bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4775: PI3K-p110β is required for leukemic transformation and HSC depletion in the absence of Pten
Authors: Yuzugullu Haluk , Baitsch Lukas , Steiner Allison , Clayton Linda K. , Gritsman Kira , Zhao Jean J. 
Published: May 2015

Abstract
The tumor suppressor PTEN, which antagonizes PI3K signaling, plays critical roles in cell cycle, cell migration and stem cell self-renewal. PTEN is frequently mutated or inactivated in T-cell acute lymphoblastic leukemia (T-ALL) and acute myelogenous leukemia (AML). In mice, HSC-specific deletion of Pten leads to myeloproliferative phenotype, transplantable leukemia, and increased cycling of hematopoietic stem cells (HSCs), leading to their depletion. Rapamycin, an mTOR inhibitor, rescues this phenotype. Thus, it is likely that PI3K itself plays an important role in Pten-deficient HSCs and leukemic cells, but the specific contributions of the PI3K isoforms are poorly understood. We demonstrate that genetic ablation or pharmacological inhibition of PI3K-p110β prevents myeloid neoplasia and prolongs survival. Importantly, p110β ablation rescues HSCs in the bone marrow (BM), and reinstates long-term hematopoietic reconstitution. Moreover, Pten deficiency leads to aberrant expression of Cxcl12 in the BM and spleen, enabling the generation of an alternative splenic niche. Inactivation of p110β rescues retention of HSCs, and perturbs the splenic niche by interfering with the Cxcl12-CXCR4 axis. This suggests that selective inhibition of p110β offers an alternative therapeutic strategy in PTEN deficient leukemias while restoring untransformed HSCs to their proper niche.
Citation Format: Haluk Yuzugullu, Lukas Baitsch, Allison Steiner, Linda K. Clayton, Kira Gritsman, Jean J. Zhao. PI3K-p110β is required for leukemic transformation and HSC depletion in the absence of Pten. [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 4775. doi:10.1158/1538-7445.AM2014-4775
Abstract 4780: The effects of the global loss of DNA methylation on the functional organization of the epigenome
Authors: Lay Fides D. , Liu Yaping , Kelly Theresa K. , Witt Heather , Blattler Adam , Farnham Peggy J. , Berman Ben P. , Jones Peter A. 
Published: May 2015

Abstract
Aberrant epigenetic changes which include alterations in DNA methylation, nucleosome positioning and histone modifications have been studied extensively in the context of tumorigenesis. The role of DNA methylation in the organization of genome-wide chromatin structure and its interaction with other epigenetic modifiers in cancer, however, remains unclear. Here, we use the Nucleosome Occupancy and Methylation whole-genome sequencing (NOMe-seq) assay to compare a colorectal cancer cell line, HCT116, with its derivatives that carry homozygous deletions of DNMT3B and are hypomorphic for DNMT1, DKO1, to examine the role of DNA methylation in the functional organization of the cancer epigenome. Upon the global loss of DNA methylation, we observe a widespread chromatin remodeling where specifically, DKO1 cells gain nucleosome depleted regions (NDRs) and/or well-phased nucleosome that are not present in the parent HCT116 cells. Interestingly, this genome-wide nucleosome repositioning in DKO1 cells is accompanied by significant histone modification changes and low level expression increase only in CpG islands (CGI), where promoters may gain permissive histone marks H2A.Z, H3K4me3 and H3K4me1 as well as the polycomb repressive mark, H3K27me3. Non-CGI promoters on the other hand, do not gain permissive or repressive histone modifications despite dramatic nucleosome reorganization, which suggests that distinct mechanisms regulate the equilibrium between DNA methylation, nucleosome and gene expression in CGI and non-CGI promoters. Taken together, our study demonstrates the cross-talk between epigenetic mechanisms wherein DNA methylation may directly control the organization of chromatin architecture.
Citation Format: Fides D. Lay, Yaping Liu, Theresa K. Kelly, Heather Witt, Adam Blattler, Peggy J. Farnham, Ben P. Berman, Peter A. Jones. The effects of the global loss of DNA methylation on the functional organization of the epigenome. [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 4780. doi:10.1158/1538-7445.AM2014-4780
Abstract 4781: Integrated epigenomic profiling reveals widespread demethylation in melanoma and reveals CSF-1 receptor as an aberrant regulator of malignant growth and invasion
Authors: Mo Yongkai , Giricz Orsolya , Hu Caroline H. , Dahlman Kimberly B. , Bhattacharyya Sanchari , Nguyen Hoa , Matusow Bernice , Bhagat Tushar , Shellooe Rafe , Burton Elizabeth , Tsai James , Zhang Chao , Habets Gaston , Shyr Yu , Greally John , Yu Yiting , Bollag Gideon E. , Stanley Richard , Trent Jeffrey , Kenny Paraic A. , West Brian L. , Sosman Jeffrey , Verma Amit K. 
Published: May 2015

