bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2269: Metformin prolongs survival in a K-rasLA2 lung cancer mouse model by inhibiting cancer stem cells and tumor growth.
Authors: Kitagawa Hiroshi , Dallos Matthew , Quinn Brendan , Kunnumakkara Ajaikumar , Dogan Irem , Hollander Christine M. , Dennis Phillip A. 
Published: August 2014

Abstract
Mutations in K-Ras are characteristic of human lung cancers and occur almost exclusively in smokers. Metformin, which is widely prescribed for the treatment of type II diabetes mellitus, may reduce lung cancer incidence in diabetics. We previously showed that metformin prevents K-Ras-mediated lung tumorigenesis in mice exposed to tobacco-carcinogen in an AMPK-independent manner. To elucidate further mechanisms of tumor prevention and estimate the survival impact of metformin on mutant K-Ras-mediated-lung tumorigenesis, we treated mutant K-Ras transgenic mice (K-RasLA2), with oral metformin. Metformin reduced tumor multiplicity by 48.9% and increased overall survival by 34% (median survival 191 days (control) vs 257 days (metformin); HR=0.27; 95% CI 0.11-0.68; p=0.009). Metformin decreased the number of bronchioloalveolar cells (BASCs), which are recognized as the cells of origin for lung adenocarcinomas initiated by oncogenic K-ras, as well as expression of cancer stem cell markers such as OCT4 and SOX2. Markers of cellular proliferation such as cyclin D1 and Ki67 were also decreased in lung tumors from metformin-treated mice. Metformin inhibited activation of multiple receptor tyrosine kinases as well as Ras-Raf signaling. Collectively, these data confirm that metformin inhibits K-Ras-induced lung tumorigenesis and identifies tumor-initiating cells as targets of metformin whose inhibition may underlie the ability of metformin to prolong survival. Clinical chemoprevention trials using metformin are warranted for high-risk populations likely to develop K-Ras mutations such as current or former smokers.
Citation Format: Hiroshi Kitagawa, Matthew Dallos, Brendan Quinn, Ajaikumar Kunnumakkara, Irem Dogan, Christine M. Hollander, Phillip A. Dennis. Metformin prolongs survival in a K-rasLA2 lung cancer mouse model by inhibiting cancer stem cells and tumor growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2269. doi:10.1158/1538-7445.AM2013-2269
Abstract 2292: Enforced expression of miR-125b promotes the in vivo expansion of human Lin- CB multi-lymphoid progenitors (MLP) and AML leukemia stem cells.
Authors: Lechman Eric R. , Hermans Karin G. , Dobson Stephanie , Eppert Kolja , Minden Mark , Dick John E. 
Published: August 2014

Abstract
We recently demonstrated stem cell gene signatures predict clinical outcome in acute myeloid leukemia (AML) (Eppert et. al., Nature Medicine, 2011). Concomitant to this work, miRNA signatures for hematopoietic stem cells (HSC) and leukemia stem cells (LSC) were also generated. miRNA are small non-coding RNAs that regulate the translation and mRNA stability of protein coding genes with significant roles in the maintenance of human HSC (Lechman et. al., Cell Stem Cell, in press). To understand the functional role of miRNA in normal human blood development, we undertook an in vivo over-expression screen of 10 miRNA candidates over-represented in HSC and LSC. Lineage depleted human umbilical cord blood cells (Lin- CB) were transduced with lentivirus expressing either a candidate miRNA or control vector and xeno-transplanted into NSG mice. Three miRNA displayed a competitive growth advantage while 4 miRNA induced a growth disadvantage along with skewing of lineage output. A top LSC array candidate, miR-125b, showed the most pronounced phenotype with overt expansion of marked cells, enlarged spleens and increased lymphoid and erythroid output. Detailed analysis of miR-125b grafts revealed a greatly expanded MLP population, in comparison to HSC and MPP. Furthermore, upon enforced in vivo expression of miR-125b in 3 AML patient samples, we observed large increases in the CD34+CD117+ populations for all three AML samples, suggesting increased LSC numbers. Secondary LDA experiments revealed up to a 34 fold increase in LSC activity in comparison to control vector transduced AML cells. These data suggest that miR-125b normally functions in the limited self-renewal of lymphoid committed early progenitors and this function may be usurped during leukemogenesis to enhance LSC self-renewal.
