bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3010: The role of NF-kappaB in mammary tumor initiation
Authors: Barham Whitney , Tikhomirov Oleg , Chen Lianyi , Ortega Ryan , Onishko Halina , Connelly Linda , Yull Fiona E. 
Published: May 2015

Abstract
Nuclear factor kappa B signaling is accepted as a major component of pro-survival signaling within breast cancer cells. However, less is known about how NF-kappaB could contribute to breast tumor initiation. Inflammatory signaling can be activated within the breast by such common factors as obesity, involution following lactation, aging, and psychological stress. Thus, understanding how activated NF-kappaB could lead to the initiation of breast tumors would provide opportunities to develop prevention strategies. We generated a doxycycline-inducible mouse model to study the effects of constitutively active IKK2 on ductal morphogenesis. In this model, Tet-o-cIKK2 mice are crossed with MMTV-rtTA transgenics to target inducible expression specifically to the mammary epithelium. Expression of cIKK2 in transplanted mammary tissue results in enlarged terminal end-buds, increased lateral branching, and intraductal hyperplasia. Transgene induction for only 3 days in a 6 week old female induces filling of ductal lumens, hypercellularity and loss of strict basal/luminal structure. Quantitative PCR of mammary tissue reveals up-regulated markers of macrophage infiltration such as CCL2 and F4/80 and markers of inflammation including Cox-2, TNF-alpha, and CXCL1. Interestingly, constitutive IKK2 activation also results in a decrease in hormone receptor levels (ERα and PR). Immunofluorescent staining shows that activation of classical NF-kappaB increases nuclear p65, as expected. However, nuclear p52 is also increased in transgene positive cells, suggesting that a subset of the effects resulting from activation of classical NF-kappaB are mediated by cross talk with the alternative pathway. Taken together, we find that activation of NF-kappaB in mammary epithelium is sufficient to induce hyperplastic growth and loss of ductal structure. Ongoing studies seek to define what additional factors, such as the right hormonal context, will cause the lesions to progress to malignancy.
Citation Format: Whitney Barham, Oleg Tikhomirov, Lianyi Chen, Ryan Ortega, Halina Onishko, Linda Connelly, Fiona E. Yull. The role of NF-kappaB in mammary tumor initiation. [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 3010. doi:10.1158/1538-7445.AM2014-3010
Abstract 3013: Different tumor-initiating cells from a IDH1 wt glioblastoma patient
Authors: Soeda Akio , Hara Akira , Kunisada Takahiro , Iwama Toru 
Published: May 2015

Abstract
Glioblastoma multiforme, as its name suggests, composes pathologically heterogeneous mixed cells, such as variable degree of cellular and nuclear polymorphism, or so called “gemistocytes” or “giant cells”. Cancer cell regulates dynamic cell-cell interactions, thus, cell-cell dynamic heterogeneity is fundamental questions to know which cells are origin, therapeutic targets or source of recurrences for these decades. Therefore, functional analysis of each heterogenous cells and their role in tumor pathogenesis are critical. To investigate the cellular origin of population diversity, we established 4 subclones from a IDH1 wild type GBM 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 analysis showed that high CD133 expression clones tended to have high proliferation and invasive capacities. Most of these clones’ cells expressed high level of CD44, an adhesion molecule in cancer stem cells regulating redox status in cancer cells. Surface expression of CD24 and CD56 showed statistically different pattern. However, these 2 did not enhance their morphology, proliferation capacities and tumorigenesis. On the other hand, cDNA analysis with using 58721 probes showed that the level of COL1A1 and IGFBP7 were matched their morphology and tumorigenesis character. 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. Different tumor-initiating cells from a IDH1 wt glioblastoma patient. [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 3013. doi:10.1158/1538-7445.AM2014-3013
Abstract 3026: Cancer stem cells maintain a hierarchy of differentiation by creating their niche
Authors: Mizutani Akifumi , Matsuda Shuichi , Yan Ting , Prieto-Vila Marta , Chen Ling , Satoh Ayano , Kasai Tomonari , Masuda Junko , Kudoh Takyuki , Murakami Hiroshi , Fu Li , Salomon David S. , Seno Masaharu 
Published: May 2015

