that is not incompatible with cell proliferation in tissue culture and in tumors in vivo but is not activated in many normal tissues even when they are rapidly proliferating. This low level activation may synergize with Mdm2 binding drugs to enhance their specific therapeutic index and offers scope for the further exploitation of tumor activated p53 stress pathways to enhance the selectivity of chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA10.
Abstract IA18: Oncogene regulation of the autophagy machinery
Authors: Levine Beth C. 
Published: June 2012

Abstract
It is well-established that many oncogenic growth signaling pathways negative regulate autophagy through a mechanism that has been presumed to be via activation of mTOR. However, it has been unknown whether oncogenes directly suppress the autophagy machinery and whether autophagy suppression contributes to oncogene-mediated tumorigenesis. We will discuss new findings indicating direct regulation of the Beclin 1 autophagy protein by the Akt oncoprotein and a role for Beclin 1 inactivation in Akt-driven tumorigenesis. The results presented will provide support for the concept that autophagy functions in tumor suppression and will demonstrate a specific biochemical mechanism by which autophagy is suppressed in human cancers with aberrant activation of the oncogenic Class I phosphatidylinositol 3-kinase/Akt signaling axis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA18.
Abstract IA2: Cancer genomes and their implications for basic and applied research
Authors: Voaelstein Bert 
Published: June 2012

Abstract
Human cancer is, in essence, a genetic disease. Though this pivotal fact has been established over the past three decades, only recently has the compendium of genetic alterations in tumors been identified at a genome-wide scale. The basic landscapes of cancer genomes are becoming clear and the implications of this research are evident. These landscapes are populated by a few “mountains” – genes that are mutated at high frequency in specific tumor types – but are dominated by hills, representing genes that are mutated in only a relatively small fraction of the tumors. The vast majority of genetic alterations are point mutations, and most of these are passengers, i.e., provide no selective growth advantage to the tumor cell. Moreover, virtually all of the driver mutations in common solid tumors are in tumor suppressor genes rather than in oncogenes. All the bona fide cancer genes identified to date affect one or more of a dozen pathways that are central to neoplasia. Appreciation of this landscape has profound implications for both understanding the disease and managing patients with cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA2.
Abstract IA22: The application of synthetic lethality as a therapeutic approach to cancer
Authors: Lord Christopher 
Published: June 2012

Abstract
As the search for suitable cancer drug targets becomes ever more difficult, the need for novel approaches to this problem is becoming more apparent. Although first proposed in the 1940s, it is only recently that the concept of using synthetic lethality (SL) to design new therapeutic approaches is being tested both in the laboratory and in the clinic. Two genes or proteins are synthetic lethal when deficiency in either is compatible with cellular viability but loss of both is not. Where one partner of a synthetic lethal relationship is a tumor suppressor gene that is lost in tumors, the other synthetic lethal partner, once identified, becomes a candidate drug target. Using this approach, we have identified PARP inhibition as being SL with loss of either the BRCA1 or BRCA2 tumor suppressor genes and clinical trials testing this approach are now showing considerable promise. Using this and other examples, I will illustrate how the SL approach can be exploited, how novel targets can be identified and how tumor types as diverse as colorectal, breast, prostate, and endometrial cancer could be treated using a SL approach.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA22.
Abstract IA6: DNA-damaging anticancer therapies modify the tumor microenvironment
Authors: Campisi Judith 
Published: June 2012

Abstract
Many anticancer therapies exploit the higher proliferative status and/or compromised DNA repair capacity that are common features of tumor cells and thus are designed to severely damage DNA. Such therapies often result in the death of the tumor cells. In some cases, however, the tumor cells—as well as normal cells in the tumor environment—undergo an essentially permanent arrest of proliferation termed cellular senescence. In addition to halting growth, senescent cells undergo marked changes in gene expression. One such change entails the robust secretion of numerous cytokines, growth factors, and proteases, which we term the senescence-associated secretory phenotype (SASP). The SASP has potent paracrine activities, and can have striking effects on the local tissue microenvironment. Among the stimuli that induce a robust SASP are DNA damaging anticancer therapeutics. We have found that such therapies induce an SASP in both the targeted tumor cells, as well as the untargeted normal cells that surround the tumor. We are currently exploring strategies aimed at selectively suppressing the SASP. We expect that such strategies will, in vivo, reduce the local and systemic inflammation that can be driven by the senescent cells and SASP that results from genotoxic chemo- or radiotherapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA6.
Abstract PR1: Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis
Authors: Labelle Mvriam , Begum Shahinoor , Hynes Richard O. 
Published: June 2012

