bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B22: Oncogene activation of K-ras in resident myofibroblasts leads to development of spontaneous bronchioalveolar carcinoma in mice
Authors: Vong Sylvia , Sugimoto Hikaru , Teng Yingqi , Xie Liang , Dewar Rajan , Kalluri Raghu 
Published: May 2012

Abstract
Stromal myofibroblasts, also known as carcinoma-associated fibroblasts, are recruited to neoplastic lesions and act as accomplices in promoting tumor progression. By secreting various growth factors, cytokines, extracellular matrix molecules, and matrix remodeling proteins, stromal myofibroblasts enhance tumor cell proliferation, angiogenesis, and tumor cell invasion. In contrast, the role of resident myofibroblasts in tumorigenesis is largely unknown. Our preliminary results strongly suggest that resident myofibroblasts may act as contributors to tumorigenesis. Selective expression of the oncogenic mutant of K-ras (K-rasG12D) in alpha smooth muscle actin-positive (αSMA+) stromal myofibroblasts is achieved by crossing αSMA-Cre+ transgenic mice to the LSL-KrasG12D f/+ mouse model (hereafter αSMAKrasG12D). While αSMAKrasG12D mice were phenotypically normal at birth, these mice developed spontaneous bronchioalveolar carcinoma by 5 weeks of age at 100% tumor penetrance. We speculate that genetic mutations in stromal myofibroblasts can disrupt stromal-epithelial homeostasis, driving hyperproliferation of epithelial cells. This fosters further accumulation of genetic mutations in the epithelial compartment, and thus, result in carcinogenesis.
Citation Information: Cancer Res 2009;69(23 Suppl):B22.
Abstract B23: Distinct roles for cancer-associated fibroblasts in breast cancer progression and metastasis
Authors: Tse Joyce C. , Sugimoto Hikaru , Cooke Vesselina G. , MacDonald Brian A. , Mehta Ankit I. , Neilson Eric G. , Zeisberg Michael , Kalluri Raghu 
Published: May 2012

Abstract
Cancer-associated fibroblasts (CAFs) are commonly identified and studied as an alpha-smooth muscle actin positive (αSMA+) population of myofibroblasts. However, recent work from our laboratory has shown that there are CAFs in the tumor microenvironment, which do not express αSMA. Most notably, fibroblast specific protein 1 (FSP1) marks a population of CAFs distinct from αSMA+ CAFs, as 90% of FSP1+ CAFs in the tumor microenvironment of the 4T1 murine breast cancer model are αSMA-negative. The functional heterogeneity of these subpopulations of CAFs remains unexplored. By using transgenic mice, which express viral thymidine kinase under control of the CAF promoters αSMA or FSP1 to selectively ablate either αSMA+ CAFs or FSP1+ CAFs in the context of breast cancer, we have identified distinct roles for the two CAF subpopulations in tumorigenesis and metastasis. While αSMA+ CAFs play a role in primary tumor growth and angiogenesis without affecting metastasis, FSP1+ CAFs do not contribute to primary tumor progression but facilitate the formation of macrometastases.
Citation Information: Cancer Res 2009;69(23 Suppl):B23.
Abstract B24: Thoc1 is required for mouse prostate tumorigenesis initiated by loss of Rb and p53
Authors: Chinnam Meenalakshmi , Wang Yanqing , Wang Xiaoling , Zhang Xiaojing , Gold David L. , Nikitin Alexander Yu , Goodrich David W. 
Published: May 2012