Abstract
Cancer stem cells (CSCs) are unique subpopulation of tumor cells that possess self-renewal and differentiation capacity, and can give rise to the entire heterogeneous population of the tumor tissue. The self-renewal and differentiation properties of CSCs are regulated and maintained by the CSC niche. However, the mechanism of this maintenance, especially the contribution of differentiated cancer cells, remains to be fully elucidated. It has been shown that vascular endothelial cells can activate the Notch signaling pathway in glioblastoma (GMB) stem-like cells, and that was required for self-renewal of GBM stem-like cells. Given the fact that GBM stem-like cells differentiate into vascular endothelial cells, it raises the possibility that these differentiated cells that arise from CSCs might generate a CSC niche. In this study, we addressed this hypothesis using a model of CSCs, miPS-LLCcm, derived from mouse induced pluripotent stem cells (miPSCs) we have established recently.
We found in vitro cultured miPS-LLCcm cells were autonomously balanced with stem-like cells and differentiated cells. The analysis of VEGFR2 and VE-cadherin expression, and in vitro tube formation assay indicated the differentiation capacity of miPS-LLCcm into vascular endothelial cells. In the presence of the conditioned medium from bulk population of miPS-LLCcm cells, self-renewal capacity of CSC population of miPS-LLCcm, which was evaluated by spheroid formation in suspension culture, was enhanced, partly in Notch depending manner. In addition, we found that the ligands for Notch activation were secreted from the differentiated tumor cells including vascular endothelial cells. In addition, the secreted factor(s) from differentiated cells appeared to regulate the differentiation lineage of CSCs, since miPS-LLCcm could not differentiate into vascular endothelial lineages after cultivation of only stem cell population.
Our results indicate that the differentiated progenies of CSCs containing vascular endothelium play important roles for regulating the CSC's properties. Therefore, miPS-LLCcm cells create their own in vitro niche to maintain themselves in the hierarchy of differentiating CSCs.
Citation Format: Akifumi Mizutani, Shuichi Matsuda, Ting Yan, Marta Prieto-Vila, Ling Chen, Ayano Satoh, Tomonari Kasai, Junko Masuda, Takyuki Kudoh, Hiroshi Murakami, Li Fu, David S. Salomon, Masaharu Seno. Cancer stem cells maintain a hierarchy of differentiation by creating their niche. [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 3026. doi:10.1158/1538-7445.AM2014-3026
Abstract 3032: The effect of a tankyrase inhibitor on the small intestine tissue homeostasis
Authors: Norum Jens Henrik , Skarpen Ellen , Brech Andreas , Kuiper Raoul , Waaler Jo , Krauss Stefan , Sørlie Therese 
Published: May 2015

