bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A33: A whole genome RNAi screen identifies BRD7 and BAF180 as p53 regulators required for senescence
Authors: Burrows Anna E. , Smogorzewska Agata , Elledge Stephen J.
Published: June 2012

Multiple tumor-suppressor mechanisms exist to promote genomic stability. One such mechanism is cellular senescence. In response to DNA damage and oncogenic stimuli, the senescence program, including the p53 and Rb pathways, is activated to prevent the proliferation of damaged cells and their potential oncogenic transformation.

We are performing a pooled whole genome shRNA screen in primary human fibroblasts to identify novel components of the senescence machinery. In addition to many known senescence regulators including cell cycle and DNA damage response factors, we have also uncovered many genes of unknown function. From this screen we have identified SWI/SNF components BRD7 and BAF180 as novel regulators of replicative and oncogene-induced senescence.

Both BRD7 and BAF180 are required for p53 transcriptional activity toward a subset of target genes including p21, and BRD7 physically interacts with p53. Overexpression of BRD7 induces premature senescence and p21 expression, highlighting its regulatory role in this pathway. We also show that BRD7 is required for expression of p21 in p53-independent contexts, such as in response to TGF-β and 1α,25(OH)2D3 (vitamin D) in epithelial cells. Lastly, BRD7 and BAF180 are deletion targets in human cancer, suggesting that their loss may provide additional mechanisms to antagonize p53 function in cancer cells.

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 A33.
Abstract A4: Hodgkin and Reed-Sternberg cells secrete soluble factors to modulate endothelial cell-T cell interactions in classical Hodgkin lymphoma
Authors: Fhu Chee Wai , Chong Siew Meng , Yap Celestial , Graham Anne , Lim Yaw Chyn
Published: June 2012

Introduction: Classical Hodgkin lymphoma (CHL) is characterized by the presence of a minority of malignant Hodgkin and Reed-Sternberg cells (H-RS cells) surrounded by an abundant mixed inflammatory infiltrate that includes CD4+ T helper 2 cells, regulatory T cells and CD8+ cytotoxic T cells. The mechanisms exploited by HRS cells to influence T cell recruitment into the involved lymph nodes are still unknown.

Objective: The aim of this study is to elucidate whether H-RS cells can induce endothelial cell activation to modulate T cell recruitment in CHL.

Procedures: Fresh cell culture supernatant (C/S) from the H-RS cell line, KM-H2, was used to stimulate endothelial cells (EC) in-vitro. Controls were EC incubated in medium alone; or with 10ng/ml TNF-α Up-regulation of adhesion molecule expression was assessed by ELISA and FACS. Using the transwell migration system and the parallel plate flow chamber apparatus respectivel, the ability of these stimulated EC to support T cell interactions in-vitro was assessed under static and defined flow conditions. Signaling pathways involved in C/S induced EC activation were examined by western blotting.

Results: KM-H2 C/S-stimulated EC up-regulate ICAM-1, VCAM-1 and E-selectin to levels comparable to those of TNF-α-stimulated EC. Both C/S-stimulated EC and TNF-α stimulated-EC support naïve and memory T-cell interactions under defined flow conditions. Furthermore, both CD4+ naïve and memory T cell demonstrated enhanced transmigration across C/S-stimulated EC monolayers in response to SDF-1α, as compared to TNF-α-stimulated or unstimulated EC.

The activation of EC by KM-H2 C/S is dependent on the NFkB pathway. Blocking of p65 nuclear translocation by the specific IκBα phosphorylation inhibitor (BAY11-8075) abrogated the stimulatory effect of C/S on EC. Phosphorylation of ERK, p38 and JNK were also detected in the KM-H2 C/S stimulated EC. Intracytoplasmic expression of TNF-α was detected in KM-H2 cells.

The bioactivity assay showed that the TNF-α sensitive cell line, L929 is sensitive to KM-H2 C/S. However, treatment of cells with TNF-α neutralizing antibody did not effectively prevent L929 cell death, nor inhibit the stimulatory effect of KM-H2 C/S on EC.

Conclusion: Our data suggest that the malignant Hodgkin and Reed-Sternberg cells secrete soluble mediators that modulate endothelial cell function and influence recruitment of T cells into the cHL lesion. While the C/S induced EC activation is dependent on the NFkB pathway, our data suggest that the dominant mediator involved is not TNF-α.