Abstract
Epigenetic alterations can direct carcinogenesis by leading to transcriptional changes and inducing genomic instability. We analyzed the methylome of malignant melanoma and observed widespread loss of DNA methylation that was found to preferentially occur outside of CpG islands. Demethylation was seen to occur early during carcinogenesis, was independent of mutational status and correlated with genomic instability. Parallel transcriptomic analyses revealed that various immune and cancer associated pathways were overexpressed and were associated with promoter demethylation. The CSF1-receptor (CSF1R) was aberrantly overexpressed and hypomethylated in nearly all cases and was strikingly expressed via an aberrant upstream promoter in 10% of melanomas. shRNA mediated knockdown and inhibition of CSF1R kinase via a clinically relevant inhibitor, PLX3397, led to decreased 3D growth and invasiveness. Co-inhibition of CSF1R and BRAF resulted in synergistic blockade of BRAF-mutant melanoma xenograft growth. Thus, widespread epigenetic changes are seen in melanoma and CSF1R is a potential therapeutic target in this disease.
Citation Format: Yongkai Mo, Orsolya Giricz, Caroline H. Hu, Kimberly B. Dahlman, Sanchari Bhattacharyya, Hoa Nguyen, Bernice Matusow, Tushar Bhagat, Rafe Shellooe, Elizabeth Burton, James Tsai, Chao Zhang, Gaston Habets, Yu Shyr, John Greally, Yiting Yu, Gideon E. Bollag, Richard Stanley, Jeffrey Trent, Paraic A. Kenny, Brian L. West, Jeffrey Sosman, Amit K. Verma. Integrated epigenomic profiling reveals widespread demethylation in melanoma and reveals CSF-1 receptor as an aberrant regulator of malignant growth and invasion. [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 4781. doi:10.1158/1538-7445.AM2014-4781
Abstract 4805: Carcinogenesis by stem cell misplacement–a novel cancer theory and its implications
Authors: Wang Rui-An 
Published: May 2015

Abstract
For rather a long period of time, it has been widely accepted that cancer was caused by gene mutations which is termed somatic mutation theory (SMT). But now the SMT theory has met with increasing doubts, disbelieves, and been facing challenges from other alternative theories. I here from a pathological perspective, and with the evidences from molecular pathology, hisopathology, and epidemiology, show that the 80 year old paradigm of carcinogenesis process from atypia to in situ carcinoma to invasive cancer is wrong. Since 90% of the human cancers are epithelially derived “carcinomas”, the turnover of this paradigm naturally negates the SMT theory for SMT sits on this model. The invasive cancer grows out in the stroma de novo from misplaced stem cells rather than deriving from the transformed in situ carcinoma cells. Also, I will show evidences that cancer cells are not so-believed “apoptosis-resistant”, but rather “short-lived sick cells”. In fact, it is the increased cell death which makes the cancer cells proliferate ceaselessly to compensate for the cell loss, and move to new locations for better chance of survival. I design this novel cancer theory as SCMT, stem cell misplacement theory. This theory is backed by huge amount of solid evidences and will bring revolutionary conceptual changes to our understanding and treatment of cancer, e.g., in situ carcinomas are not genuine cancer biologically, thus should not be treated the same as cancer.
Citation Format: Rui-An Wang. Carcinogenesis by stem cell misplacement–a novel cancer theory and its implications. [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 4805. doi:10.1158/1538-7445.AM2014-4805
Abstract 4806: Angiogenesis is independently influenced by interstitial flow and concentration gradients of tumor secreted morphogens
Authors: Shirure Venktesh S. , George Steven C. 
Published: May 2015