Abstract
In the small intestine the Wnt/β-catenin pathway is involved in regulation of stem cells and tissue homeostasis. Aberrant Wnt signaling is known to cause intestinal cancers. Tankyrase enzymes play crucial roles in the regulation of the Wnt signaling pathway. Inhibition of tankyrase activity is an effective way of inhibiting Wnt/β-catenin signaling. A small molecule tankyrase inhibitor, G007-LK, was developed that inhibits tumor growth in a APC-mutant colorectal cancer xenograft model. In in vivo experiments at high doses (60 mg/kg), G007-LK treatment resulted in severe necrosis and inflammation in the small intestine, possibly affecting the stem cells. Different cell populations in the small intestine have been shown to have stem cell properties, including the Lgr5+ cell population located at the bottom of the crypts and the cells residing in +4 position counting from the crypt base. Both of these cell populations can give rise to all the various cell types of the small intestine.
In the current project, we have used in vivo models to address the effect of the tankyrase inhibitor, G007-LK, on small intestine tissue homeostasis. H&E staining of fixed tissue sections showed no significant differences between mice treated with 10 mg/kg G007-LK or vehicle. We performed lineage tracing from the Lgr5+ stem cells of the small intestine and observed that treatment with G007-LK reduced the number of cells traced from Lgr5+ stem cells. Immunohistochemistry (IHC) staining for the proliferation marker Ki67 showed reduced number of positive cells in the small intestinal crypts of the G007-LK- compared to vehicle-treated mice. As expected, IHC staining for β-catenin showed reduced number of positive nuclei in the G007-LK- compared to vehicle-treated mice, suggesting reduced signaling via the Wnt/β-catenin pathway.
Taken together, our data show that a daily dose of the tankyrase inhibitor G007-LK (10 mg/kg), is well tolerated by mice. Administration of the tankyrase inhibitor to the mice reduces the number of lineage traced cells from the Lgr5+ stem cell population in the small intestine, without altering the general histology of the tissue.
Citation Format: Jens Henrik Norum, Ellen Skarpen, Andreas Brech, Raoul Kuiper, Jo Waaler, Stefan Krauss, Therese Sørlie. The effect of a tankyrase inhibitor on the small intestine tissue homeostasis. [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 3032. doi:10.1158/1538-7445.AM2014-3032
Abstract 3034: Integrin αvβ3 drives Slug activation and stemness in the pregnant and neoplastic mammary gland
Authors: Desgrosellier Jay S. , Lesperance Jacqueline , Seguin Laetitia , Shattil Sanford J. , Cheresh David A. 
Published: May 2015

Abstract
While integrin αvβ3 expression is linked to breast cancer progression its role in epithelial development is unclear. Here, we show that αvβ3 plays a critical role in adult mammary stem cells (MaSCs) during pregnancy. While αvβ3 is a luminal progenitor marker in the virgin gland, we noted increased αvβ3 expression in MaSCs at mid-pregnancy. Accordingly, mice lacking αvβ3 or expressing a signaling deficient receptor showed defective mammary gland morphogenesis during pregnancy. This was associated with decreased MaSC expansion, clonogenicity and expression of Slug, a master regulator of MaSCs. Surprisingly, αvβ3 deficient mice displayed normal development of the virgin gland with no effect on luminal progenitors. TGFβ2, but not RANKL, induced αvβ3 leading to Slug nuclear accumulation and MaSC clonogenicity. In human breast cancer cells, αvβ3 was necessary and sufficient for Slug activation and tumorsphere formation. Thus, pregnancy-associated MaSCs require a TGFβ2/αvβ3/Slug pathway, which may also contribute to breast cancer progression.
Citation Format: Jay S. Desgrosellier, Jacqueline Lesperance, Laetitia Seguin, Sanford J. Shattil, David A. Cheresh. Integrin αvβ3 drives Slug activation and stemness in the pregnant and neoplastic mammary gland. [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 3034. doi:10.1158/1538-7445.AM2014-3034
Abstract 304: Feasibility study of next-generation sequencing on residual formalin-fixed paraffin-embedded tissues
Authors: Carrick Danielle Mercatante , Altekruse Sean , Camalier Corrine , Cozen Wendy , Hernandez Brenda , Lynch Charles , McGregor Paul , Mehaffey Michele G. , McShane Lisa , Rohan JoyAnn Phillips , Williams Mickey , Gillanders Elizabeth M. , Mechanic Leah E. , Schully Sheri 
Published: May 2015