Abstract
A large percentage of prostate cancers show either mutational inactivation or deregulation of the Rb tumor suppressor gene. Rb mediates its tumor suppressor function through its association with other cellular proteins. Most of the Rb-binding proteins interact with the A/B pocket domain and the C terminal region. Less than 10 proteins are known to interact with Rb N terminal domain, a domain that appears to be required for normal Rb function in vivo. The Thoc1 gene encodes a protein that binds the Rb N terminal domain. We hypothesize that some of pRb functions in vivo could be mediated in part by interaction with pThoc1. Thoc1 protein has been found to be an essential component of the TREX (transcription/export) complex which is important for mRNP biogenesis and physically couples transcription elongation with RNA processing and export. We have previously reported that E1A/Ras transformed MEFs (mouse embryonic fibroblasts) but not normal MEFs were dependent on Thoc1 for their survival. These observations suggest that tumor cells specifically may be dependent on Thoc1 for survival and Thoc1 may play a role in tumorigenesis. To test our hypothesis, we used a mouse model of prostate cancer where prostatespecific deletion of Rb and p53 genes leads to development of metastatic adenocarcinoma. We find that compound loss of Thoc1, Rb and p53 increased the life-span of mice compared to mice with loss of Rb and p53 alone. Histopathological analyses of prostate tissue showed that initiation of tumorigenesis is delayed in the absence of Thoc1. Tumors that do arise in these mice retain expression of Thoc1. These findings indicate that Thoc1 is required for prostate tumorigenesis. Conditional deletion of Thoc1 alone in mouse prostate does not appear to affect normal prostate development. To test whether Thoc1 is relevant to human prostate cancer, we examined expression of Thoc1 protein in matched normal and prostate tumor tissue cores on tissue microarray. Analysis of nearly 600 patient samples reveals that Thoc1 is significantly overexpressed in tumor tissue compared to normal prostate tissue and pThoc1 levels positively correlated with tumor grade and negatively correlated with biochemical recurrence as indicated by elevated PSA (prostate-specific antigen) levels. Taken together the above findings suggest that Thoc1 is synthetic lethal with the genetic and epigenetic alterations in prostate tumor cells, and hence it may be a potential target for prostate cancer therapy.
Citation Information: Cancer Res 2009;69(23 Suppl):B24.
Abstract B25: DDB1 is a cell-nonautonomous tumor suppressor targeted by HBx in the liver
Authors: Yamaji Sachie , Zhang Mingjun , Zhang Jing , Bibikova Elena , Hodgson Amanda J. , Slagle Betty L. , Goff Stephen P. , Cang Yong 
Published: May 2012

Abstract
Hepatocellular carcinoma (HCC) is the fifth most frequent cancer and the third leading cause of cancer death worldwide. A major aetiologic risk factor for HCC is chronic infection of hepatitis B virus (HBV), which encodes a small regulatory x protein (HBx) critical for HBV-induced hepatocarcinogenesis. How HBx contributes to HCC is not clear, but is likely dependent on its association with host factors to activate transcription and regulate mitogenic pathways.
Here we demonstrate that deletion of one such HBx-interacting protein, the Damaged DNA Binding Protein 1 (DDB1), in liver parenchymal hepatocytes leads to development of HCC in mice, after prolonged inflammation resulting from continuous loss of DDB1-deficient hepatocytes and regeneration of DDB1-proficient hepatocytes. Expression of HBx in this regenerating liver impairs the proliferation of regenerated DDB1-proficient hepatocytes, and significantly accelerates the onset of tumorigenesis. Surprisingly, tumors arising from these animals are made up of cancer cells displaying no disruption of the DDB1 gene. This cell-nonautonomous function of DDB1 inactivation in HCC initiation can be further enhanced by deletion of the tumor suppressor p53 or administration of chemical carcinogen.
Our results indicate that cancer initiating mutations are not necessarily present in cancer initiating cells, but can be exploited by oncogenic signals such as HBx expression and p53 mutation to promote cancer progression.
Citation Information: Cancer Res 2009;69(23 Suppl):B25.
Abstract B26: Lack of cyclin D1 kinase activity leads to reduced levels of ErbB2-induced senescence and activation of the Wnt signaling pathway in the mammary gland
Authors: Brown Nelson E. , Kuperwasser Charlotte , Hinds Philip W. 
Published: May 2012

