bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA1: Lgr5 stem cells in self-renewal and cancer
Authors: Clevers Hans 
Published: August 2014

Abstract
The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We originally defined Lgr5 as a Wnt target gene, transcribed in colon cancer cells. Two knock-in alleles revealed exclusive expression of Lgr5 in cycling, columnar cells at the crypt base. Using an inducible Cre knock-in allele and the Rosa26-LacZ reporter strain, lineage tracing experiments were performed in adult mice. The Lgr5+ve crypt base columnar cells (CBC) generated all epithelial lineages throughout life, implying that it represents the stem cell of the small intestine and colon. Similar obserations were made in hair follicles and stomach epithelium.
Single sorted Lgr5+ve stem cells can initiate ever-expanding crypt-villus organoids in 3D culture. Tracing experiments indicate that the Lgr5+ve stem cell hierarchy is maintained in these organoids. We conclude that intestinal crypt-villus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche. The same technology has now been developed for the Lgr5+ve stomach stem cells.
Intestinal cancer is initiated by Wnt pathway-activating mutations in genes such as APC. As in most cancers, the cell of origin has remained elusive. Deletion of APC in stem cells, but not in other crypt cells results in progressively growing neoplasia, identifying the stem cell as the cell-of-origin of adenomas. Moreover, a stem cell/progenitor cell hierarchy is maintained in early stem cell-derived adenomas, lending support to the “cancer stem cell”-concept.
Fate mapping of individual crypt stem cells using a multicolor Cre-reporter revealed that, as a population, Lgr5 stem cells persist life-long, yet crypts drift toward clonality within a period of 1-6 months. Lgr5 cell divisions occur symmetrically. The cellular dynamics are consistent with a model in which the resident stem cells double their numbers each day and stochastically adopt stem or TA fates after cell division. Lgr5 stem cells are interspersed between terminally differentiated Paneth cells that are known to produce bactericidal products. We find that Paneth cells are CD24+ and express EGF, TGF-a, Wnt3 and the Notch ligand Dll4, all essential signals for stem-cell maintenance in culture. Co-culturing of sorted stem cells with Paneth cells dramatically improves organoid formation. This Paneth cell requirement can be substituted by a pulse of exogenous Wnt. Genetic removal of Paneth cells in vivo results in the concomitantloss of Lgr5 stem cells. In colon crypts, CD24+ cells residing between Lgr5 stem cells may represent the Paneth cell equivalents. We conclude that Lgr5 stem cells compete for essential niche signals provided by a specialized daughter cell, the Paneth cell.
Citation Format: Hans Clevers. Lgr5 stem cells in self-renewal and cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA1.
Abstract IA13: Glioma stem cells and cancer
Authors: Parada Luis F. 
Published: August 2014

Abstract
Malignant GBMs are incurable tumors that progress within a year's time. Genome wide studies have pinpointed prevalent cancer associated mutions in GBM and among these, the tumor suppressors p53, Pten and NF1 are among the most frequently found. We have developed mouse models of GBM via mutation of p53, Pten and NF1 in the brain. Among the many key insights gleaned from studies with our mouse models have been: 1) The first demonstration that stem cells are the major source of these tumors. 2) The demonstration that all tumor cells are not equivalent and that the Cancer Stem Cells, a subpopulation of cells, are the root of tumor progression. 3) The discovery of a distinct form of GBM that arises in a different cell population and that has unique properties. This novel form of GBM has until now been grouped together with the predominant form of GBM. Our work will lead to a separation of prognosis and treatment for the different forms. In addition, using high throughput screens, we have small compounds in development that specifically target GBM cells but not normally dividing cells. I will discuss these advances and the implications for glioma, solid tumors and cancer in general.
Citation Format: Luis F. Parada. Glioma stem cells and cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA13.
Abstract IA15: Genetic and functional tumor heterogeneity
Authors: Swanton Charles 
Published: August 2014