Abstract
Next Generation Sequencing (NGS) technologies are being used for detection of somatic mutations in tumors and studies of germline variation. However, most NGS studies used DNA isolated either from whole blood or fresh frozen tissue specimens. Meanwhile, the tissue specimens available from most National Cancer Institute (NCI) funded cohorts and the Surveillance, Epidemiology and End Results (SEER) registries (http://seer.cancer.gov/biospecimen/) are primarily formalin fixed paraffin embedded (FFPE). There are limited data, on a small number of FFPE tissue samples, which suggest NGS is feasible. Much less is known about the feasibility of these technologies for large scale studies or using older FFPE specimens (e.g. 5-30 years old).
The main objective of this project was to conduct a pilot study to determine whether the DNA obtained from archival FFPE tissue is of sufficient quality and quantity to conduct NGS. Sixty high-grade serous ovarian adenocarcinomas from FFPE tissues which were between 7 and 31 years old were obtained from three SEER registries. DNA was extracted, quantified, quality assessed, and subjected to whole exome sequencing. DNA extraction (yields and quality) and whole exome sequencing (depths of coverage and exome coverage obtained) results from this study will be presented. Ultimately, data derived from this analysis could serve as the basis for determining the utility of archival FFPE biospecimens for characterization and discovery projects utilizing NGS technologies instead of relying on frozen biospecimens.
Citation Format: Danielle Mercatante Carrick, Sean Altekruse, Corrine Camalier, Wendy Cozen, Brenda Hernandez, Charles Lynch, Paul McGregor, Michele G. Mehaffey, Lisa McShane, JoyAnn Phillips Rohan, Mickey Williams, Elizabeth M. Gillanders, Leah E. Mechanic, Sheri Schully. Feasibility study of next-generation sequencing on residual formalin-fixed paraffin-embedded tissues. [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 304. doi:10.1158/1538-7445.AM2014-304
Abstract 3040: Forced astroglial differentiation depletes glioblastoma stem cells
Authors: Spina Raffaella , Voss Dillon M. , Sloan Andrew E. , Bar Eli E. 
Published: May 2015

Abstract
Glioblastoma are among the least curable cancers in man, at least in part because of stem-like cellular subpopulations (herein referred to as glioma stem cells, GSC) refractory to current therapies. The cancer stem cell hypothesis suggests that tumor cells are organized in a pyramidal unidirectional differentiation cascade with GSC at the top and functionally defined by the ability to self-renew and initiate tumors identical to the original tumors from which they are derived. GSCs are maintained by both cell intrinsic and microenvironmental factors and conditions. In this study we focused on identifying potential small molecules which may target tumor heterogeneity by promoting differentiation of GSC into less aggressive, more differentiated subpopulations. To this end, we have developed reporter models for astroglial and neuronal differentiation in HSR-GBM1, HSR040622 and HSR040821 tumor-derived, GSC-enriched, neurospheres lines, using lineage-specific reporter constructs. We employed these reporter lines to screen a library of over 600 bioactive small molecules for potential inducers of GSC differentiation. We identified several molecules which significantly induce astroglial differentiation in multiple GSC-enriched lines. We focus in this report on one of these inhibitors (AD1 = Astroglial Differentiation-1) which induces astroglial differentiation by over 20 to 30-fold as compared with DMSO control. In addition, AD1 treatment resulted in a 40-60% reduction in cell growth in HSR-GBM1, 60% in HSR040622, and 40% reduction in HSR040821, as determined by direct cell counting. As differentiation should result in reduced self-renewal capacity, we next determined the effect of AD1 on sphere formation using the extreme limited dilution assay (ELDA). We found that AD1 significantly reduced clonogenic capacity of HSR-GBM1 reporter line by over 90%. These data strongly suggest that AD1-induced astroglial differentiation may be the cause for the reduced clonogenic capacity. We are currently determining the plasticity of the system in term of reversal of the differentiation state in vitro and in vivo. Our results support the therapeutic value of a drug-induced differentiation and define how differentiation affects the GSC compartment in glioma.
Citation Format: Raffaella Spina, Dillon M. Voss, Andrew E. Sloan, Eli E. Bar. Forced astroglial differentiation depletes glioblastoma stem 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 3040. doi:10.1158/1538-7445.AM2014-3040
Abstract 3044: Cancer associated fibroblasts-derived HGF regulates cancer stem cell-like properties in hepatocellular carcinoma
Authors: Lau Yuen Ting , Lo Jessica , Ng Irene Oi Lin , Lee Terence Kin Wah 
Published: May 2015

