bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C77: A mesenchymal-like subpopulation within squamous cell carcinomas with chemotherapy resistance and phenotypic plasticity
Authors: Basu Devraj , Nguyen Thierry-Thien , Montone Kathleen , Zhang Gao , Wang Li Ping , Rustgi Anil , Lee John , Weinstein Gregory , Herlyn Meenhard 
Published: May 2012

Abstract
A major barrier to curative therapy for most malignancies is intrinsic drug resistance within discrete tumor cell subpopulations, which are presently ill-defined. Previous studies show that carcinoma cell lines abundantly expressing mesenchymal markers have increased resistance to both conventional chemotherapy and epidermal growth factor receptor (EGFR)-targeted agents. However it is unclear whether small mesenchymal-like subpopulations contribute to therapy resistance in individual carcinomas with predominantly epithelial features. Here we identified a mesenchymallike subset expressing low E-cadherin (Ecad lo) and high vimentin (Vim hi) within human squamous cell carcinomas of the esophagus (ESCC) and head and neck (HNSCC). This minority subset was readily isolated from two HNSCC lines (SCC9 and OCTT2) and was identifiable in vivo, not only in mouse xenografts of these lines but also in the clinical specimen from which a HNSCC cell line (OCTT2) was derived. The minority Ecad lo/Vim hi subset contained more low-turnover cells and was less proliferative overall, correlating with increased resistance to the conventional chemotherapeutic agent paclitaxel. The Ecad lo/Vim hi subpopulation also demonstrated diminished activity in the MAP kinase/PI3-kinase pathways, likely arising from decreased EGFR expression and correlating with increased in vitro resistance to the EGFR-targeted agent, cetuximab. This mesenchymal-like subpopulation displayed comparable drug resistancein vivo, becoming enriched by cetuximab treatment in a mouse xenograft derived directly from a clinical HNSCC specimen. Furthermore, the Ecad lo/Vim hi and Ecad hi/Vim lo subsets were dynamic and reversible in their phenotypes, showing the capacity to repopulate each other from single cell clones. Taken together, these results show that a low-turnover, mesenchymal-like subpopulation in squamous cell carcinomas has diminished EGFR pathway function and elevated intrinsic resistance to both conventional and targeted chemotherapies. They further suggest that this mesenchymal-like subset retains the plasticity to repopulate other malignant subpopulations post therapy.
Citation Information: Cancer Res 2009;69(23 Suppl):C77.
Abstract C9: An in vitro model of osteoblastic bone metastasis in prostate cancer
Authors: Lescarbeau Reynald M. , Kaplan David L. 
Published: May 2012

Abstract
Prostate cancer progression is characterized by a striking affinity to spread to bone, where it forms metastases predominately of an osteoblastic phenotype, resulting in a significant source of morbidity. Currently, animal models for studying the development of these osteoblastic metastases are limited due to a lack of spontaneous osteoblastic metastasis development. In order to recapitulate osteoblastic metastasis development, an in vitro, three dimensional culture system was created utilizing silk fibroin scaffolds. LNCaP cells were seeded to silk scaffolds with human bone marrow derived mesenchymal stem cells (hMSCs) and cultured for 6 weeks. Examination after co-culture revealed through histological analysis that hMSCs underwent osteogenic differentiation in response to LNCaP paracrine signals. Paracrine interactions between hMSCs and LNCaPs were studied and IL-6, known to promote androgen independent growth, was found to be transiently expressed by hMSCs over the first two weeks of co-culture. In addition to secreted soluble signaling factors, the effect of extracellular matrix signals on the LNCaP cells was examined. LNCaP cells grown in a decellularized matrix, derived from hMSCs having undergone osteogenic differentiation, showed a 12 fold survival advantage in androgen depleted conditions over controls. This data indicates the ability of the co-culture system to stimulate differentiation of hMSCs towards an osteogenic linage and release soluble and extracellular matrix cues which stimulate androgen independent disease progression. The in vitro co-culture system presents a scalable and high throughput method for studying the molecular mechanisms underlying the osteoblastic component of prostate cancer bone metastasis.
Citation Information: Cancer Res 2009;69(23 Suppl):C9.
Abstract IA-1: From chromosome engineering to chromatin remodeler: CHD5 is a tumor suppressor mapping to human 1p36
Authors: Mills Alea A. 
Published: May 2012

