bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3358: Acquired epithelial-mesenchymal transition synergizes with normal epithelial cells to induce hepatic metastases
Authors: Zubeldia Idoia G. , Bleau Anne-Marie , Gil-Puig Carmen , Vidal-Vanaclocha Fernando , Calvo Alfonso , Lecanda Jon 
Published: June 2012

Abstract
Identification of the required hallmarks for the tumor cells to disseminate to the liver represents an important milestone to delay cancer progression, and consequently to avoid the harmful consequences for patients. Largely unknown, a myriad of cell properties seem to cooperate in a successful metastatic process and in the chemo-/radio- therapeutic resistance. Our aim is to define the intrinsic characteristics of tumor cells that may contribute to epithelial-mesenchymal transition (EMT) in early and late metastatic events. We previously observed that: i) metastatic cells reaching the liver microenvironment display cancer stem features associated with EMT and increased TGFβ1-signaling (Zubeldia et al. Proceedings AACR, 2010; 51, #2304); ii) hepatic secondary tumors are enriched with a subpopulation of cells with a distinctive Sca1+ phenotype and a concurrent increased expression of other cancer stem markers (Zubeldia et al. Proceedings MRS-AACR, 2010; #A105). First, we demonstrated the high tumorigenicity of these metastatic liver-derived cell lines after subcutaneous injection in nude mice, without obvious correlation with their origin regarding TGFβ1-signaling. However, as shown by bioluminescent imaging, some of the novel metastatic liver-derived cell sublines were unable to achieve metastases following intrasplenic injection in C57BL/6J mice. We also noted a differential efficiency of each clone in primary tumor formation in this experimental model. Importantly, we found that co-injection of these cells (isolated from liver metastases) with non transformed hepatocytes (AML12) resulted in a significant increase of metastasis formation. We show an important role of normal cells for metastatic spread in early steps of tumor formation, and suggest the protective activity that the untransformed epithelial cells may have throughout the metastatic progression. We will present the therapeutic implications of our findings for the clinical treatment of carcinomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3358. doi:10.1158/1538-7445.AM2011-3358
Abstract 3371: Expression levels of EMT-related genes in hepatocellular carcinoma
Authors: Nagai Tomoyuki , Arao Tokuzo , Matsumoto Kazuko , Kudo Kanae , Hagiwara Satoru , Sakurai Toshiharu , Ueshima Kazuomi , Haji Seiji , Kudo Masatoshi , Nishio Kazuto 
Published: June 2012

Abstract
Epithelial-Mesenchymal Transition (EMT) has been recognized as a cellular process by which epithelial cells undergo mesenchymal phenotype leading to increased motility and invasion in cancer cells. We recently have reported that sorafenib exerts a potent inhibitory activity against the EMT by inhibiting MAPK signaling and SNAI1 expression in hepatocellular carcinoma (HCC). Large-scale clinical data on SNAI1 expression and the prognosis of patients with HCC was recently reported, and the overexpression of Snail and/or Twist was correlated with a worse prognosis. However, it remains largely unclear on clinico-pathological features of other EMT-related genes and whether these genes are overexpressed in HCC compared with paired non-cancer lesion of the liver.
Here, we examined the mRNA expression levels of EMT-related genes including SNAI1/Snail, SNAI2/slug, ZEB1/TCF8, ZEB2/SIP1, TWIST, CDH1/E-cadherin, CDH2/N-cadherin, VIM/vimentin and FN1/fibronectin in HCC. RNA was extracted from frozen surgical HCC samples (n=48) and their paired liver samples (n=14). Real-time RT-PCR amplification was performed. Glyceraldehyde 3-phosphate dehydrogenase (GAPD) was used to normalize the expression levels in the subsequent quantitative analyses. E-cadherin was significantly downregulated in most of HCC (12/14) and those of 5 HCC were markedly downregulated below 25% of paired liver. Interestingly, we found that ZEB1 is tended to be upregulated in HCC, while ZEB2 was downregulated. Regarding EMT-inducible transcription factors, SNAI1, SNAI2, ZEB1, ZEB2 and TWIST, these expression levels were overexpressed in several HCC samples.
In conclusion, our findings indicate that some HCC subpopulation actually undergo EMT via upregulation of SNAI1, SNAI2, ZEB1, ZEB2 and TWIST. Evaluation of clinico-pathological features on these expression and analysis of additional HCC samples up to 100 cases are now under way.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3371. doi:10.1158/1538-7445.AM2011-3371
Abstract 3377: The effect of E-cadherin loss on melanoma formation and metastasis in a conditional mouse model
Authors: Rosenbaum Lara E. , Damsky William E. , Bosenberg Marcus 
Published: June 2012