Citation Format: Eric R. Lechman, Karin G. Hermans, Stephanie Dobson, Kolja Eppert, Mark Minden, John E. Dick. Enforced expression of miR-125b promotes the in vivo expansion of human Lin- CB multi-lymphoid progenitors (MLP) and AML leukemia stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2292. doi:10.1158/1538-7445.AM2013-2292
Abstract 2297: The evidence of glioblastoma heterogenity.
Authors: Soeda Akio , Hara Akira , Kunisada Takahiro , Iwama Toru 
Published: August 2014

Abstract
Gliomas are composed of heterogeneous combinations of cells, with different phenotypic characteristics and different proliferative potentials; however, there is no convincing evidence that only the single glioma stem cells (GSC) could be representative of patient tumor and which cell type were the root for tumor growth. Because most tumors have a clonal origin, GSCs must give rise to phenotypically diverse progenies, including matured GSCs with indefinite self-renewing potential, as well as differentiated cancer cells with limited proliferative potential. To investigate the cellular origin of population diversity, we established 4 subclones from a glioblastoma patient. These subclones were subsequently propagated and analyzed. All clones expressed stem cell makers (nestin, sox2, musashi) heterogeneously. The morphology, self-renewal and proliferative capacities of the subclones were varying. FACS and cDNA microarray analysis showed that each subclones were composed of distinct population of cells. The sensitivities of some drug were different. In animal models, xenografts from subclones, tumor-progression/invasion and animal survivals were also different. Some clones invaded contra-lateral hemisphere via tract fiber. Our observations suggest that single cell derived subclones from a patient is capable of producing phenotypically heterogeneous self-renewing progenies in an in vitro and in vivo setting. The functional analysis of the heterogeneous GSC clones may provide a better understanding of GSC biology and novel means for testing of new treatment strategies that focus on the eradication of the true GSCs.
Citation Format: Akio Soeda, Akira Hara, Takahiro Kunisada, Toru Iwama. The evidence of glioblastoma heterogenity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2297. doi:10.1158/1538-7445.AM2013-2297
Abstract 2298: Cell-specific effects of BRafV600E expression disrupt gliogenesis and lead to astrocytoma formation.
Authors: Lerner Robin G. , Ihara Yuichiro , Reichholf Brian , Qu Dian , Sugiarto Sista , Griveau Amelie , James David , McMahon Martin , Petritsch Claudia 
Published: August 2014

Abstract
Within the adult mammalian brain the asymmetric distribution of cell-fate determinants during mitosis maintains a balance between differentiated and self-renewing cells. We have previously shown that disruption of asymmetric divisions in oligodendrocyte progenitor cells (OPC) causes cells to aberrantly self-renew and fail to differentiate, giving rise to oligodendroglioma (Sugiarto et al. Cancer Cell; 2011; 20; 320-40).
Here we proposed to address whether asymmetric divisions are also disrupted in precursors of malignant astrocytoma, a highly aggressive and therapy resistant type of glioma.
The constitutively active BRaf mutant BRafV600E is mutated in a subset of malignant astrocytoma alongside deletion of Cdkn2a, and can transform NSCs into astrocytoma precursors (Huillard et al. PNAS; 2012; 109; 8710-5). We used BRafCA mice (Dankort et al. Genes Dev. 2007; 21; 379-84) with Cre recombinase-activated expression of BRafV600E and deletion of Ink4a/Arf to generate an in situ model of NSC-derived malignant astrocytoma. In vivo studies to assess asymmetric division and related defects were complemented by studies of BRafV600E expressing, Ink4a/Arf-deleted neurosphere cells in cell-based assays of asymmetric division, self-renewal and differentiation.