Abstract
Deletions encompassing the 1p36 region of human chromosome 1 have been associated with a spectrum of malignancies, however the tumor suppressor had not been identified. In an effort to identify tumor suppressors within this interval, we used chromosome engineering to generate mouse models with loss- and gain of regions of the genome corresponding to human 1p36. This strategy allowed us to identify a 4.3 megabase interval with potent tumor suppressive activity. Whereas loss of this region caused a marked increase in cellular proliferation that culminated in cancer in vivo, gain of the same interval triggered excessive tumor suppression as observed by augmented cellular senescence in cultured cells and apoptosis in vivo. Using genetic and molecular analyses, we identified the chromatin remodeling protein Chromodomain, helicase, DNA-binding domain protein 5 (Chd5) as the tumor suppressor within the interval, and revealed that Chd5 functions as a master regulator that facilitates p16/Rb- and p19/p53-modulated pathways. Analyses of human gliomas revealed that CHD5 is frequently deleted, suggesting that CHD5 loss contributes to malignancy. Here I will present our current efforts aimed at elucidating the epigenetic role of CHD5 in tumor suppression.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-1.
Abstract IA-12: Oncology drug discovery and development in the 21st century
Authors: Hait William N. 
Published: May 2012

Abstract
Oncology drug discovery and development is poised to enter an era of unparalleled growth. Based on an increasingly detailed understanding of human genetics and cancer biology, new targets have emerged that go beyond nucleic acids and microtubules to members of signal transduction pathways that are upstream of these fundamental cellular structures. In addition, an appreciation of the effects of the tumor microenvironment on cancer cell pathophysiology and metabolism has focused increasing attention on targets in these areas. With more than 200 compounds in the Pharmaceutical Industry's pipeline, substantial improvements in the lives of cancer patients are anticipated.
Yet major hurdles exist. Despite the increased knowledge and investment in drug development, the entry of new drugs into the clinic has not kept pace. Key barriers include but are not limited to: 1. Understanding the role of a drug target in the context of an individual's malignancy; 2. Predicting characteristics of a patient and his or her cancer that is most likely to benefit from a specific therapy; 3. Predicting the toxicity of new agents; 4. Outmoded clinical trial designs; 5. Developing rational drug combinations; 6. Accrual to clinical trials; 7. Appropriate resourcing of regulatory agencies and; 8. the price of developing cancer drugs.
This presentation will address each of these challenges and suggest ways in which progress can be made.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-12.
Abstract IA-13: Mechanisms regulating anchorage independent survival
Authors: Schafer Zachary , Grassian Alex , Song Loling , Mailleux Arnaud , Schmelzle Tobias , Irie Yoko , Gao Grace , Overholtzer Michael , Jiang Zhenyang , Gerhart-Hines Zachary , Puigsever Pere , Brugge Joan S. 
Published: May 2012

Abstract
One of the earliest recognized features of tumor cells in culture is their ability to proliferate and survive without attachment to extracellular matrix. This ‘anchorage independence’ of tumor cells distinguishes their behavior from normal cells and is believed to be important to allow tumor cells to proliferate outside of their natural niches during early stages of tumor formation as well as during invasion and metastasis. My presentation will focus on findings from our laboratory on the mechanisms responsible for death of cells deprived of matrix and how oncogenes and other factors promote anchorage independence.
We have found that three distinct death processes — apoptosis, metabolic impairment, and a novel non-apoptotic mechanism, referred to as entosis, involving invasion of one cell within another and lysosomal degradation — contribute to death of cells deprived of their appropriate matrix. The major topic of my presentation will be new unpublished findings on metabolic pathways that are regulated by matrix attachment. We have found that detachment of mammary epithelial cells from ECM causes an ATP deficiency due to loss of glucose transport. Overexpression of ErbB2 rescues the ATP deficiency by restoring glucose uptake through PI(3)K activation. Interestingly, we found that the ATP deficiency could also be rescued by antioxidant treatment without rescue of glucose uptake. This restoration was found to be dependent on stimulation of fatty acid oxidation (FAO), which is inhibited by detachment-induced reactive oxygen species (ROS). The significance of these findings was supported by studies in 3D acinar cultures and anchorage-independent colony formation. These results reveal both the importance of matrix attachment in regulating metabolic activity and an unanticipated mechanism for cell survival in altered matrix environments through antioxidant restoration of ATP generation.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-13.
Abstract IA-22: Cellular responses to telomerase perturbations
Authors: Li S. , Matsuguchi T. , Stohr B.A. , Xu L. , Perry K. , Ren B. , Blackburn Elizabeth H. 
Published: May 2012