Abstract
Despite advances in genomic technologies, most advanced solid tumors remain incurable and drug resistance is almost inevitable with limited biomarkers available to personalize therapy. Two important lessons have emerged from the comprehensive genomic analyses of cancers, which may provide an explanation for difficulties that have been encountered in biomarker development. First, each tumor contains an individual assortment of multiple genomic aberrations, few of which are shared between patients with the same histopathological tumor subtype. Second, emerging evidence suggests that these anomalies appear to vary within the tumor, indicating substantial intratumor heterogeneity. Increasingly, molecular evidence suggests that intratumor heterogeneity may contribute to tumor growth through a branched (polytypic) rather than a linear pattern of tumor evolution. Branched evolutionary growth and intratumor heterogeneity results in coexisting cancer cell subclones with variegated genotypes and associated phenotypes that may be regionally separated within the same tumor and alter in dominance over time. Variegated phenotypes, resulting from intratumoral genetic heterogeneity and the emergence of new subclones at relapse, are likely to have important implications for developing novel targeted therapies and for preventing the emergence of drug resistance. Intratumor heterogeneity and sampling bias may also contribute to the recently reported failures in implementation of robust biomarkers in the clinical setting. In this talk, evidence for genetic, epigenetic and transcriptomic intratumour heterogeneity, impacting upon signal transduction pathway phenotypic heterogeneity, will be reviewed. Darwinian models for biomarker discovery will be discussed based on trunk and branched tumor growth models that may improve drug discovery and clinical outcome prediction.
Citation Format: Charles Swanton. Genetic and functional tumor heterogeneity. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA15.
Abstract IA16: Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress
Authors: Young Regina , Ackerman Daniel , Quinn Zachary , Mancuso Anthony , Gruber Michaela , Liu Liping , Giannoukos Dionysios , Bobovnikova-Marjon Ekaterina , Diehl J. Alan , Keith Brian , Simon M. Celeste 
Published: August 2014

Abstract
Solid tumors exhibit heterogeneous microenvironments, often characterized by limiting concentrations of oxygen (O2), glucose, and other nutrients. How oncogenic mutations alter stress response pathways, metabolism, and cell survival in the face of these challenges is incompletely understood. Here we report that constitutive mTORC1 activity renders hypoxic cells dependent on exogenous desaturated lipids, as levels of de novo synthesized unsaturated fatty acids are reduced under low O2. Specifically, we demonstrate that hypoxic Tsc2-/- cells deprived of serum lipids exhibit a magnified UPR response, but fail to appropriately expand their ER, leading to IRE1-dependent cell death that can be reversed by the addition of unsaturated lipids. UPR activation and apoptosis were also detected in Tsc2-deficient kidney tumors. Importantly, we observe this phenotype in multiple human cancer lines and suggest that cells committed to unregulated growth within ischemic tumor microenvironments are unable to balance lipid and protein synthesis due to a critical limitation in desaturated lipids.
Citation Format: Regina Young, Daniel Ackerman, Zachary Quinn, Anthony Mancuso, Michaela Gruber, Liping Liu, Dionysios Giannoukos, Ekaterina Bobovnikova-Marjon, J. Alan Diehl, Brian Keith, M. Celeste Simon. Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA16.
Abstract PR02: “Guardians of repeats”: Novel and significant relationship of p53 and interferon
Authors: Leonova Katerina , Gudkov Andrei 
Published: August 2014

Abstract
Large parts of mammalian genomes are transcriptionally inactive and enriched with various classes of interspersed and tandem repeats. Here we show that the tumor suppressor protein p53, along with DNA methylation, plays an essential role in maintaining silencing of a large portion of the mouse genome. In the absence of functional p53, hypomethylation of DNA results in massive transcription of major classes of short interspersed repeats (SINEs B1 and B2), both strands of near-centromeric satellite DNAs consisting of tandem repeats, and multiple species of non-coding RNAs. In p53-deficient mouse fibroblasts treated with the DNA demethylating agent 5-aza-2'-deoxycytidine, the abundance of these new transcripts exceeds the level of β-actin mRNA by more than 150-fold. Accumulation of these largely double-stranded transcripts, in the absence of p53, is accompanied with a strong endogenous type I interferon response that induces apoptotic cell death. Transcriptional activation of repeats and non-coding RNAs is observed in a significant proportion of spontaneous mouse tumors, presumably reflecting naturally occurring DNA hypomethylation and p53 inactivation. These observations suggest that p53 and IFN cooperate to prevent accumulation of cells with activated repeats. This model, which we have named TRAIN (Transcription of Repeats Activates INterferon), assigns a novel role to p53 as a guardian of repeats. TRAIN model provides plausible explanation for frequent deregulation of interferon pathway observed in a variety of tumors. Overall, this work highlights the cooperation between p53 and interferon as key players needed to maintain genetic stability, and even further outlines their significance in tumor progression and the evolution of the species.
Citation Format: Katerina Leonova, Andrei Gudkov. “Guardians of repeats”: Novel and significant relationship of p53 and interferon. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr PR02.
Abstract A18: The role of the microenvironment protein cathelicidin LL-37 in pancreatic ductal adenocarcinoma
Authors: Sainz Bruno , Frias Javier , Cioffi Michele , Alcala Sonia , Heeschen Christopher 
Published: August 2014

