bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 327: Properties associated with cancer progression in primary clonal epithelial and mesenchymal-like murine mammary tumor cells
Authors: Palen Katie A. , Johnson Bryon D. , Gershan Jill A. 
Published: August 2012

Abstract
The majority of cancer patients die from tumor relapse. Consequently, characteristics of tumor cells that may contribute to aggressive cancer progression are under intense investigation. Tumors are composed of heterogeneous populations of cells that express a continuum of epithelial and mesenchymal markers. There is mounting evidence that mesenchymal tumor cells acquire invasive features and are refractory to conventional treatment, but in order to decipher the contribution of both epithelial and mesenchymal-like tumor cells to disease relapse we must understand the cellular and molecular properties of each cell type. Using a combination of different culture conditions and cell sorting strategies, we cloned epithelial and mesenchymal-like tumor cells that were derived from FVB Tg MMTV/Neu spontaneous mammary tumors. The availability of these clonal primary cell lines provides an unique opportunity to compare tumor cell properties that may contribute to aggressive disease such as proliferation, resistance to apoptosis, tumorigenicity, invasiveness, expression of growth factor and cytokine receptors, inflammatory cytokine secretion, immunogenicity, and expression or down-regulation of immune-modulatory molecules. Some of our preliminary data has revealed that (1) Epithelial cells are more proliferative in vitro, and cell proliferation was reduced upon exposure to the tyrosine kinase inhibitor, TKI-258. TKI-258 did not significantly decrease the proliferation of mesenchymal-like tumor cells, (2) A population of epithelial-enriched cells was more tumorigenic as compared to mesenchymal-like-enriched cells when administered to an immune competent syngeneic host, (3) Epithelial cells express greater Neu transgene, IL-6 and TNF-α transcripts than mesenchymal-like cells, and (4) When low passage clonal epithelial and mesenchymal-like cells were used as a whole cell tumor vaccine in FVB wild-type mice there was an increase in CD8 T cell activation as compared to that elicited by administration of a non-clonal high passage tumor cell line. We are continuing to explore molecular and functional differences between the clonal epithelial, clonal mesenchymal and the non-clonal tumor cell line cells. Characterization of epithelial and mesenchymal-like tumor cells represents an initial step in deciphering how tumor cells contribute to aggressive cancer progression and will offer insight into how epithelial and mesenchymal-like tumor cells respond to therapeutic interventions. The ultimate goal will be to tailor anticancer therapy toward eradicating the unique type of tumor cells that populate patient tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 327. doi:1538-7445.AM2012-327
Abstract 3279: Potential beneficial effects of the BRCA1 mutation carrier state on bone strength
Authors: Liu Ying , Yen Hai-Yun , Gabet Yankel , Wu Nancy , Pike Malcolm C. , Frenkel Baruch , Maxson Robert , Dubeau Louis 
Published: August 2012

Abstract
We previously suggested, based on observations in a mouse model in which we conditionally inactivated Brca1 in ovarian granulosa cells, that mutant mice are exposed to higher estradiol levels and also have prolonged estradiol exposure unopposed by progesterone due to an increase in the proestrus phase of their estrus cycle relative to metestrus. We sought to examine the biological significance of increased hormonal stimulation in homozygous Brca1 conditional knockout mice and to test the hypothesis that the effect is also present in mice with a heterozygous mutation such as present in human BRCA1 mutation carriers. We use endometrial cellular proliferation as an indicator for short-term effects of a Brca1mutation. Long-term effects were examined by measurements of long bone parameters using micro-computed tomography. The relative effects of heterozygous versus homozygous Brca1 mutations were evaluated by measuring the expression of enzymes involved in estradiol biosynthesis in granulosa cells. Mutant mice synchronized in the proestrus phase of their estrus cycle showed an increase in endometrial stromal cell proliferation in (P = .01). Mutant mice also showed an increase in trabecular bone density (P = .01) and femoral length (P = .02). Protein expression of aromatase and Hsd3B was higher in granulosa cells of mice carrying a heterozygous mutation in their ovarian granulosa cells compared to wild type littermates (P = .005 and .006 respectively). Our results provide a potential explanation for epidemiological observations to the effect that height is associated with increased risk for breast and ovarian cancer. The results also suggest that BRCA1 mutations, while associated with increased cancer risk, may also have some inherent advantages such as increased bone strength that may have contributed to the maintenance of mutated BRCA1 alleles in the human gene pool. Heterozygous Brca1 mutations such as present in human BRCA1 mutation carriers are not silent.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3279. doi:1538-7445.AM2012-3279
Abstract 3292: A genetically engineered mouse model for high grade serous “ovarian” carcinoma arising in the fallopian tube
Authors: Perets Ruth , Muto Katherine W. , Bijron Jonathan G. , Kenneth Chin T. , Poole Barish B. , Crum Christopher P. , Dinulescu Daniela M. , Drapkin Ronny 
Published: August 2012