Abstract
Interactions of cancer cells with the primary tumor microenvironment are important determinants of cancer progression towards metastasis but it is unknown whether additional prometastatic signals are provided during the intravascular transit to the site of metastasis. Here, we have tested whether platelets present in the bloodstream can provide a signaling platform for cancer cells outside of the primary tumor and influence the metastatic potential of tumor cells. We show that platelet-tumor cell interactions are sufficient to prime tumor cells for subsequent metastasis. Platelet-derived TGFß and direct platelet-tumor cell contacts synergistically activate the TGFß/Smad and NF-κB pathways in cancer cells, resulting in their transition to an invasive mesenchymal-like phenotype and enhanced metastasis in vivo. Inhibition of NF-κB signaling in cancer cells or ablation of TGFß1 expression solely in platelets protects against lung metastasis in vivo. Thus, our study establishes platelets as a major and critical source of TGFß bioavailable to cancer cells in the circulation, and reveals that the metastatic potential of tumor cells continues to evolve outside the primary tumor site, in response to tumor-host interactions in the bloodstream. Platelet-tumor cell interactions and the signaling pathways that they trigger are therefore crucial determinants of cancer metastasis and potential targets for anti-metastatic therapies.
This abstract is also presented as Poster A9.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR1.
Abstract PR16: Important bidirectional function in the Notch-Delta signaling in pancreatic carcinogenesis and metastasis
Authors: Mazur Pawel K. , Lubeseder-Martellato Clara , Grüner Barbara M. , Kaznowska Ewa , Sipos Bence , de Angelis Martin Hrabé , Schmid Roland M. , Sage Julien , Siveke Jens T. 
Published: June 2012

Abstract
Pancreatic cancer is a dismal disease with a median survival of less than 6 months. Its high mortality is due to aggressive development and early lymphatic and hematogenic dissemination. Notch signaling has been shown to regulate pancreatic carcinogenesis; however, a specific role of the Notch ligands has not been extensively studied thus far. Here we investigate the role of Delta1 ligand in pancreatic carcinogenesis and metastasis.
Our study using a reporter mouse indicates that Delta1 is mainly expressed in centroacinar and ductal cells as well as in pancreatic intraepithelial neoplasia (PanIN) lesions. Expression in those vulnerable cell compartments and preneoplastic lesions imply relevance for carcinogenesis. Moreover, during cancer development, Delta1 shows the highest relative increase in expression among all Notch ligands suggesting it predominantly functions in Notch pathway activation. Its potentially important role in tumorigenesis was investigated using a KrasG12D-driven pancreatic carcinogenesis mouse model inbreed with a Delta1LacZ/+ haploinsufficient mouse. In KrasG12D;Delta1LacZ/+ mice we observed a delay in PanIN progression and increased development of mucinous cystic neoplasia. Obtained results support our hypothesis. Moreover, in vitro data indicates that Delta1 is critical for Notch2 activation that directly regulates pancreatic cancer progression via cMyc induction.
We also analyzed expression and role of the intracellular domain of Delta1 (Delta1-IC). We found that Delta1-IC is accumulated in pancreatic cancer distal metastasis. Our investigations strongly suggest that Delta1-IC can enhance metastatic potential by interaction with transducers of TGFβ signaling: Smad3 and Smad4. We found that Delta1-IC by co-binding to Smad3-regulated promoter proteins can increase TGFβ-induced transcriptional changes in the cell leading to increased cellular motility and EMT capacity. We establish that nuclear accumulation of Delta1-IC correlates with patients' poor outcome and presents of metastasis as well as tumor stage. Our investigation proofs the importance of Notch signaling and points to its bidirectional function in pancreas carcinogenesis and metastasis.
This abstract is also presented as Poster A62.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR16.