Abstract
Proper orchestration of the Oncogene-induced Senescence (OIS) checkpoint relies upon the activation of the ARF-p53 and/or the p16 INK4a-pRB tumor suppressor pathways. Overexpression of cyclin D1, as observed in a large proportion of human breast cancers, is believed to confer proliferative advantage through pRb inactivation. The aim of the current study is to assess the role of cyclin D1-associated kinase activity during ErbB2-induced senescence in the mammary epithelium using a kinase-deficient cyclin D1 knock-in mouse (cyclin D1KE/KE) as a model. The effect of cyclin D1WT/WT or cyclin D1KE/KE on MMTV-ErbB2-induced senescence was analyzed in mammary glands of double-transgenic animals. Surprisingly, we observed that cyclin D1KE/KE/MMTV-ErbB2 mammary glands fail to upregulate markers of cellular senescence when compared to preneoplastic cyclin D1WT/WT/ MMTV-ErbB2 mammary glands. These findings correlated with high levels of proliferation and increased cellularity per duct section despite the fact that the cyclin D1KE/KE/MMTV-ErbB2 mammary epithelial cells do not progress to tumor formation. Moreover, this ectopic proliferation was not accompanied by phosphorylation at Ser780 of pRb, suggesting that other D-cyclins were unable to compensate for the lack of cyclin D1-associated kinase activity. Interestingly, failure to implement the senescence program in mutant mammary epithelium was accompanied by an activation of the Wnt signaling pathway that led to stabilization of beta-catenin in mutant mammary epithelial cells, an observation that others have found to correlate with senescence bypass in MEFs. In addition, induction of senescence in cyclin D1WT/WT/ MMTV-ErbB2 mammary glands did not lead to the accumulation of the gene products encoded by the INK4a/ARF locus. Instead, p18 INK4c expression was increased in D1WT/WT/ MMTV-ErbB2 mammary glands above the basal levels observed in cyclin D1WT/WT mammary tissue that did not express MMTV-ErbB2. A comparable induction was not observed in cyclin D1KE/KE/ MMTV-ErbB2 mammary glands. Taken together, our results suggest a dual role for cyclin D1-associated kinase activity in ErbB2-induced senescence and tumor formation. Cyclin D1 kinase activity is necessary for the full transformation of ErbB2-expressing cells, but it may also play an active role in the cascade that leads ErbB2-overexpressing cells to senesce such that cells that are kinase-deficient can still proliferate due to Wnt signaling activation.
Citation Information: Cancer Res 2009;69(23 Suppl):B26.
Abstract B30: EBV LMP2A bypasses p53 inactivation in a MYC model of lymphomagenesis
Authors: Bieging Kathryn T. , Amick Alexandra C. , Longnecker Richard 
Published: May 2012

Abstract
Although Epstein-Barr virus (EBV) is linked to Burkitt's lymphoma (BL), the role of the virus in lymphomagenesis is unclear. LMP2A, encoded by EBV, is detected in BL biopsies and has pro-survival functions. We generated mice expressing MYC and LMP2A in B cells. Pretumor LMP2A/λ-MYC mice have significantly enlarged spleen size. In addition, LMP2A/λ-MYC mice show greatly accelerated tumor onset compared to λ-MYC mice. Inactivation of the p53 pathway and failure to induce the pro-apoptotic BH3-only protein, BIM are two major paths to tumor formation in MYC tumor models. Similar to previous work, we found p53 mutations in λ-MYC tumors, however we detected no p53 mutations in the rapidly arising LMP2A/λ-MYC tumors. We further demonstrate that the p53 pathway is functionally intact in LMP2A/λ-MYC tumors, which show increased levels of PUMA and sensitivity to p53 activation by Nutlin. We also show that BIM is induced in LMP2A/λ-MYC tumor cells. Despite the presence of p53 mutations in EBV+ human BL, our mouse model can be used to understand BL development in humans. We believe that LMP2A is important early in lymphomagenesis. The pro-survival function of LMP2A leads to an initial expansion of cells that have acquired a MYC translocation. This expansion is shown in our mouse model by enlarged spleens in pre-tumor mice. In humans, early expansion of cells increases the probability that a p53 mutation will occur in a cell with translocated MYC. Once the p53 mutation occurs, weak immune surveillance may select against high levels of LMP2A, consistent with low levels of LMP2A transcripts found in tumor biopsies. We have identified a novel mechanism that permits lymphomagenesis in the presence of an intact p53 pathway. This work also uncovers a contribution of Epstein-Barr virus (EBV) to molecular events that have documented importance in BL pathogenesis, and may underlie the poorly understood link between EBV and BL.
Citation Information: Cancer Res 2009;69(23 Suppl):B30.
Abstract B33: Dissecting the role of Nrf3 (NF-E2-related factor 3) in chemical carcinogenesis using knock-out mice
Authors: Chevillard Grégory , Nouhi Zaynab , Derjuga Anna , Paquet Marilene , Blank Volker 
Published: May 2012

Abstract
In this study, we investigated the role of the transcription factor Nrf3 in chemical carcinogenesis induced by benzo[a]pyrene, a common carcinogen found in cigarette smoke, car exhaust and charcoal-grilled meats. Wild type and Nrf3-deficient mice were treated weekly for 4 consecutive weeks with benzo[a]pyrene and then sacrificed 30 weeks after the first administration of carcinogen. Here, we report that mice exposed to benzo[a]pyrene rapidly exhibit labored breathing further accompanied with different signs of morbidity. Kaplan-Meyer survival rate analyses indicate that mice deficient for Nrf3 die earlier that wild type mice following benzo[a]pyrene exposure. Upon necropsy, gross morphology analyses showed the presence of an increased number of lung and thymus lesions in Nrf3-deficient mice compared to wild type mice whereas the number of stomach lesions is identical in both genotypes. Pathology analysis strongly suggests that observed lesions in lung and thymus are from lymphoma origin. Overall, our study reveals that mice deficient for Nrf3 are highly sensitive to chemicalinduced carcinogenesis suggesting a protective role of the transcription factor Nrf3 in this process. This provides new important insights into the molecular mechanisms involved in the development of lymphomas induced by chemical agents. We also propose the Nrf3-deficient mice as a new in vivo model to study tumor formation and response to chemoprotective agents.
Citation Information: Cancer Res 2009;69(23 Suppl):B33.
Abstract B34: Multigenic models of metastatic colon cancer in Drosophila
Authors: Bangi Erdem , Cagan Ross L. 
Published: May 2012