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR1) of the Conference Proceedings.
Citation Format: Bruno Sainz, Jr., Javier Frias, Michele Cioffi, Sonia Alcala, Christopher Heeschen. The role of the microenvironment protein cathelicidin LL-37 in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A18.
Abstract A2: The importance of metabolic heterogeneity and its consequences on tumor invasion, metastatic growth, and treatment
Authors: Robertson-Tessi Mark , Gillies Robert J. , Gatenby Robert A. , Anderson Alexander R.A. 
Published: August 2014

Abstract
Heterogeneity of both the tumor microenvironment and cellular phenotype plays a key role in guiding tumor behavior. Metabolism acts as a central integrator to mediate cellular response to the changing environment, linking the effects of hypoxia, acidosis, proliferation and necrosis. Using a hybrid multi-scale mathematical model of tumor growth in a vascularized tissue, we investigate the selection pressures exerted by the tumor microenvironment as the cancer progresses. A key focus is the metabolism of both normal and tumor cells, and how small changes in phenotype can lead to the development of more metabolically aggressive groups of cells. Development of a glycolytic phenotype due to microenvironmental selection pressures leads to acid-mediated invasion. Results from the model suggest that these aggressive cells have a dramatic advantage as a metastatic seed, compared to less aggressive seeds from the same primary. In addition, there are significant differences in metastatic growth rate depending on the soil, suggesting that prevention or treatment of metastases in different organs may require different strategies. Application of pH buffering therapy has been shown in mouse models to slow down or prevent both primary tumor and metastatic growth. This treatment has been simulated in the model, and the results show that the effect of the treatment is highly sensitive to the timing of application. Additional results suggest that diffusible cytotoxic treatments such as chemotherapy may increase the metabolic aggressiveness of a tumor post-treatment due to the altered selection pressure caused by the drug. Chemotherapy removes the metabolic stratification of the tumor and allows more aggressive cells to grow towards blood vessels and normal tissue. A third treatment we consider is the use of anti-angiogenic therapy, which foments the development of aggressive phenotypes due to degradation of the tumor microenvironment. The model highlights the role of metabolic heterogeneity and microenvironmental selection in driving tumor invasion and metastatic development.
Citation Format: Mark Robertson-Tessi, Robert J. Gillies, Robert A. Gatenby, Alexander R.A. Anderson. The importance of metabolic heterogeneity and its consequences on tumor invasion, metastatic growth, and treatment. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A2.
Abstract A35: Aligned collagen is a prognostic signature for survival in human breast carcinoma
Authors: Conklin Matthew W. , Eickhoff Jens , Riching Kristin , Pehlke Carolyn , Eliceiri Kevin , Provenzano Paolo , Friedl Andreas , Keely Patricia J. 
Published: August 2014

Abstract
Evidence for the potent influence of stromal organization and function on invasion and metastasis of breast tumors is ever growing. Here we have performed a rigorous examination of the relationship of a tumor-associated collagen signature (TACS-3), to the long term survival rate of human patients diagnosed with invasive breast cancer. TACS-3 is characterized by bundles of straightened and aligned collagen fibers that are oriented perpendicular to the tumor boundary. An evaluation of TACS-3 was performed in biopsied tissue sections from 196 patients by second harmonic generation (SHG) imaging of the backscattered signal generated by collagen. Univariate analysis of a Cox proportional hazard model demonstrated that the presence of TACS-3 was associated with poor disease-specific and disease free survival, resulting in hazard ratios between 3.0-3.9. Furthermore, TACS-3 was confirmed to be an independent prognostic indicator regardless of tumor grade and size, ER or PR status, HER-2 status, node status, and tumor subtype. Interestingly, TACS-3 was positively correlated to expression of stromal syndecan-1, a receptor for several extracellular matrix proteins including collagens. Ongoing research is currently investigating both the biochemical signaling pathways that give rise to the TACS-3 phenotype as well as the extent of the influence the mechanical properties of an aligned matrix have on invasion. Because of the strong statistical evidence for poor survival in patients with TACS, and since the assessment can be performed in routine histopathologic samples imaged via SHG or using picrosirius, we propose that quantifying collagen alignment is a viable, novel paradigm for the prediction of human breast cancer survival.
Citation Format: Matthew W. Conklin, Jens Eickhoff, Kristin Riching, Carolyn Pehlke, Kevin Eliceiri, Paolo Provenzano, Andreas Friedl, Patricia J. Keely. Aligned collagen is a prognostic signature for survival in human breast carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A35.
Abstract A45: An in vivo examination of the effects of ARID3B on ovarian cancer metastasis in nude mice
Authors: Roy Lynn , Samyesudhas Serene , Carrasco Martin , Dahl Karen Cowden 
Published: August 2014