Abstract
Telomerase is a ribonucleoprotein that replenishes the DNA at telomeres, thereby counteracting telomere shortening. Telomerase is highly active in many human malignancies. Telomerase functions in cancer maintenance include replenishing telomeric DNA and maintaining cell immortality. The telomerase RNA component provides a short template that is copied to make telomeric DNA. We found that mutating the template to cause various aberrant telomeric sequences to be added in human cancer cells rapidly caused massive ATM-dependent and ATM-independent chromosome fusions and cell death.
We also showed previously that human cancer cells responded rapidly to abrupt depletion of telomerase RNA by rapid and distinctive cellular/transcriptional responses, despite no obvious bulk telomere shortening or loss of telomere integrity. This and evidence from others indicates that, in addition to its telomere-elongating role, telomerase may play other roles in cells: cells lacking or overexpressing telomerase show a variety of responses even in the absence of detectable effects on telomere integrity or functionality. We are performing ChIP—SEQ experiments to identify genomic sites of telomerase interaction. New results of experiments exploring these roles of telomerase in cancer will be presented. Together, these and other findings indicate that telomerase, both via its roles in telomere maintenance and other roles, provides potential new inroads into cancer therapies.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-22.
Abstract IA-3: The regulation of p53 tumor suppressing activities
Authors: Lozano Guillermina 
Published: May 2012

Abstract
The p53 tumor suppressor is often altered in tumors via single nucleotide changes that alter critical amino acids in the DNA binding domain. These p53 mutants lose DNA binding activity and some mutants exhibit a gain-of-function phenotype that is manifested as metastasis in vivo. We have discovered that p53 mutants are normally unstable similar to wild type p53, and become stable in some tumors leading to the increased metastasis. Mdm2, a negative regulator of wild type p53 also negatively regulates mutant p53. Decreased Mdm2 gene dosage delays a cancer phenotype in tumor prone mouse models. In humans, an Mdm2 single nucleotide polymorphism (SNP) increases the levels of MDM2 and correlates with an earlier age of tumor onset. We have generated mice with the human MDM2 SNP and show that the SNP accelerates a tumor phenotype in mice.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-3.
Abstract IA-5: Dissecting tumor suppressor gene networks in vivo
Authors: Lowe Scott W. 
Published: May 2012

Abstract
Cancer arises through an evolutionary process whereby normal cells acquire mutations that erode growth controls, leading to the inappropriate expansion of aberrantly proliferating cells. Such mutations can involve activation of oncogenes or inactivation of tumor-suppressor genes, each contributing one or more new capabilities to the developing cancer cell. However, cancer is not an inevitable consequence of oncogenic mutations; instead, cells acquiring such mutations can be eliminated or kept in check by innate tumor-suppressor programs that can be activated in these damaged cells. Our laboratory studies tumor-suppressor networks controlling apoptosis and senescence and how their disruption influences malignant behavior. We previously showed that apoptosis and cellular senescence are potent barriers to oncogene-driven tumorigenesis and that each contributes to the antitumor action of many chemotherapeutic drugs. Thus, not only do mutations that disrupt apoptosis and senescence promote tumor progression but, depending on the particular lesion, they can also reduce the efficacy of cancer therapy. To facilitate our research, we have recently developed new mouse cancer models based on the genetic manipulation of stem and progenitor cells ex vivo followed by transplantation of the altered cells into the appropriate organ of syngeneic recipient mice. This approach allows us to rapidly study the impact of many genes and gene combinations on tumorigenesis in a “mosaic” setting where tumor-initiating cells are embedded in normal tissues. Furthermore, we have developed powerful methods for using RNAi to suppress gene function in vivo in either a stable and reversible manner. Current efforts in the laboratory strive to integrate mosaic mouse models, RNA interference, and cancer genomics to identify new components of tumor suppressor gene networks and characterize their impact on tumorigenesis and treatment response. In addition, we are developing new RNAi interference methods to explore the role of tumor suppressor genes in tumor maintenance, and the cell death mechanisms involved in tumor regression.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-5.
Abstract IA-6: Single nucleotide polymorphisms in the p53 pathway
Authors: Levine Arnold J. 
Published: May 2012