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 A4.
Abstract A56: Tumor alarm gene FHIT activates tumor suppressive system by self-scarifying
Authors: Oh Ah-Young , Lee Sun-Hye , Chung Ji-Yun , Jung Youn-Sang , Park Bum-Joon
Published: June 2012

Human fragile histidine triad (FHIT) is known to be a putative tumor suppressor gene because of frequent deletion and mutation in various kinds of human cancers, in particular, human lung cancer. However, its biological function as tumor suppressor gene, has not been demonstrated. In fact, there are conflict results on the role of FHIT. Oncogenic property of FHIT has been proposed such as overeactivation of ATR/CHK1 pathway in FHIT deficient cells, and low tumor incidence in FHIT-deficient mice. In contrast, tumor suppressive functions such as cell cycle inhibition and induction of apoptosis also proposed. Here we provide the evidences about unexpected working mechanism of FHIT as a tumor alarm gene. FHIT can awake the intracellular tumor suppressive system through reduction or deletion itself. FHIT reduction or deleted cells significantly increase the p21/WAF1 expression as well as p14/ARF-p53. It is achieved at posttranslation level and p53-dependent manner. So loss of FHIT can sequester the cell cycle in G1 phase. FHIT reduction can be achieved by oncogene activation and DNA damage. Thus, FHIT-deficient cells did not response to additional tumor risk and accumulation of additional genetic mutation is easily fixed in genome, which may contribute to tumor progression.

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 A56.
Abstract A59: Life and death decision by E2F1 depends on Jab1-mediated expression of E2F apoptotic target genes and is counteracted by PI3K activation.
Authors: Lu Huarui , Hallstrom Timothy C.
Published: June 2012

Rb regulation of cell cycle progression and tumorigenesis is dependent on its control of E2F transcription factor function, a family of proteins that initiate both cell proliferation and cell death. Several classes of E2F target genes have been categorized based on their roles in DNA replication, G2/M & mitosis, apoptosis, DNA repair, etc. However, the mechanisms controlling appropriate expression of genes responsible for these cell fates is poorly understood. We previously showed that Jab1 promotes E2F1-induced apoptosis but not DNA replication as an E2F1-specific binding partner. In this study, we performed gene expression analysis to better understand the control of E2F1 function by Jab1/CSN5. Microarray assay revealed a significant number of apoptotic E2F target genes such as Cyp26b1 and AMPKα2 are profoundly impaired by Jab1 shRNA knockdown, whereas DNA replication genes are generally still highly expressed. The findings of microarray were further confirmed using quantitative real-time PCR. Subsequent chromatin immunoprecipitation indicates that Jab1/E2F1 complex resides on the promoters of E2F1 apoptotic and G2/M, but not DNA replication targets genes. Meanwhile, we found that PI3K activation blocks expression of E2F1/Jab1 co-induced apoptotic target genes and apoptosis induction at least in part by interfering with formation of the pro-apoptotic Jab1/E2F1 complex as determined by co-immunoprecipitation. More importantly, we detected a highly significant correlation between elevated Jab1 levels and PI3K activity in breast, ovarian, lung and prostate cancers. These findings suggest the possibility that Jab1, when elevated in these tumors, may evade triggering tumor-suppressive E2F1 apoptosis and instead induce proliferation through the frequent, simultaneous co-activation of PI3K activity.

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 A59.
Abstract B60: From plasma peptide to phenotype: An emerging role of quiescin-sulfhydryl oxidase 1 in tumor cell invasion
Authors: Katchman Benjamin A. , Antwi Kwasi , Hostetter Galen , Demeure Michael , Wantanabe Aprill , Decker G. Anton , Miller Lawrence J. , Von Hoff Daniel D. , Lake Douglas F.
Published: June 2012

Quiescin-sulfhydryl oxidase (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. We previously mapped a peptide in plasma from pancreatic ductal adenocarcinoma patients back to an overexpressed QSOX1 parent protein in tumor cells. It is not known why, or in what capacity, pancreatic tumors overexpress QSOX1. To begin to address this question, we first showed through immunohistochemistry that QSOX1 is overexpressed in patients diagnosed with pancreatic cancer, while it is not expressed in adjacent normal tissue or infiltrating lymphocytes. To determine the potential advantages QSOX1 might provide to tumor cells we knocked down QSOX1 using shRNA that suppressed both short and long isoforms of the protein. Loss of QSOX1 expression suppressed cell growth over time, while changes in cell cycle and apoptotic markers were minimal. However, QSOX1 shRNA dramatically inhibited the abilities of BxPC3 and Panc-1 pancreatic tumor cells to invade through Matrigel in a modified Boyden chamber assay. Mechanistically, gelatin zymography indicated that QSOX1 may play an important role in intracellular processing and extracellular activation of MMP-2 and MMP-9. Taken together, our results suggest that pancreatic tumors that express QSOX1 demonstrate an invasive phenotype through MMP activation.