Abstract
Angiogenesis facilitates growth and entry of tumors into the systemic circulation leading to metastasis. Morphogens, such as vascular endothelial growth factor (VEGF), secreted by the tumors are believed to guide nearby vasculature towards the tumor. The distribution of morphogens in tissues is affected by interstitial fluid flow, which also exerts forces in the tissue microenvironment. Numerous cells in the tumor microenvironment can sense and respond to force, yet our understanding of the independent effect of interstitial flow in tumor angiogenesis is limited. This is due, in part, to inadequate experimental models that cannot decouple spatial morphogen concentrations and interstitial flow. Notably, control of these parameters is not possible in animal models, and 2D cell systems lack the complexity of in vivo tissue. We addressed these limitations by designing a microfluidic platform of polydimethlsiloxane (PDMS) polymer consisting of three parallel microporous tissue compartments (&lt; 0.1 mm3 total volume) that are media-fed with microfluidic lines. Endothelial colony forming cell-derived endothelial cells (ECFC-EC) and stromal fibroblasts in extracellular matrix proteins (e.g., fibrin and collagen) seeded in the central compartment formed interconnected microvascular networks with hollow lumens in 7-14 days. A mathematical model of mass and momentum transport in the microfluidic device was used to determine experimental conditions that either minimize the concentration gradients or the interstitial flow across the tissue chamber. The conditions were validated experimentally using various molecular size fluorescent dextrans. In the absence of a concentration gradient, microvessels demonstrated a striking bias for angiogenesis against the direction of the interstitial flow. Furthermore, the extent of migration against the flow increased with increasing interstitial flow. In separate experiments with minimal/no interstitial flow, angiogenisis is biased towards a positive concentration gradient of the morphogens such as VEGF. In conclusion, we have developed a novel microfluidic platform that can decouple the effects of concentration gradients and interstitial flow. Using this platform we show that angiogenesis is independently influenced by interstitial flow and concentration gradients of tumor secreted morphogens.
Citation Format: Venktesh S. Shirure, Steven C. George. Angiogenesis is independently influenced by interstitial flow and concentration gradients of tumor secreted morphogens. [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 4806. doi:10.1158/1538-7445.AM2014-4806
Abstract 4808: Aflibercept is highly active in clinically relevant, patient derived xenografts of colorectal cancer
Authors: Bagley Rebecca G. , Amalou Zakia , Chiron Marielle , Vuaroqueaux Vincent , Caron Anne , Baltes Nina , Fiebig Heinz H. 
Published: May 2015

Abstract
Aflibercept (ziv-aflibercept in USA), a new fusion protein, targets vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PlGF). Aflibercept + FOLFIRI is approved for treating metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin containing regimen. We investigated the pharmacological activity of aflibercept in CRC patient derived xenografts (PDX), most metastases-derived, and characterized PDX molecular and phenotypic properties. In 48 CRC PDX, Whole Exome Sequencing revealed: 85% APC, 79% TP53, 51% KRAS, 3% NRAS, 25% PIK3CA, 11% PTEN and 8% BRAF mutants. There was no significant association between angiogenic factors, tumor mutation profiles, and response to aflibercept.
In tumors, protein levels of human (h) VEGF-A were significantly higher than mouse (m) VEGF-A, hPlGF, and mPlGF (Chiron et al, ESMO, 2013). Affymetrix probes detected VEGF-A and PIGF but not VEGF-B mRNA in most PDX. There was no significant association between expression of angiogenic factors and response to aflibercept. Histological sections of CRC tumors from PDX, xenografts created from cell lines, and patients’ tumor specimens indicated that stromal involvement in human tumors was recapitulated in PDX but not in tumors from cell lines. PlGF expression was analyzed by immunohistochemistry on colon cancer tissue arrays. A significant number of colon cancer specimens were positive for PlGF, expressed in tumor cells and stroma. Aflibercept resulted in anti-tumor activity in 47/48 CRC PDX models and complete tumor stasis in 31/48 models. Efficacy data from 5 PDX models responsive to aflibercept and CRC standard of care (SOC) drugs, all administered as monotherapies, are below. The robust activity of aflibercept in CRC PDX models that are sensitive to SOC drugs suggest that CRC patients would benefit from aflibercept treatment, independently of mutational status or expression of angiogenic factors.
In Vivo Sensitivity Profile (optimal Tumor/Control (%))CRC PDX ModelPrior TreatmentsAflibercept 25 mg/kg, SC, 2x/wk5-FU100 mg/kg, IP, 1x/wkIrinotecan 50 mg/kg, IV, 1x/wkOxaliplatin 10 mg/kg, IP, Q2WCetuximab30 mg/kg, IV,1x/wkKRAS StatusCFX 1991Not available-2.531.51.856.342.1MutantCFX 2032Not available3.147.76.760.535.7MutantCFX 2048Not available-10.326.221.350.12.6Wild-typeCFX 20655-FU, leucovorin-11.920.614.471.82.2Wild-typeCFX 2067None6.253.045.158.914.2Wild-type
Citation Format: Rebecca G. Bagley, Zakia Amalou, Marielle Chiron, Vincent Vuaroqueaux, Anne Caron, Nina Baltes, Heinz H. Fiebig. Aflibercept is highly active in clinically relevant, patient derived xenografts of colorectal 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 4808. doi:10.1158/1538-7445.AM2014-4808
Abstract 4849: Implications of cancer induced blood coagulation in cancer diagnosis and therapy
Authors: Hisada Yohei , Yasunaga Masahiro , Hanaoka Shingo , Saijou Shinji , Sugino Takashi , Tsuji Atsushi , Saga Tsuneo , Tsumoto Kouhei , Manabe Shino , Kuroda Jun-ichiro , Kuratsu Jun-ichi , Matsumura Yasuhiro 
Published: May 2015