Abstract
In 2011, 21,880 women were diagnosed with ovarian cancer and more than 13,850 died from the disease. Unfortunately, the prognosis for most women diagnosed with ovarian cancer is poor due to most patients being diagnosed with local and distant metastases. ARID3B, a DNA binding protein from the AT-rich interactive domain (ARID) family, is overexpressed in late stage neuroblastoma and ovarian cancer. In early development, ARID3B is essential as evidenced by the deaths of Arid3B null embryos by midgestation. The importance of ARID3B in early development and its overexpression in cancer suggest a potential role in cancer progression and metastasis. In addition, our laboratory identified two isoforms of ARID3B a full length (FL) and a short form (SH) that is missing the c-terminal exons 5-9. To determine the effects of the two ARID3B isoforms on metastasis in vivo, human ovarian cancer SKOV3IP cells (selected for their ability to metastasize) overexpressing red fluorescent protein (RFP), ARID3B-FL, or ARID3B-Sh were injected intraperitoneally into nude mice. The mice underwent live optical fluorescence imaging using the Multispectral FX (Kodak) imaging system at frequent intervals to assess tumor burden. The mice were sacrificed when they began to show signs of significant illness. Live imaging of the mice demonstrated that ARID3B-FL expressing SKOV3IP cells formed more and larger tumors more quickly than either SKOV3IP-RFP cells or SKOV3-ARID3B-Sh cells. After sacrificing the mice, tumors and organs were recovered from the abdomen and were imaged ex vivo for tumor burden. Tumors were separated from the organs, weighed, and imaged. The average weights of the tumors were 1.91g for SKOV3IP-RFP derived tumors, 3.22g for SKOV3IP ARID3B-Sh tumors, and 5.46g for SKOV3IP-FL derived tumors. The average tumor burden was greatest for the mice bearing SKOV3IP ARID3B-FL tumors. Gross examination of the tumors post-mortem and post fixation suggested that the tumors from the RFP and ARID3B-Sh expressing cell lines were less vascular or had less vascular leakage than those from the ARID3B-FL mice. Survival analysis showed that the median survival for SKOV3IP ARID3B-FL tumor bearing mice was significantly lower than mice bearing RFP or the ARID3B-Sh expressing tumors (RFP=51 days, ARID3B-Sh=52 days, ARID3B-FL=36 days; P=0.0074). Currently, our lab is addressing potential mechanisms for how ARID3B functions in metastasis. The data presented here suggest that ARID3B plays a significant role in peritoneal metastasis in ovarian cancer.
Citation Format: Lynn Roy, Serene Samyesudhas, Martin Carrasco III, Karen Cowden Dahl. An in vivo examination of the effects of ARID3B on ovarian cancer metastasis in nude mice. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A45.
Abstract A56: Bone morphogenetic protein antagonist DMH1 inhibits metastasis in a mouse model of breast cancer
Authors: Owens Philip , Pickup Michael W. , Gorska Agnieszka E. , Novitskiy Sergey V. , Hong Charles C. , Moses Harold L. 
Published: August 2014

Abstract
Bone Morphogenetic Proteins (BMPs) are secreted cytokines/growth factors belonging to the Transforming Growth Factor β (TGFβ) superfamily. BMPs have recently been shown to be overexpressed in human breast cancers; however, loss of BMP signaling in mammary carcinomas has also been shown to accelerate metastases. Human breast cancers display active BMP signaling by phosphorylated Smads 1, 5 and 8 in both the tumor and the stromal microenvironment. We hypothesized that inhibiting BMP signaling in both the tumor epithelium as well as the surrounding microenvironment would prevent tumor progression. To test this hypothesis we used DMH1, which is a selective and specific antagonist of the type I BMP receptor. Mice that express the MMTV.PyVmT oncogene were either treated with DMSO vehicle or DMH1 for six weeks following initial mammary tumor palpation. Following six weeks, animals were euthanatized and evaluated for lung metastases. Whole mount staining of lungs revealed a statically significant reduction in lung metastasis in DMH1 treated animals compared to vehicle treated (p-value = 0.03). Primary tumors demonstrated reduced proliferation (BrdU incorporation) and increased apoptosis (cleaved-caspase-3) when treated with DMH1. RNA isolated from peripheral blood at the time of sacrifice indicated decreased circulating tumor cells measured by real-time PCR. Overall, the BMP pathway represents an understudied pathway that may be suitable for targeted therapy in breast cancer.
Citation Format: Philip Owens, Michael W. Pickup, Agnieszka E. Gorska, Sergey V. Novitskiy, Charles C. Hong, Harold L. Moses. Bone morphogenetic protein antagonist DMH1 inhibits metastasis in a mouse model of breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A56.