Abstract
Ovarian cancer is the most lethal gynecologic malignancy because the vast majority of cases are detected in late stage, a finding that has thwarted attempts to understand the pathogenesis and cell-of-origin of this disease. The traditional view of epithelial ovarian pathogenesis asserts that all tumor subtypes share a common origin in the ovarian surface epithelium (OSE). There is robust data to support the OSE as the site of origin for many ovarian tumors, including low-grade carcinomas and borderline tumors. However, the pathogenesis of high-grade serous ovarian carcinoma, the most common type of ovarian cancer, continued to defy explanation by the OSE model. More recent studies suggested that the fallopian tube epithelium (FTE), rather than the OSE, may be the site-of-origin for a majority of pelvic serous carcinomas (PSC, defined as ovarian, peritoneal and tubal high grade serous carcinomas). We show here that the FTE can be site of origin for PSC by genetically engineering a mouse model that specifically targets the FT secretory cell with defined genetic alterations that are characteristic of human PSC. These mice develop tubal intraepithelial serous carcinomas, a precursor to PSC, that are morphologically and immunophenotypically similar to the lesions described in human patients. Furthermore, these intraepithelial lesions progress to widespread peritoneal disease that recapitulates the presentation of high-grade PSC in women. The tumors express common serous markers such as P53, αH2A.X, PAX8 and CA-125. Taken together our model is the first fully genetically engineered mouse model that truly recapitulates human serous carcinoma pathogenesis. Our model serves as proof-of-concept that the FTE can be site-of-origin to PSC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3292. doi:1538-7445.AM2012-3292
Abstract 3293: p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans
Authors: Wild Peter J. , Ikenberg Kristian , Fuchs Thomas , Georgiev Strahil , Noske Aurelia , Roessle Matthias , Caduff Rosmarie , Dellas Athanassios , Fink Daniel , Moch Holger , Krek Wilhelm , Frew Ian 
Published: August 2012

Abstract
Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II carcinoma subtypes. The PI3K-Akt-mTOR signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, immunohistochemical analyses of 521 human endometrial carcinomas identified frequent mTOR pathway activation in type I as well as type II endometrial carcinoma subtypes and mTOR pathway activation and p53 expression each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the PI3K-mTOR pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and PI3K-mTOR pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3293. doi:1538-7445.AM2012-3293
Abstract 3314: Phenotypic plasticity in glioma stem cells mediated by NFκB signaling
Authors: Bhat Krishna P. L. , Vaillant Brian , Balasubramainyan Veerakumar , Ezhilarasan Ravesanker , Hollingsworth Faith , James Johanna , Wani Kahlida , Goodman Lindsey , Sulman Erik , Colman Howard , Aldape Kenneth 
Published: August 2012

Abstract
Here we report the identification of two major subtypes of glioma stem cells (GSCs) that closely mirror previously described glioblastoma (GBM) groups, namely proneural (PN) and mesenchymal (MES), based on gene expression patterns. Using flow cytometry, we found that PN GSCs express both CD15/SSEA1, a marker for neural stem cells, as well as CD44, a MES marker. In contrast MES GSCs were CD15low/CD44high. MES GSCs and CD44high subpopulations in PN GSCs showed increased expression of transcription factors previously reported to induce the MES phenotype (STAT3, C/EBP-α, and TAZ), and were -resistant to α-irradiation. By distilling cytokines that can induce MES differentiation, we found that TNF-α found in patient-derived microglial conditioned media or conditioned media from MES GSCs caused a PN-to-MES transition through activation of NFκB resulting in radio-resistance. We found that NFκB mediates MES transition indirectly by inducing the transcriptional circuitry of STAT3, C/EBP-α, and TAZ. Blockade of NFκB activation using minocycline abrogated the MES phenotype (both induced and constitutive), reduced tumor growth, and rendered GSCs radio-sensitive. Taken together, our findings reveal that phenotypic and surface marker plasticity is common in GSCs, and that the NFκB driven PN-to-MES transition provides an escape mechanism for GSCs to evade cytotoxic treatment. Based on our studies, we propose that minocycline, a commonly used antibiotic, could target GSCs and should be further evaluated in preclinical studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3314. doi:1538-7445.AM2012-3314
Abstract 3318: Phenotypic heterogeneity and instability of tumor-initiating cells in high-grade serous cancer
Authors: Stewart Jocelyn M. , Shaw Patricia A. , Bernardini Marcus Q. , Ailles Laurie E. , Neel Benjamin G. 
Published: August 2012