Abstract
A large body of clinical evidence indicates that abnormal coagulation occurs in a variety of cancers, especially invasive cancers. If cancer clusters erode adjacent normal or tumor vessels, hemorrhage may occur, and fibrin clots immediately form in situ to stop the bleeding. The fibrin clots are subsequently replaced by collagen, similar to the case in the normal wound healing process. Although there are many points in common between cancer-induced stroma and normal wound healing, the critical difference between the two is that the pathophysiological condition in cancer lasts for as long as cancer cells survive in the body (Adv Drug Deliv Rev 2012).
First, we successfully developed a mAb that reacts only with human insoluble fibrin, not human fibrinogen (Cancer Sci 2011). In contrast to previously reported anti-fibrin monoclonal antibodies (mAbs), our anti-fibrin clot mAb (clone 102-10) recognizes an unexplored hole that is uncovered only when a fibrin clot forms. The epitope of the 102-10 mAb was mapped to a hydrophobic region on the Bβ-chain that interacted closely with a counterpart region on the γ-chain in the soluble state. New anti-Bβ and anti-γ mAbs specific for peptides lining the discovered hole appeared to bind exclusively to fibrin clots. Analysis of the kinetics of fibrin clot deposition using 102-10 in several disease models indicated that fibrin clot formation occurs only in the acute phase of the disease process, thrombosis, inflammation or trauma, and that these clots virtually disappear within a few weeks to be substituted by collagen. Then, we developed a new PET probe using 102-10. The radiolabelled mAb was injected into mice bearing chemically induced spontaneous tumors, and the probe showed clear and specific accumulation in the tumors. We named this detection strategy cancer stromal targeting (CAST) diagnois. Immunohistochemistry using this mAb revealed higher fibrin deposition in WHO grade 4 gliomas than in lower-grade gliomas. Because erosive tumors are highly likely to show micro-hemorrhages, even early asymptomatic tumors detected with radiolabeled 102-10 mAb may be aggressively malignant (Sci. Rep. 2013).
In conclusion, CAST diagnosis and therapy based on anti-insoluble fibrin mAb may be a useful new strategy in the field of oncology.
Citation Format: Yohei Hisada, Masahiro Yasunaga, Shingo Hanaoka, Shinji Saijou, Takashi Sugino, Atsushi Tsuji, Tsuneo Saga, Kouhei Tsumoto, Shino Manabe, Jun-ichiro Kuroda, Jun-ichi Kuratsu, Yasuhiro Matsumura. Implications of cancer induced blood coagulation in cancer diagnosis and therapy. [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 4849. doi:10.1158/1538-7445.AM2014-4849
Abstract 4863: Quantification of cell fusion events between breast cancer cells and breast epithelial cells
Authors: Mohr Marieke , Zänker Kurt , Dittmar Thomas , Edenhofer Frank 
Published: May 2015