Abstract
The p53 protein and the signal transduction pathway controlled by that protein responds to a wide variety of stress signals which can disrupt the fidelity of DNA replication and cell division. To prevent these errors or mutations the p53 pathway responds by initiating a process of cell cycle arrest, senescence or apoptosis which either permits repair of these errors or kills the clone of cells that contain these mutations. Central to this pathway are a series of proteins that respond to the stress signals and regulate the levels and activity of the p53 pathway. We have identified a number of single nucleotide polymorphisms (SNP) in those genes that regulate p53 activity and functions and these SNPs can play a role in the incidence of cancers in a population, the age of onset of cancers and the response to therapy. Some of the haplotypes containing these SNPs appear to be under positive evolutionary selection pressures in some human populations. The reason for this appears to be the role of p53 in the implantation of embryos into the uterus and the impact of some of these SNPs upon the fecundity of mice and humans. This process is mediated by the p53 regulated gene, Leukemia Inhibitory Factor or LIF, a cytokine that is essential for the implantation of embryos. SNPs in the p53 gene, the MDM-4 gene and the LIF gene regulate the efficiency of implantation of embryos in humans. It could well be that the p53 protein is also involved in the surveillance of developmental abnormalities.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-6.
AIB1:ERα Transcriptional Activity Is Selectively Enhanced in Aromatase Inhibitor–Resistant Breast Cancer Cells
Authors: O'Hara Jane , Vareslija Damir , McBryan Jean , Bane Fiona , Tibbitts Paul , Byrne Christopher , Conroy Ronán M. , Hao Yuan , Gaora Peadar Ó , Hill Arnold D.K. , McIlroy Marie , Young Leonie S. 
Published: May 2012

AbstractPurpose: The use of aromatase inhibitors (AI) in the treatment of estrogen receptor (ER)-positive, postmenopausal breast cancer has proven efficacy. However, inappropriate activation of ER target genes has been implicated in the development of resistant tumors. The ER coactivator protein AIB1 has previously been associated with initiation of breast cancer and resistance to endocrine therapy.Experimental Design: Here, we investigated the role of AIB1 in the deregulation of ER target genes occurring as a consequence of AI resistance using tissue microarrays of patients with breast cancer and cell line models of resistance to the AI letrozole.Results: Expression of AIB1 associated with disease recurrence (P = 0.025) and reduced disease-free survival time (P = 0.0471) in patients treated with an AI as first-line therapy. In a cell line model of resistance to letrozole (LetR), we found ERα/AIB1 promoter recruitment and subsequent expression of the classic ER target genes pS2 and Myc to be constitutively upregulated in the presence of both androstenedione and letrozole. In contrast, the recruitment of the ERα/AIB1 transcriptional complex to the nonclassic ER target cyclin D1 and its subsequent expression remained sensitive to steroid treatment and could be inhibited by treatment with letrozole. Molecular studies revealed that this may be due in part to direct steroid regulation of c-jun-NH2-kinase (JNK), signaling to Jun and Fos at the cyclin D1 promoter.Conclusion: This study establishes a role for AIB1 in AI-resistant breast cancer and describes a new mechanism of ERα/AIB1 gene regulation which could contribute to the development of an aggressive tumor phenotype. Clin Cancer Res; 18(12); 3305–15. ©2012 AACR.
Combination of an Allosteric Akt Inhibitor MK-2206 with Etoposide or Rapamycin Enhances the Antitumor Growth Effect in Neuroblastoma
Authors: Li Zhijie , Yan Shuang , Attayan Navid , Ramalingam Sridevi , Thiele Carol J. 
Published: May 2012