Abstract
Serous ovarian cancer (SOC) is the leading cause of morbidity/mortality from gynecologic malignancy. Current therapies significantly increase survival, yet 70-90% of SOC patients recur within five years and die of their disease. The cancer stem cell (CSC) hypothesis holds that only some tumor cells have the potential to initiate and maintain tumors. Moreover, CSC might be resistant to many therapeutic agents that are effective against bulk tumor cells, which could contribute to treatment failure. We have established a large collection of primary human SOC samples and developed a robust, quantitative assay for SOC tumor-initiating cells (TIC). Using this assay, we found that TIC from primary SOC can be identified based on their expression of the surface marker CD133. However, we also observed heterogeneity and instability of the TIC phenotype with disease progression. We examined whether instability in the TIC phenotype may be due to the acquisition of additional genetic alterations in the CD133- compared to the CD133+ fraction. Preliminary analysis suggests that most genetic alterations are common in both fractions; however, in 3/6 cases, additional genetic alterations were observed in the CD133- fraction, suggesting the emergence of CD133- TIC might be, at least in part, genetically driven. The mechanism of genetic instability is currently under investigation. In addition, we have used expression microarrays to examine differences between CD133+ and CD133- populations. We find that &gt;1000 probes are differentially expressed in these two groups. We have identified several pathways with altered expression in TIC-enriched fractions. The biological role of these pathways in HG-SOC is under investigation. Our ability to identify and characterize TIC in this disease may facilitate development of new and more effective therapeutic strategies for ovarian cancer, thereby benefitting patients with this devastating disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3318. doi:1538-7445.AM2012-3318
Abstract 3321: Cationic polyurethanes-short branch PEI-mediated delivery of Mir145 inhibited epithelial-mesenchymal transdifferentiation and cancer stem-like properties and in lung adenocarcinoma
Authors: Chien Chian-Shiu , Chiou Shih-Hwa 
Published: August 2012

Abstract
The high invasiveness and frequent recurrence of lung adenocarcinoma (LAC) are major reasons for treatment failures and poor prognoses. Alterations in microRNAs (miRNAs) expression have been shown in lung cancers. Recent reports have demonstrated that tumors contain a small subpopulation of cancer stem cells (CSCs) that possesses self-renewing capacity and is responsible for tumor malignancy including metastasis, relapse, and chemoradioresistance. However, a miRNAs-based therapeutic approach in LAC-associated CSCs (LAC-CSCs) is still blurred. Using miRNA/mRNA-microarray and Quantitative RT-PCR, we found that the expression of miR145 is negatively correlated with the levels of Oct4/Sox2/Fascin1 in LAC patient specimens, and an Oct4highSox2highFascin1highmiR145low phenotype predicted poor prognosis. We enriched LAC-CSCs by side population sorting or identification of CD133 markers and found that LAC-CSCs exhibited low miR145 and high Oct4/Sox2/Fascin1 expression, CSC-like properties, and chemoradioresistance. To clarify the role of miR145, we used a polyurethane-short branch-polyethylenimine (PU-PEI) as the vehicle to deliver miR145 into LAC-CSCs. PU-PEI-mediated miR145 delivery reduced CSC-like properties, and improved chemoradioresistance in LAC-CSCs by directly targeting Oct4/Sox2/Fascin1. Importantly, the repressive effect of miR145 on tumor metastasis was mediated by inhibiting the epithelial-mesenchymal transdifferentiation (EMT) and metastastic ability, partially by regulating Oct4/Sox2/Fascin1, Tcf4, and Wnt5a. Finally, in vivo study showed that PU-PEI-mediated miR145 delivery to xenograft tumors reduced tumor growth and metastasis, sensitized tumors to chemoradiotherapies, and prolonged the survival times of tumor-bearing mice. Our results demonstrated that miR145 acts as a switch regulating lung CSC-like and EMT properties, and provide insights into the clinical prospect of miR145-based therapies for malignant lung cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3321. doi:1538-7445.AM2012-3321
Abstract 3329: A let-7 signaling pathway targets metastatic genes enriched in tumor initiating cells
Authors: Frankenberger Casey A. , Yun Jieun , Eves Eva M. , Diehn Max , Minn Andy J. , Rosner Marsha R. 
Published: August 2012