Our results provide unprecedented evidence that BRafV600E, although uniformly expressed in NSC and their progeny, disrupts asymmetric divisions in a cell-type specific manner. NSCs continue to divide asymmetrically but their progeny, including OPC, divide more symmetrically and exhibit defects in differentiation and proliferation. These defects are reversible with BRafV600E-specific inhibitor PLX4720, and are associated with increased expression of the mitotic kinase polo-like kinase 1, increased pERK and decreased pAKT.
These data describe a mechanism by which NSC-targeted expression of BRafV600E may generate numerous subpopulations of tumor cells with distinct characteristics. This heterogeneity may mirror that seen in malignant astrocytoma, which has often been associated with high incidence of therapy resistance (Burger et al. Cancer. 1985; 56; 1106-11).
Citation Format: Robin G. Lerner, Yuichiro Ihara, Brian Reichholf, Dian Qu, Sista Sugiarto, Amelie Griveau, David James, Martin McMahon, Claudia Petritsch. Cell-specific effects of BRafV600E expression disrupt gliogenesis and lead to astrocytoma formation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2298. doi:10.1158/1538-7445.AM2013-2298
Abstract 2304: Biologically distinct mammary tumors develop from Trp53 null tissue transplanted to juvenile versus adult gland.
Authors: Nguyen David H. , Mao Jian-Hua , Barcellos-Hoff Mary Helen 
Published: August 2014

Abstract
The biology of the organism is a key regulator of breast cancer development. Our previous work showed that irradiating the host accelerated the development of carcinomas from unirradiated Trp53 null mammary fragments transplanted into the inguinal fat pads previously divested of endogenous epithelia (Nguyen et al., Cancer Cell, 2011). In this report, we investigated the age of transplantation by comparing carcinogenesis in Trp53 null mammary outgrowths that were transplanted during pubertal, 5 week-old mice compared to 10 week-old adult hosts. Tumors arising over the course of a year from Trp53 null tissue transplanted into adult hosts (AH) (n=26), were compared to tumors arising following transplantation in juvenile hosts (JH) (n=55). The rate of tumor occurrence was not significantly different as a function of the transplantation age but once detected, JH tumors grew several times faster. JH tumors were more perfused, as indicated by 2-fold larger blood vessels (p=0.015), and exhibited a 2-fold higher mitotic index (p=0.009) compared to AH tumors. Tumors transplanted at either age were predominantly ER+ (80% JH vs. 60% AH), but more tumor cells were ER immunoreactive as measured by the Allred score in JH tumors compared to AH tumors (p=0.0001). Microarray analysis of 10 JH and 6 AH tumors identified 119 genes that were modulated by at least 1.5-fold in JH tumors. Main biological processes enriched in JH tumors were organ morphology, proliferation, and lipid metabolism. The resulting profile revealed a luminal transcriptional program in JH tumors that included expression of Foxa1 and Areg; Foxa1 protein expression in JH tumors was confirmed by immunohistochemistry. The distinct biology of tumors arising from tissue undergoing morphogenesis in the context of puberty suggests that: (1) the window of susceptibility for breast cancer involves host biology during puberty; and (2) that the tumor intrinsic subtype is not necessarily epithelial autonomous, but can be influenced by the host environment. Supported by DOD-BCRP and DOE Low Dose Radiation Program.
Citation Format: David H. Nguyen, Jian-Hua Mao, Mary Helen Barcellos-Hoff. Biologically distinct mammary tumors develop from Trp53 null tissue transplanted to juvenile versus adult gland. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2304. doi:10.1158/1538-7445.AM2013-2304
Abstract 2309: Identification and targeting of small noncoding RNAs implicated in tumor angiogenesis.