Abstract
Recent data suggest that cell-cell fusion contributes to the development of hybrid cell clones showing genetic and behavioural alterations. But less is known about forces triggering cell fusion processes between breast cancer cells and tumor surrounding cells. The influence of chronic inflammation and tumor microenvironment is increasingly being recognized as an etiology for cancer progression and cell fusion. However, information on how and which components particularly affect cell-cell fusion and thereby disease outcome remains elusive.
Available facilities to quantitate these cell-cell fusion processes in vitro could provide a novel method to identify cancer promoting components of the stroma. In the present study cell-cell fusion was measured by using a cre/ loxP reporter system. Therefore, two breast cancer cell lines stable transfected with a double fluorescence reporter vector and a breast epithelial cell line containing cre recombinase were generated and cell fusion was promoted by co-culturing cells under appropriate conditions. Regarding the complex nature of tumor milieu the potential influence of several inflammatory and anti-inflammatory cytokines were tested and revealed alterations in fusogenic behaviour of cell lines. Increased fusion activity was observed while adding the proinflammatory cytokine TNFα or epithelial growth factor (EGF). It could also be assumed that hypoxia is a stimulus for cell-cell fusion. In contrast the chemoattractant SDF-1α which is involved in many cancer metastatic mechanisms hadn't any influence. Interestingly, both breast cancer cell lines showed markedly different fusion activity after activation of the transcription factor NfκB.
The present study establishes an efficient tool for quantification of cell-cell fusion processes in vitro by cre mediated recombination of a loxP reporter system. This highlights a new opportunity to identify a potential link between components priming and triggering cell-cell fusion and therefore carcinogenesis.
Citation Format: Marieke Mohr, Kurt Zänker, Thomas Dittmar, Frank Edenhofer. Quantification of cell fusion events between breast cancer cells and breast epithelial 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 4863. doi:10.1158/1538-7445.AM2014-4863
Abstract 4870: Proteomics of phyllodes tumor revealed that decorin increase in the extracellular matrix by periostin deficiency decreased cancer cell motility and invasion
Authors: Ishiba Toshiyuki , Nakanishi Akira , Sato Takanobu , Nakagawa Tsuyoshi , Nagahara Makoto , Oono Ryo , Uetake Hiroyuki , Sugihara Kenichi , Miki Yoshio 
Published: May 2015

Abstract
The ability of cancer cells to metastasize is dependent on the interactions of their cell surface molecules with microenvironment. However the tumor microenvironment, especially cancer-associated stroma, is poorly understood. To search for proteins which are present in the stroma, we investigated the phyllodes tumor, which contains breast stromal tissue, specific expression proteins compared with normal tissue by using iTRAQ-based quantitative proteomic approach. Periostin and versican core protein were up-regulated in phyllodes tumor. Decorin, mimecan, hemoglobin subunit alpha, hemoglobin subunit beta and ketatin, type1 cytoskeletal 19 were up-regulated in normal tissue. Periostin and decorin are one of component of the extracellular matrix. Periostin upregulation has been reported in many cancer types and is consequently defined as a tumor-enhancing factor. On the other hand, decorin upregulation inhibits tumor growth by antagonizing tumor angiogenesis. Periostin upregulation in phyllodes tumor and decorin upregulation in normal tissue was validated by immunohistochemical analysis from phyllodes tumor thirty five patients. We determined the interaction between decorin and periostin in phyllodes tumor tissues and breast cancer cell line BT-20 cells, by using immunoprecipitation and mass spectrometry analysis. Furthermore, we uncovered the plasma membrane translocation of decorin from cytoplasm in BT-20 or T-47D cells by siRNA-mediated knockdown of periostin, and detected the secreted decorin to the extracellular medium using Multiple Reaction Monitoring (MRM) method. The periostin siRNA-treated BT-20 cells motility and invasion were prevented by the secreted decorin into the extracellular medium. The overexpression of decorin suppressed the metastatic breast cancer cell line, MDA-MB-231 cells motality and invasion. These results demonstrated the secreted decorin by periostin deficiency decreased cancer cells motality and invasion. This molecular mechanism may become the new target for anti-cancer therapy.
Citation Format: Toshiyuki Ishiba, Akira Nakanishi, Takanobu Sato, Tsuyoshi Nakagawa, Makoto Nagahara, Ryo Oono, Hiroyuki Uetake, Kenichi Sugihara, Yoshio Miki. Proteomics of phyllodes tumor revealed that decorin increase in the extracellular matrix by periostin deficiency decreased cancer cell motility and invasion. [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 4870. doi:10.1158/1538-7445.AM2014-4870