Abstract
Purpose: Activation of Akt is a marker of decreased event-free or overall survival in neuroblastoma patients. MK-2206, a novel allosteric Akt inhibitor, is now tested in clinical trials in adult cancers. In this study, effect of MK-2206 on tumor growth and murine survival, alone or in combination, with etoposide or rapamycin was evaluated.
Experimental Design: The anticell proliferation effect of MK-2206 was tested in eight neuroblastoma cell lines by MTS assay. Caspase-3/7 activity, cell-cycle analysis, and reactive oxygen species (ROS) production were determined. Effect of MK-2206 combined with etoposide or rapamycin was evaluated in vitro and in vivo. Akt phosphorylation was measured by Western blotting in neuroblastoma cells and tumors.
Results: In vitro, MK-2206 treatment inhibited neuroblastoma cell proliferation, which was accompanied by a cell line selective G1 arrest of cell cycle or production of ROS. A synergistic effect between MK-2206 and etoposide was detected in four tested neuroblastoma cell lines via caspase-dependent apoptosis, whereas increased inhibition of cell growth induced by combination of MK-2206 and rapamycin was mediated by ROS production. In vivo, MK-2206 alone decreased tumor growth and increased murine survival at dose that inhibited Akt phosphorylation in tumors. MK-2206, in combination with etoposide or rapamycin, caused a significant decrease in tumor growth and increase of murine survival compared with MK-2206 alone.
Conclusion: Akt inhibition by MK-2206 increased the efficacy of etoposide or rapamycin. Our study supports future clinical evaluation of MK-2206 in combination with conventional cytotoxic therapy or with rapamycin in high-risk neuroblastoma patients. Clin Cancer Res; 18(13); 3603–15. ©2012 AACR.
The Proteasome Activator PA200 Regulates Tumor Cell Responsiveness to Glutamine and Resistance to Ionizing Radiation
Authors: Blickwedehl Jennifer , Olejniczak Scott , Cummings Ryan , Sarvaiya Nilofar , Mantilla Ana , Chanan-Khan Asher , Pandita Tej K. , Schmidt Marion , Thompson Craig B. , Bangia Naveen 
Published: May 2012

Abstract
The cellular response to ionizing radiation (IR) involves a variety of mechanisms to repair damage and maintain cell survival. We previously reported that the proteasome activator PA200 promotes long-term cell survival after IR exposure. The molecular function of PA200 is to enhance proteasome-mediated cleavage after glutamate; however, it is not known how this molecular function promotes survival after IR exposure. Here, we report that upon IR exposure, cellular demand for exogenous glutamine is increased. Cells containing PA200 are capable of surviving this IR-induced glutamine demand, whereas PA200-deficient cells show impaired long-term survival. Additional glutamine supplementation reverses the radiosensitivity of PA200-knockdown cells suggesting impaired glutamine homeostasis in these cells. Indeed, PA200-knockdown cells are unable to maintain intracellular glutamine levels. Furthermore, when extracellular glutamine is limiting, cells that contain PA200 respond by slowing growth, but PA200-knockdown cells and cells in which post-glutamyl proteasome activity is inhibited are nonresponsive and continue rapid growth. This cellular unresponsiveness to nutrient depletion is also reflected at the level of the mTOR substrate ribosomal S6 kinase (S6K). Thus, inability to restrict growth causes PA200-deficient cells to continue growing and eventually die due to lack of available glutamine. Together, these data indicate an important role for PA200 and post-glutamyl proteasome activity in maintaining glutamine homeostasis, which appears to be especially important for long-term survival of tumor cells after radiation exposure. Mol Cancer Res; 10(7); 937–44. ©2012 AACR.