Authors: Mellick Albert S. , Plummer Prue N. , Mittal Vivek 
Published: August 2014

Abstract
Bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to angiogenesis-mediated tumor growth. In previous studies[1], we showed that EPCs can be tracked from the BM to sites throughout the body, including the BM compartment of the tumor stroma. We also demonstrated that the Inhibitor of DNA binding 1 (ID1) proximal promoter can be used to silence genes in EPCs, through directed delivery of short hairpin RNA inhibition. Here we report the elucidation of a novel small RNA pathway regulated by miR-10b, required for regulation of EPC function and tumor angiogenesis. We demonstrate that this pathway is required for tumor vascular biology and through in situ hybridization (ISH) that it is preferentially up-regulated in the vasculature of aggressive late stage Infiltrating Ductal Carcinomas, and not in more contained Ductal Carcinomas. Such analysis reveals the clinical implications of in vivo targeting of miRNAs, such as miR-10b in cancer therapeutics, and reveals the need for cell specific localisation of miRNA expression in understanding tumor malignancy.[2]
1. Mellick AS, Plummer P, Nolan D, et al. Using Transcription Factor Id1 to Selectively Target Endothelial Progenitor Cells Offers Novel Strategies to Inhibit Tumor Angiogenesis and Growth. Cancer Res. 70:7273-82, 2010.
2. Plummer PN, Freeman R, Taft R, Vider J, Sax M, Umer BA, Gao D, Johns CA, Mattick JS, Wilton SD, Ferro V, McMillan NA, Swarbrick A, Mittal V, Mellick AS. MicroRNAs regulate tumor angiogenesis modulated by endothelial progenitor cells. Cancer Res. 2012 Jul 25. [Epub ahead of print].
Citation Format: Albert S. Mellick, Prue N. Plummer, Vivek Mittal. Identification and targeting of small noncoding RNAs implicated in tumor angiogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2309. doi:10.1158/1538-7445.AM2013-2309
Abstract 2315: Reversible disruption of mSWI/SNF-like BAF complexes by the SS18-SSX oncogenic fusion in synovial sarcoma.
Authors: Kadoch Cigall , Crabtree Gerald R. 
Published: August 2014

Abstract
Recent exon sequencing studies have revealed frequent mutations in subunits of SWI/SNF or BAF complexes and implicated them as tumor suppressors. Indeed, we estimate that they are mutated in 15.8 percent of sequenced human cancers. Interestingly, the subunits most commonly mutated are not required for chromatin remodeling in vitro and thus may contribute to chromatin regulation in a novel way. One difficultly in understanding the role of these complexes in cancer is distinguishing primary driving mutations from passenger mutations. To investigate the underlying mechanism we studied human synovial sarcoma (SS), in which transformation results from a remarkably precise and uniform translocation of exactly 78 amino acids of SSX to the SS18 protein. In a proteomic study we discovered that SS18 is a dedicated, non-exchangeable subunit of BAF complexes. We demonstrate that the hallmark SS18-SSX fusion incorporates into BAF complexes, evicting both the wild-type SS18 protein and the tumor suppressor, hSNF5 (BAF47). The altered complex binds the Sox2 locus, reversing polycomb-mediated repression and results in Sox2 activation. Sox2 is uniformly expressed in SS tumors and is essential for their proliferation. Increasing the concentration of wild-type SS18 leads to reassembly of the wild-type complex, retargeting of BAF complexes away from the Sox2 locus, polycomb-mediated repression of Sox2 and cessation of proliferation. This mechanism of transformation depends on only two amino acids of SSX and hence provides a potential foundation for therapeutic intervention.
Citation Format: Cigall Kadoch, Gerald R. Crabtree. Reversible disruption of mSWI/SNF-like BAF complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2315. doi:10.1158/1538-7445.AM2013-2315
Abstract 2320: Oncogenic K-ras and loss of Smad4 mediate invasion by activating a NF-kappaB/EGFR axis that induces expression of MMP9/uPA in human pancreas progenitor cells.
Authors: Bera Alakesh , Zhao Shujie , Cao Lin , Freeman James W. 