Abstract
Melanoma claims the lives of thousands of individuals each year despite the development of novel therapeutic agents. The vast majority of these deaths are due to cancer metastasis and prognosis in each case is often difficult to determine. This lack of effective therapy and prognostic indicators emphasize the need for a better understanding of the genetic and phenotypic changes in melanoma formation and progression. One such change may be the loss of E-cadherin, an important molecule in cell-cell adhesion. E-cadherin is downregulated with melanoma disease progression, suggesting that it may function to restrict melanoma invasion and metastasis. Though changes in E-cadherin expression have been suggested to be important in cancer progression in in vitro studies, few have investigated this change functionally in vivo. In order to characterize the role of E-cadherin in melanoma formation and metastasis, we have utilized a well-characterized conditional mouse model combining the Braf V600E mutation with Pten tumor suppressor loss. This model allows us to specifically and reproducibly induce melanoma in mice in a spatially and temporally restricted model. We have combined this model with conditional E-cadherin inactivation in order to evaluate the role of E-cadherin loss on changes in cell morphology and signaling in addition to melanoma formation, progression and metastasis. Loss of E-cadherin significantly decreases survival of mice in the Braf/Pten tumor model and alters the expression of markers of epithelial to mesenchymal transition (EMT). These findings functionally delineate the role of E-cadherin loss in melanoma formation and progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3377. doi:10.1158/1538-7445.AM2011-3377
Abstract 3378: HO-1 challenges the epithelial mesenchymal transition in prostate cancer
Authors: Gueron Geraldine , Salles Angeles , Labanca Estefania , Coluccio Federico , Navone Nora , De Siervi Adriana , Vazquez Elba 
Published: June 2012

Abstract
Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Tumorigenesis is highly associated with inflammation. Key mediators of this event may play multiple roles in the etiology of PCa and the onset of its progression. The metastatic spread of PCa cells relies on their ability to undergo EMT acquiring undifferentiated properties, loosing the tight junctions between them, hence becoming more motile and invasive. In this context, heme oxygenase-1 (HO-1), the inducible isoform of the rate-limiting enzyme in heme degradation, emerges as a potential epithelial mesenchymal transition (EMT) modulator counteracting oxidative and inflammatory damage. Here we assessed the expression profile of the EMT markers and the interplay between EMT regulators in androgen sensitive (MDAPCa2b and LNCaP) and insensitive (PC3) PCa cell lines under HO-1 modulation. Our results show that treatment with hemin, a potent and specific inducer of HO-1, increased mRNA levels of E-cadherin, β-catenin, and endoglin. Stable transfection of HO-1 in PC3 (PC3HO-1) also showed a significant increase of these epithelial markers. PC3HO-1 xenografts growing subcutaneously in athymic nude mice showed significant up-regulation of these markers compared to control tumours. Furthermore, using an RT-qPCR-generated gene array we identified the adhesion molecule COL4A3 as a novel downstream target of HO-1. HO-1 modulation limited the metastatic potential of neoplastic cells by up-regulating COL4A3 production. Moreover, a quantitative analysis of cell adhesive forces revealed that HO-1 induction increased PCa cell adhesion to a collagen IV matrix. Taken together these results implicate for the first time HO-1 in the modulation of the EMT and cell adhesion in PCa progression. Targeting EMT program directly or indirectly through HO-1 modulation may represent a novel avenue to decrease tumor bulk and eradicate undifferentiated cells with potential to colonize a rare field.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3378. doi:10.1158/1538-7445.AM2011-3378
Abstract 338: Truncating TP53 mutations have prognostic significance in head and neck squamous cell carcinoma
Authors: van der Plas Marlon , Brakenhoff Ruud H. , Kuik Dirk J. , Buijze Marijke , Bloemena Elisabeth , Snijders Peter Jf , René Leemans C. , Braakhuis Boudewijn Jm 
Published: June 2012