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 B60.
Abstract B62: Role of classical protein kinase C (PKC) in intestinal cancer
Authors: Kunz Sandra , Leitges Michael
Published: June 2012

PKCs represent a family of serine/threonine kinases consisting of a least 10 isoforms, divided into three subclasses based on their Ca2+ and DAG dependency. The classical PKC (cPKC) isoforms alpha, beta-I, beta-II, and gamma are calcium and diacylglycerol (DAG) dependent whereas novel PKCs (delta, epsilon, eta, and theta) are calcium independent. In contrast the atypical PKC zeta and lambda/iota do neither need calcium ions nor DAG for their activation. All PKCs are thought to be involved in cell growth and differentiation. In particular, studies focusing on expression profiles of PKCs during tumor formation and progression imply a functional link. For example, have we been able to show that PKC-alpha and -beta are differently regulated in the APCMin mouse model, which represents a well-established model for intestinal cancer. Based on these data, we further have identified PKC-alpha as to act like a tumor suppressor in this context. Given the fact that PKCs are activated by PMA/TPA and therefore defined as tumor promotors, this was a very surprising observation.

Material and Methods: This project makes use of mouse intestinal epithelial cell lines that we established from various genetic backgrounds. Using standard Western blot protocols, we first analyzed the abundance and activation status of different signal cascades upon epidermal growth factor (EGF) stimulation.

Results: Earlier studies by us (Oster and Leitges, 2006) have indentified an alteration of the EGF receptor signaling in the APCMin model due to PKC-alpha deficiency. To understand the underlying mechanism, we analyzed EGF receptor signaling in mouse intestinal epithelial cell lines. Thus far it became obvious that PKC-alpha deficiency causes a prolonged Erk1/2 and Akt activity whereas JNK activation was only detectable in the alpha deficiency.

Conclusion: In sum, we have shown that EGF receptor signaling capacity is functionally linked to PKC-alpha activity.

Literature: Oster H, Leitges M. Protein kinase C alpha but not PKC zeta suppresses intestinal tumor formation in APCmin mice. Cancer Res. 2006;66:6955–6963.

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 B62.
Abstract B64: Outcome of multimodality treatment of pediatric Ewing's sarcoma/PNET
Authors: Pathy Sushmita , Mohanti Bidhukalyan , Bakshi Sameer
Published: June 2012

Aim: To study the clinical symptoms and treatment outcome of multimodality treatment of ES/PNET in Dr BRAIRCH, AIIMS from June 2006 to May 2009.

Material and Methods: The study included 63 patients, 46 male and 17 female, all less than 18 years of age, and registered in our pediatric oncology clinic. All patients had histopathological diagnosis. Majority of patients had involvement of extremity (25/63), followed by thorax (14/63) and head and neck (10/63). Forty-eight patients presented with localized disease and 15 presented with distant metastasis. Chemotherapy consisted of VAC+IE regimen. Mean number of chemotherapy cycles was 13.5. Patients received chemotherapy and local treatment in the form of surgery and radiotherapy. Forty-one patients received CT+RT, 22 patients underwent surgery followed by RT.

In 50 patients, RT was administrated with a curative intent. A dose of 45 Gy in 25 fractions over 5 weeks followed by boost 15Gy in eight fractions over 1.5 wk was delivered. Mean RT dose was 47.9 Gy. Ten patients received palliative RT.

Results: Mean disease-free survival was 23.22 months (std error 1.92 and 95% CI 19.48-26.96). Median DFS was 21.3 months (std error 1.94 and 95%CI 17.50–25.10).

Conclusion: The above regime was well tolerated and detailed clinical profile, treatment outcome will be presented.