Abstract
Colon cancer is the third most common form of cancer and the second leading cause of cancer-related death in theWestern world. When it is detected at late stages with distant metastases already present, it is unlikely to be curable. This is largely due to the resistance of many late stage tumors to most targeted therapies and even chemotherapy. Development of new animal models of colon cancer that reflect the complex, multigenic and heterogeneous nature of human tumors will be essential in improving our ability to understand the biology of this disease and develop new targeted therapies. The Drosophila colon is remarkably similar to the human colon in terms of the signaling pathways that regulate its maintenance. We took advantage of this similarity to establish models of metastatic colon cancer in Drosophila that closely reflect features of human cancer. To this end, we utilized recent mutational profiling data from human colon tumors to generate flies carrying double, triple and quadruple combinations of mutations that are frequently found together in human tumors. We then investigated the tumorigenic and metastatic potential of these combinations by targeting them specifically to the adult Drosophila colon. We focused our initial analysis on three quadruple combinations: 1) rasG12V p53RNAi apcRNAi ptenRNAi, 2) rasG12V p53RNAi apcRNAi Smad4RNAi and 3) egfr p53RNAi apcRNAi Smad4RNAi. Colon epithelial cells carrying these combinations of mutations started expressing metastasis-related factors and established membrane processes; we are currently exploring the molecular nature of these tumor-like phenotypes. Eventually, these cells migrated through the basal membrane and the surrounding visceral muscle layer and colonized other sites within the body to form secondary tumors. Interestingly, these migratory cells were often found closely associated with trachea, a tubular network that provides oxygen to tissues in Drosophila. A more detailed characterization of the behavior of these cells as they leave the gut epithelium, as well as the secondary tumors are currently underway. We are also investigating emergent properties of these combinations by monitoring the behavior of cells carrying various double and triple combinations that make up the quadruple combinations we first analyzed. These models provide excellent paradigms to study tumorigenesis and metastasis in the context of a whole animal. Our findings will also shed light on the heterogeneity found in individual tumors, an important step towards personalized medicine.
Citation Information: Cancer Res 2009;69(23 Suppl):B34.
Abstract B36: The Ewing's sarcoma fusion oncogene EWS-FLI1 induces tumors and developmental phenotypes in zebrafish
Authors: Leacock Stefanie W. , Basse Audrey N. , Chandler Garvin L. , Kirk Anne , Amatruda James F. 
Published: May 2012

Abstract
Ewing's sarcoma, a member of the small round blue cell family of tumors, is an aggressive and malignant bone tumor of children and young adults. The cells are generally poorly differentiated, although can also have characteristics of neuroectodermal cells. Ewing's tumors are characterized by a t(11:22) that generates a fusion of the EWS protein and the FLI1 transcription factor. This fusion oncoprotein, EWS-FLI1, represents a potential therapeutic target for treatment of Ewing's sarcoma. However, the molecular mechanisms by which EWS-FLI1 mediates tumorigenesis remain unknown. Few animal models exist in which to study the function of EWS-FLI1. Here, we report the use of zebrafish as a new vertebrate model of EWS-FLI1 function and tumorigenesis.
Using the zebrafish Tol2 transposon system, we have developed several transgenic models to study the function of EWS-FLI1 in a vertebrate model organism. First, we have injected zebrafish with transposons containing human EWS-FLI1 driven by either the heat shock or the β-actin promoter. A subset of the injected fish developed tumors when raised to adulthood. These tumors strongly resemble Ewing's sarcoma. This finding demonstrates that the functional targets of EWS-FLI1 that mediate tumor development are conserved from zebrafish to human. We observe an increased incidence of tumors in a p53 mutant background, suggesting that the p53 pathway may suppress EWS-FLI1 driven tumorigenesis. We are performing microarray analysis to identify candidate downstream effector genes and to compare to previously identified EWS-FLI1 target genes.
In addition to these tumors, we identified transgenic lines that transmit the EWS-FLI1 transgene to their progeny. The embryos that express EWS-FLI1 exhibit abnormal embryonic development. This result suggests that EWS-FLI1 may regulate conserved developmental pathways. These transgenic lines represent a novel physiological context in which to study the cellular function of EWS-FLI1. From these two models of EWS-FLI1 expression in the zebrafish, we conclude that human EWS-FLI1 functions in zebrafish and that these models provide a novel context in which to study the function of this fusion oncogene. Additionally, the rapid development and small size of the zebrafish will allow us to utilize these models for genetic and chemical screens for specific EWS-FLI1 inhibitors for the treatment of Ewing's sarcoma.
Citation Information: Cancer Res 2009;69(23 Suppl):B36.
Abstract B39: Nkx2-1 down-regulation underlies lung adenocarcinoma progression towards malignancy
Authors: Winslow Monte M. , Dayton Talya L. , Snyder Eric L. , Chiang Derek Y. , Kim Caroline , Verhaak Roel , Crowley Denise , Bronson Roderick T. , Meyerson Matthew , Jacks Tyler E. 
Published: May 2012