Abstract
Background: TP53 is a key gene in cellular homeostasis and is frequently mutated in head and neck squamous cell carcinoma (HNSCC). There is a variety of TP53 mutations, each with its own biological and clinical implication. Some HNSCC are TP53 wild type, amongst those caused by infection with the human papillomavirus (HPV). Aim of the study was to assess the prognostic significance of TP53 mutations in HNSCC and to identify the most relevant mutation.
Methods: TP53 mutation status was assessed by direct sequencing in 141 consecutive HNSCC treated by surgery with radiotherapy when indicated and with a known HPV-status. The type of mutation was correlated with overall survival in a multivariate two-sided Cox regression analysis with wild type as reference.
Results: HPV infections was found in 12 out of 141 cases (9%). Although a relation between HPV infection and a favorable prognosis was observed, the association was not significant. A TP53 mutation was found in 88 (62.4%) of the carcinomas and was not associated with survival. Tumors with a mutation resulting in a truncated protein (n=36, 25.5% consisting of nonsense, frame shift and splice site mutations), had a significantly worse overall survival (Hazard ratio: 2.54 with 95% confidence intervals of 1.28 and 5.05, p=0.008). Multivariate analysis showed that a truncating mutation is an independent risk factor, adjusted for HPV status. A missense (i.e. non-truncating) mutation did not influence prognosis. Other ways of mutation classification (disruptive vs. non-disruptive, hotspot vs. non-hotspot and DNA-binding vs. non-DNA-binding) were less discriminative and co-factors, including HPV-status were confounding in these associations.
Conclusion: Truncating mutations in the TP53 gene are an important independent predictor for a poor prognosis of HNSCC patients. This patient group is an ideal target population for adjuvant therapy with chemoradiation or viral vector mediated TP53 gene transfer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 338. doi:10.1158/1538-7445.AM2011-338
Abstract 3380: Transient Tgfβ exposure causes persistent transdifferentiation in mouse mammary epithelial cells in vitro and in vivo
Authors: Dunphy Karen A. , Roberts Amy L. , Yan Haoheng , Tao Luwei , Hagen Mary J. , Jerry D Joseph 
Published: June 2012

Abstract
Transforming growth factor beta (Tgfβ) is transiently increased during involution in the mammary gland following a pregnancy and may promote the risk of pregnancy associated breast cancer (PABC). While tgfβ inhibits growth of normal mammary epithelium and has a functional role in restoring the pre-pregnancy architecture of the mammary gland, this cytokine also has tumor promoter function because it promotes epithelial to mesenchymal transition (EMT) and initiates metastatic behavior in tumor cells. We hypothesize that transient Tgfβ exposure, to mimic involution, selects for cells that are susceptible to EMT and increases risk for PABC. We have found that short term 14 day treatment of CDβGeo cells, a mouse mammary epithelial cell line, with Tgfβ (5ng/ml) promotes EMT. These cells are persistently transdifferentiated (pTD) even after withdrawal of Tgfβ. In contrast to the parental CDβGeo cells, the pTD cells have decreased expression of E-cadherin (3-fold, p&lt;0.05) and increased levels of N-cadherin (4-fold, p&lt;0.05). The pTD cells also exhibited a striking increase in motility and invasion in Matrigel (invasion index &gt;3-fold, p&lt;0.01), but there was no difference in proliferation rates between CDβGeo cells and pTD cells. The pTD cells also were strongly tumorigenic when transplanted into cleared mammary fat pads (80% of pTD,TE50=43 days vs &lt;10% of CDβGeo at 80days; p&lt;0.01). Levels of Snail mRNA were also increased in pTD (2-fold;p&lt;0.01) and in the tumors derived from the pTD transplants (&gt;5-fold;p&lt;0.01). In addition, expression of Tgfb2 mRNA was also increased (2.8-fold;p&lt;0.05) in the pTD cells. These results demonstrate that transient exposure to Tgfβ causes persistent transdifferentation with increases in Snail and Tgfb2 expression in CDβGeo cells and suggest maintenance of transdifferentiation through an autocrine positive feedback loop.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3380. doi:10.1158/1538-7445.AM2011-3380
Abstract 3396: Neural stem cells, cancer stem cells and microRNAs: The medulloblastoma paradigm
Authors: Miele Evelina , Ferretti Elisabetta , Po Agnese , De Smaele Enrico , Begalli Federica , Screpanti Isabella , Gulino Alberto 
Published: June 2012