Abstract
Cancer stem cells (CSCs) play pivotal roles in tumor growth and therapeutic response; hence it is of fundamental importance to understand how CSCs is regulated inside the tumor mass. Similar to the regulation of normal stem cells by their ‘niche’, CSCs are also regulated by cells within the tumor microenvironment. Although most cases of HCC develop within a background of cirrhosis in which liver tissue is enriched in activated myofibroblasts, the role of cancer associated fibroblasts (CAFs) on liver CSCs within the tumor microenvironment has not yet studied. In order to achieve the goal of developing an effective therapy for HCC by specifically eliminating liver CSCs, we aim to dissect the cross-talks between HCC cells and CAFs. To study this, CAFs from fresh HCC tissues was successfully isolated, cultured and characterized by α-SMA immunoreactivity. Conditioned medium from CAFs enriched the populations of liver CSCs as reflected by an increased ability of self-renewal, chemoresistance, invasiveness and expression of stemness-associated genes and markers CD44 and CD47; and its CSC- stimulating effect was further enhanced when CAFs was stimulated with the conditioned medium of HCC cells. Using cytokine antibody array, hepatocyte growth factor (HGF) was found to be preferentially secreted by CAFs and increased upon stimulation by HCC cells. To verify whether the effect of CAFs on regulation of liver CSCs is due to HGF, the effect of recombinant HGF on regulation of liver CSCs was examined. Recombinant HGF at the physiological levels of CAFs (2ng/mL and 10ng/mL) promoted stem-like properties of HCC cells, and the effect of CAFs on CSC properties was alleviated with addition of HGF neutralizing antibody and c-met inhibitor (PHA665-752). In a cohort of HCC patient’s samples, HGF expression was significantly correlated with α-SMA (p=0.0003), suggesting the paracrine effect of CAFs on HCC cells. Further experiments showed that HCC cells induced proliferation and migration of CAFs to tumor-associated stroma; and CAFs in turn secretes HGF to regulate the CSC plasticity by activating NF-κB-mediated EMT transition. This study potentially dissects the signaling cross-talks between HCC cells and CAFs within the tumor microenvironment which may potentially open a new avenue to develop targeted therapy against this deadly disease.
Citation Format: Yuen Ting Lau, Jessica Lo, Irene Oi Lin Ng, Terence Kin Wah Lee. Cancer associated fibroblasts-derived HGF regulates cancer stem cell-like properties in hepatocellular carcinoma. [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 3044. doi:10.1158/1538-7445.AM2014-3044
Abstract 3045: Defining an elusive multiple myeloma stem cell population in mice
Authors: Kellner Joshua , Hua Yunpeng , Liu Bei , Li Zihai 
Published: May 2015

Abstract
Multiple Myeloma (MM) is a debilitating disease of proliferating and malignant plasma cells that is currently incurable. The ability of monoclonal recurrence of disease suggests it might arise from a stem cell-like population capable of self-renewal. The difficulty to isolate the cancer stem-like cell in MM in both mice and men has introduced confusion toward this hypothesis. XBP1s is a key positive regulator for unfolded protein response and a master transcription factor for plasma cell development. It was previously reported that transgenic overexpression of XBP1s in the B cell lineage of mice (XBP1s-Tg), induces a multiple myeloma phenotype resembling human MM. We have now defined a post-germinal center, pre-plasma B cell population that was significantly increased in XBP1s-Tg mice as the hallmarks of MM was demonstrated. This non-memory B cell population resembled a stem/progenitor cell population, with increased expression of aldehyde dehydrogenase (ALDH), Notch1 and c-kit. Importantly, utilizing an in vitro culture for differentiating plasma cells, the increased population began to differentiate into plasma cells, increasing in size and gaining CD138 expression, the hallmark marker for plasma cells. In conclusion, we have defined a transitional pre-plasma cell population that could potentially be a stem/progenitor population of multiple myeloma. These results provide a novel insight into stem cell biology with regard to multiple myeloma and the use of murine models of myeloma to study the disease.
Citation Format: Joshua Kellner, Yunpeng Hua, Bei Liu, Zihai Li. Defining an elusive multiple myeloma stem cell population in mice. [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 3045. doi:10.1158/1538-7445.AM2014-3045