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 B64.
Abstract C15: Telomere length assessment in human archival tumor tissues by quantitative PCR method
Authors: Wang Hui , Go Ning , Pirot Zhu , Bassett Katia
Published: June 2012

Telomeres are essential for maintenance of genomic stability. Short telomeres have been associated with genomic instability, and initiation and progression of human cancers. To protect their telomeres, up to 90% of human cancers activate telomerase. Inhibition of telomerase by imetelstat, a specific and potent inhibitor, has resulted in telomere shortening, as well as tumor response in animal models. We propose that tumors with short telomeres may be more responsive to imetelstat than tumors with long telomeres. This hypothesis will be tested by measuring baseline telomere lengths in archival tumors of patients in imetelstat Phase II clinical trials, and correlating tumor telomere length with clinical outcome. In order to accomplish this, a fast, high-throughput qPCR-based method for telomere length measurement in genomic DNA extracted from FFPE tissue sections was developed. Using this assay, telomere repetitive DNA sequences and single-copy gene control were successfully amplified. The assay required very little genomic DNA (1–10ng per PCR reaction). Thus, small tissue sections (20 mm2) could be easily accommodated. Using this technique, we were able to perform the first comparison of relative telomere lengths in 22 human breast cancer samples and 8 human tumor cell lines in matched fresh-frozen and FFPE samples. Telomere lengths measured in FFPE samples by the qPCR method strongly correlated with the telomere lengths measured by TRF in matched fresh-frozen samples. Therefore, our method provides a useful tool for assessment of telomere length as a potential predictive biomarker of responsiveness to telomerase inhibition in clinical archival tumor tissue.

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 C15.
Abstract C2: Aspartic acid residues drive the membrane translocation of pHLIP, a therapeutic and imaging agent for solid tumors
Authors: Barrera Francisco N. , An Ming , Wijesinghe Dayanjali D. , Weerakkody Dhammika A. , Anderson Michael , Andreev Oleg A. , Reshetnyak Yana K. , Engelman Donald M.
Published: June 2012

The pHLIP peptide is a new therapeutic and imaging agent for cancer treatment. The pHLIP (pH-Low-Insertion Peptide) is soluble in solution but interestingly, it is able to interact with the plasma membrane and insert as a monomeric transmembrane helix (pKa=6.0). The insertion requires an acidic extracellular environment, such as that found in most solid tumors and inflammation sites. The pHLIP, which is nontoxic in mice, is specifically distributed to tumors (with minor labeling of kidney), as imaged by PET and near-infrared fluorescence.

The insertion of pHLIP is unidirectional, as the C-terminus is translocated across the membrane, while the N-terminus remains exposed to the extracellular medium. The insertion energy can be employed to translocate into the cytoplasm membrane-impermeable molecules. As a proof of principle, we showed that the polar toxin phalloidin (which binds to F-actin, inhibiting its depolymerization) is translocated in a pH-dependent fashion into HeLa, JC, and M4A4 cancer cells, inhibiting cell growth and causing cytoeskeletal immobilization and multinucleation.

Here we study the molecular determinants of pHLIP membrane insertion. The pH-mediated translocation is thought to be triggered by the protonation (loss of negative charge) of carboxyl groups present in pHLIP. Accordingly, the four aspartic acid (Asp) residues of pHLIP were sequentially mutated, and the efficacy of the membrane insertion and exit was studied in a liposome system. We found a correlation between the number and location of Asp with the peptides ability in insert into and exit from the membrane in a pH-dependent manner. We also observed that the number of Asp in the peptide determines the insertion properties (pKa and the cooperativity), suggesting that the tumor labeling properties of pHLIP can be specifically tuned to better match the physiological acidity of solid tumors.

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 C2.
Abstract C20: The epigenomic fingerprint of hepatocellular carcinoma
Authors: Parpart Sonya , Roessler Stephanie , Dong Fei , Rao Vinay , Loffredo Chris , Wang Xin Wei
Published: June 2012

Globally, hepatocellular carcinoma (HCC) accounts for 70% to 85% of primary liver cancers. HCC remains in the top 10 among the most common cancers and ranks second in the leading cause of male cancer death worldwide. Patients are typically diagnosed with late-stage disease leading to poor survival rates in the United States and developing countries. Serum alpha-fetoprotein (AFP) is a key HCC biomarker associated with patient prognosis. However, serum AFP levels are heterogeneous among HCC patients, suggesting that the biology of AFP+ and AFP- tumors may be different. Identifying the molecular mechanisms underlying these differences may improve our understanding of HCC development and guide future approaches to increase survival. Recently, microRNAs (miRNAs) have been shown to be deregulated in many cancers and are useful biomarkers for early detection, prognosis, and treatment. In this vein, we performed global miRNA profiling analyses of HCCs that differ in AFP expression. We found that miR-29 family members, including miR-29a, miR-29b, and miR-29c, are top-ranked downregulated miRNAs in AFP+ tumors whose expression is inversely correlated with AFP in 242 HCC specimens, suggesting that miR-29 may act as a tumor suppressor in AFP+ HCC. In fact, we have found an association between decreased miR-29 and poor survival. In addition, there is a significant association between AFP and DNA methyltransferases DNMT3A and DNMT3B, which were recently shown to be direct targets of miR-29. Furthermore, we have found an overall trend toward increased methylation in HCC patients with high levels of AFP. These findings led us to hypothesize that AFP may inhibit miR-29, which in turn increases DNA methyltransferase activity and modulates epigenetic changes that contribute to poor outcome in HCC. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) reveals that AFP and DNMT3B are both inversely correlated with miR-29 expression in HCC cell lines. We are testing currently whether AFP regulates miR-29 expression and alters DNA methylation patterns in HCC cells. We are also examining how miR-29 expression is regulated to determine whether AFP directly targets mir-29 to effect epigenetic changes or whether this occurs through other signaling pathways. Taken together, these studies will elucidate the molecular mechanisms that link AFP and miR-29 expression to epigenetic alterations and may aid in the development of novel therapeutic agents that may improve survival of HCC patients.