Abstract
Metastasis leads to most cancer-related deaths, yet many of the molecular determinants and their mechanisms of action remain unknown. To uncover genetic programs that control the progression of lung adenocarcinoma towards malignancy, we developed and analyzed an autochthonous mouse model of this disease. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of genetically-engineered mice induces the development of widely metastatic lung adenocarcinoma. Using cell lines derived from primary tumors and metastases, we determined the genome-wide expression changes that embody a metastatic profile. Here we show that the NK-2 related homeobox transcription factor, Nkx2-1 (Ttf-1/Titf1), controls cancer progression and malignant phenotypes. Lung adenocarcinoma progression in our model is associated with loss of Nkx2-1 expression, consistent with the poor prognosis for patients with NKX2-1 negative lung adenocarcinoma. In cells derived from non-metastatic tumors, shRNA-mediated reduction of Nkx2-1 results in increased metastatic potential in vivo and phenotypic alterations in vitro consistent with increased metastatic ability. Interrogation of Nkx2-1 regulated genes and analysis of tumors at defined stages of development indicate that Nkx2-1 may constrain tumors by repressing embryonically-restricted transcriptional regulators and components of the extracellular matrix.
Citation Information: Cancer Res 2009;69(23 Suppl):B39.
Abstract B40: Histone H3 methylation couples DNA damage detection to activation of the Tip60 tumor suppressor
Authors: Sun Yingli , Price Brendan 
Published: May 2012

Abstract
Cancer is a heterogeneous disease which arises primarily from the accumulation of mutations and deletions in the cells DNA. However, recent work has implicated both DNA methylation and histone modifications in the etiology and progression of cancer. For example, abnormal patterns of histone methylation have been identified in breast cancer, raising the possibility that altered patterns of histone methylation can be exploited both as a biomarker to monitor disease status and as a novel therapeutic target.
Here, we report on a novel role for histone methylation in regulating the ability of the Tip60 acetyltransferase to repair DNA double strand breaks (DSBs). Tip60 is a haplo-insufficient tumor suppressor, and loss of heterozygosity at the Tip60 locus and reduced levels of nuclear Tip60 have been detected in both breast and prostate cancer. Tip60 is an acetyltransferase, and can acetylate several DNA repair proteins implicated in breast cancer, including myc, p53 and ATM. Previously, we demonstrated that Tip60 acetylates and activates the ATM protein, a key component of the cells DSB repair mechanism. Here, we demonstrate that methylation of histones creates docking sites for the recruitment of the Tip60 DNA repair complex to sites of DNA damage. Further, interaction between Tip60 and methylated histones serves to specifically activate Tip60'fs acetyltransferase activity at DSBs. Reduction in histone methylation levels compromises Tip60 activation, leading to reduced DNA repair and increased genomic instability. These results indicate that the level and distribution of specific histone methylation marks across the chromatin is a critical determinant of cells ability to repair and survive DNA damage. Thus histone methylation may regulate the genomic stability of cells and their intrinsic sensitivity to agents, including radio- and chemo-therapy, which directly damage DNA. Altered histone methylation associated with breast cancer may therefore contribute to both genomic instability and to resistance to therapy. Finally, since histone methylation is reversible, the enzymes controlling histone methylation represent an exciting new target for therapy in breast cancer.
Citation Information: Cancer Res 2009;69(23 Suppl):B40.