Abstract
Stem-like “Tumor Initiating Cells” (TICs) have been isolated from a number of tumors including breast, and they are likely involved in all aspects of tumor biology including metastasis. Recent studies have established a link between epithelial stem-like properties and the epithelial-mesenchymal transition (EMT), a step that leads to invasion and metastasis. Identifying key signaling pathways that regulate both tumor initiating and metastatic events could enable more accurate prognosis and reveal important mediators of the process that could serve as novel therapeutic targets. Previous studies from our laboratory and others have shown that let-7 inhibits breast tumor initiation and metastasis. Previously, we have shown that BACH1, a transcription factor that is a direct target of let-7, promotes metastasis. Using gene expression arrays to quantify transcription in BACH1 depleted cells, we show that BACH1 regulates a number of downstream targets including Bone Metastasis Signature (BMS) genes. Utilizing an approach based on experimental and clinical validation, we identify genes implicated in both tumor initiation and metastasis. Gene set analysis confirmed that the BACH1 target genes significantly correlate to the metastatic pathway including BACH1, let-7 and BMS gene expression across a set of more than 1200 primary human tumors, and, in tumors selected for a basal phenotype, the expression levels of individual BACH1 target genes can significantly stratify metastasis free survival in patients. Using FACS to sort metastatic breast cancer cell lines, we see a significant increase in the transcription levels of BACH1 regulated genes when comparing TICs to non-tumor initiating cells. Additionally, in metastatic cell lines known to be enriched in TICs, BACH1 depletion reduces the population of cells expressing cell surface markers (CD44+CD24-/lowESA+) specific to a tumor initiating phenotype. And finally, gene set enrichment analysis indicates that BACH1 and the BACH1 target genes are enriched in human and mouse primary breast TICs relative to non-initiating tumor cells. Taken together, these results suggest that let-7 regulates a signaling cascade involving BACH1 and BACH1 target genes that promotes both tumor initiation and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3329. doi:1538-7445.AM2012-3329
Abstract 3331: MicroRNAs regulate breast cancer stem cells and spontaneous metastases in orthotopic xenograft models
Authors: Liu Huiping , Bockhorn Jessica , Dalton Rachel , Nwachukwu Chika , Prat Aleix , Yee Kathy , Huang Simo , Swanson Kaitlin , Perou Charles M. , Olopade Olufunmilayo I. , Clarke Michael F. , Greene Geoffrey L. 
Published: August 2012

Abstract
To examine the role of microRNAs (miRNAs) in breast cancer progression, we profiled miRNA and gene expression in both clinical breast tumors and human-in-mouse breast tumor models, where breast cancer stem cells (BCSCs) contribute to spontaneous metastasis. CD44+ cells from both primary tumors and lung metastases were highly enriched for tumor initiating cells. Based on the miRNA profile analyses, we identified a limited number of miRNAs that are differentially expressed in metastatic triple-negative breast tumors and regulate BCSCs and tumor invasion in vitro. To facilitate miRNA functional studies in vivo, we also developed tumor imaging approaches by transducing BCSCs with optical reporter fusion genes (Luc2-eGFP or -tdTomato), which enabled both bioluminescence imaging (BLI) and FACS-based analysis and sorting. With non-invasive BLI approaches, as few as 10 cells of stably labeled BCSCs can be tracked in vivo. When optical reporters are expressed along with miRNA precursors or inhibitors, the effects of introduced miRNA candidates can be evaluated by selective imaging of labeled tumor cells, thereby eliminating the noise of unlabeled cells. Using this model system and imaging technology, we have screened and identified miRNAs that regulate BCSCs and metastatic CSCs (MCSCs) by targeting polycomb repressors (BMI1 and the PC2 components) and cytoskeleton genes (TWF1 and VIM). Clinical studies demonstrated that the expression of candidate miRNAs was associated with and regulated by GATA3, suggesting a transcriptional regulation of aberrantly expressed miRNAs in breast tumors. The GATA3-miRNA-target genes signaling pathway was also strongly associated with relapse-free survival of breast cancer patients, indicating the clinical importance of the miRNA-gene network in breast cancer. Supported in part by the University of Chicago Women's Board Fellowship (J.B.), NIH T90 Fellowship DK070103-05, DOD Postdoctoral Fellowship W81XWH-09-1-0331, and Chicago Fellows Program and CTSA UL1 RR024999 at The University of Chicago (H.L.), University of Chicago Cancer Research Center Pilot Research Fund, UCMC/Northshore Collaborative Research Award and the Virginia and D.K. Ludwig Fund (G.L.G and H.L). NIH R01 and Breast Cancer Research Foundation (M.F.C. and H.L.).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3331. doi:1538-7445.AM2012-3331