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 C20.
Abstract C26: Chromatin remodeling system and visualization of the “archaic” cancer attractors
Authors: Zhang Yue , Calderwood Stuart K. , Moriguchi Hisashi , Li Yinghua
Published: June 2012

The cancer cell attractors theory provides a novel understanding of carcinogenesis. The mechanisms that the ectopic expression of some germline genes result in somatic tumors such as melanoma and brain tumors are emerging but not well understood. From mammals to model organisms like Caenorhabditis elegans and Drosophila melanogaster, the versatile Mi-2/Nucleosome remodeling and histone deacetylation (NuRD) complexes alongside their functionally related chromatin remodeling complexes (CRCs), i.e. the dREAM/Myb-MuvB(MMB)complex and polycomb group (PcG) complex are typical bottle-necked regulators of cell attractors. The trajectory that benign cells switch to cancerous could be the reverse (or close) of navigation of embryonic cells converging from a series of intermediate transcriptional states to a final adult state, which is supported by Gene Expression Dynamics Inspector (GEDI) assays and some cross-species genetic evidences. Hence Cancer could be triggered by cells undergoing abnormal cell attractor transitions, and may be reversible with “cyto-education”. In additon, we identified multidrug resistence genes and extracellular matrix (ECM) genes as conserved hub molecule fro Mi-2/NuRD. A complementary study will go to tumorigenicity and immunogenicity of induced pluripotent stem celles and the strategies of supppression.

The understanding of involvement of CRCs in locking cancer attractors may forecast cancer “weather” and help find the recipes of perturbing genes to achieve successful reprogramming such that the reprogrammed cancer cell function in the same way as the normal cells.

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 C26.
Abstract C28: Binding to BCOR defines a subfamily of Psc ortholog mediated polycomb group complexes
Authors: Junco Sarah E. , Bardwell Vivian J. , Kim Chongwoo A. , Wang Renjing , Robinson Angela , Ilangovan Udayar , Taylor Alex , Gearhart Micah D. , Hart P. John , Hinck Andrew P. , Borries Demeler
Published: June 2012

NSPC1 is a Polycomb group (PcG) protein that functions within a multiprotein complex containing BCOR (BCL6 Co-Repressor), a protein which has been shown to drive formation of diffuse large B cell leukemia. NSPC1 is one of six human homologs (BMI1, MEL18, NSPC1, MBLR, PCGF3 and PCGF5) of the Drosophila Polycomb group (PcG) protein Psc. While BMI1 and MEL18 can bind directly to another PcG protein called Polyhomeotic (PH), multi-protein complexes involving MBLR and NSPC1 are absent of PH and no function has yet to be assigned to PCGF3 or PCGF5. We show that the ubiquitin (Ub) fold of NSPC1 and PCGF3 does not bind PH, but instead directly interacts with a previously unrecognized 115 residue region within BCOR while the Ub folds of BMI1 and MEL18 bind only PH. Preliminary structural studies using nuclear magnetic resonance and analytical ultracentrifugation indicate that this region of BCOR can independently fold and possesses a novel structure thereby identifying this domain as a unique PcG recruiting module. Thus, we propose the presence of at least two distinct functional classes of Psc orthologs: Class I, (BMI1 and MEL18) that binds PH and Class II (PCGF3, NSPC1 and likely PCGF5) which bind BCOR. The existence of different classes of Psc homologs demonstrates the evolution of the PcG in order to diversify its silencing function.

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 C28.
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

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

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

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

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

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

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

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

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

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

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.