Published: August 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely fatal and highly metastatic in nature. Several pathways and mutations contribute to the development and pathogenesis of PDAC. Activating K-ras mutations and inactivating mutations of Smad4 are two common genetic alterations that occur in the development and progression of PDAC. To further study the role of these two mutations in the pathogenesis of PDAC, immortalized human pancreas nestin postive cells (HPNE) were genetically modified by expressing oncogenic K-ras (GD12) and /or by shRNA knock down of Smad4. Present studies show that these two mutations caused increase in expression of EGFR and erbB2 growth factor receptors and increased expression and nuclear translocation of NF-κB. The increase in EGFR expression and nuclear translocation of NF-κB was associated with development of an invasive phenotype as measured by matrigel assays.
Our data also demonstrated that MMP9 and uPA were substantially up regulated in HPNE cells that express K-ras or along with loss of Smad4 activities. MMP-9 and uPA are two extracellular matrix (ECM)-degrading proteinases known to play important roles in driving invasion and metastasis. Zymography studies confirm the expression and enzymatic activities of uPA and MMP-9 in the progenitor cells. The mechanism underlying this uPA/MMP9 induction is linked with NF-κB activation. Immuno-fluorescence, Western blot and chromatin immuno-precipitation (ChIP) analysis confirm the nuclear translocation of NF-κB RelA (p65) sub-unit, by induction of K-ras. Following signaling cascade, EGFR activated by the K-ras mediated NF-κB nuclear localization and further activation induced by loss of Smad4. Our results also suggest that the EGFR pathway as a critical mediator connecting Ras to NF-κB in proteolytic enzyme secretion as well as cancer invasion.
In conclusion, the present study reveals a new insight in pancreatic progenitor cell invasion which includes signal transduction of K-ras activity and Smad4 inactivation in regulation of NF-κB/EGFR axis to induce expression of uPA and MMP9. Therefore, induction of K-ras and loss of Smad4 could play important roles in PDAC invasion through NF-κB/EGFR activation and subsequent induced expression of MMP9 and uPA, and might be suitable molecular candidates for the development of new therapeutic strategies for pancreatic cancer.
Citation Format: Alakesh Bera, Shujie Zhao, Lin Cao, James W. Freeman. Oncogenic K-ras and loss of Smad4 mediate invasion by activating a NF-kappaB/EGFR axis that induces expression of MMP9/uPA in human pancreas progenitor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2320. doi:10.1158/1538-7445.AM2013-2320
Abstract 2322: The KIAA1549:BRAF fusion gene regulates mTOR signaling and gliomagenesis in a cell type- and brain region-specific manner.
Authors: Kaul Aparna , Chen Yi-Hsien , Emnett Ryan J. , Dahiya Sonika , Gutmann David 
Published: August 2014

Abstract
The two most common genetic alterations in low-grade pediatric brain tumors (glioma) are NF1 gene inactivation and tandem duplications involving the BRAF kinase gene. In this study, we sought to define the role of KIAA1549:BRAF fusion (fusion BRAF; f-BRAF) gene in glioma development. We demonstrate that f-BRAF regulates cerebellar NSC proliferation by activating the mTOR pathway downstream of MAPK. Also, f-BRAF expression in cerebellar neuroglial progenitors is sufficient to induce glioma-like lesions in mice. Interestingly, f-BRAF expression does not increase the proliferation of NSCs derived from other brain regions, nor does it increase primary astrocyte proliferation. These brain region- and cell type-specific growth promoting effects of f-BRAF are mediated by tuberin/Rheb-dependent modulation of mTOR, leading to S6-kinase activation and p27 degradation. Finally, we demonstrate that mTOR activation is also observed in fusion BRAF-associated human sporadic pilocytic astrocytomas. Our findings highlight the importance of spatial, cellular and molecular heterogeneity in brain tumor development, and provide compelling preclinical evidence for the use of mTOR pathway inhibitors for both sporadic and familial low-grade gliomas.
Citation Format: Aparna Kaul, Yi-Hsien Chen, Ryan J. Emnett, Sonika Dahiya, David Gutmann. The KIAA1549:BRAF fusion gene regulates mTOR signaling and gliomagenesis in a cell type- and brain region-specific manner. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2322. doi:10.1158/1538-7445.AM2013-2322