Abstract
Increasing evidence supports the idea of cancer as an aberrant morphogenetic process in which master developmental pathways (e.g. Hedgehog, Hh) are subverted. Stem cells (SC) sustain cell development through proliferation and differentiation events, from cell progenitor transitions until a fully differentiated phenotype. SC with similar properties have been also identified in most cancers. These cancer stem cells (CSC) may represent both the potential “cell of origin” of the tumor and a never ending reservoir responsible for tumor maintenance and progression. A paradigm of altered development as a cause of malignant transformation via aberrant Hh signaling is provided by Medulloblastoma (MB), the most common brain malignancy of childhood, in which also CSC have been described. Besides, microRNAs (miRNAs) have been recently identified as key molecules in the gene expression regulation both in development and in cancer: an altered expression of miRNAs is involved in neoplastic disorders and CSC behaviour.
The overall aims of our work were to exploit the Hh-dependent tumorigenesis process of cerebellar stem/progenitor cells as a paradigmatic model to understand the link between subverted cell development and neoplastic transformation and tumor maintenance. We performed high-throughput miRNAs expression profiling of both neural and medulloblastoma stem cells (NSC, Mb SC). Of note, a number of miRNAs were found differentially expressed with stemness (both in NSC and in CSC). Moreover, we found different pattern of miRNAs expression in Mb SC samples in comparison with the normal counterpart (NSC). These observations suggest the presence of stemness specific and cancer stemness specific microRNA. Differentially expressed miRNAs will be selected for further testing on regulation of signaling pathways involved in the control of stemness and cell development. This study will provide new insight in miRNAs regulation and role in maintenance of the stem cell-like properties of neuronal tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3396. doi:10.1158/1538-7445.AM2011-3396
Abstract 3400: Stem-like tumor cells confer drug resistant properties to mantle cell lymphoma
Authors: Jung HyunJoo , Nami McCarty 
Published: June 2012

Abstract
Hematological malignancies harbor sub-populations of cancer-initiating cells (C-ICs) that play important roles in contributing to tumor initiation, progression and drug-resistance. Mantle cell lymphoma (MCL) is highly refractory to conventional chemotherapy regimens as well as new antibody-based therapeutic interventions.
We recently observed clonogenic cancer-initiating cells in human MCL (MCL-ICs) and showed that MCL initiating activities were enriched in the cells that lack the prototypic B cell marker CD19. We discovered that MCL-ICs are highly tumorigenic and display self-renewal capacities in vivo; in contrast, CD45+CD19+ MCL cells, which constitute the vast majority of cells within the tumors, show no self-renewal capacities and greatly reduced tumorigenicity.
Given the newly appreciated roles of cancer-initiating cells in the drug resistance of cancers, it is critical to investigate whether MCL-ICs play roles in drug resistance of human MCL. We have discovered MCL-ICs were more resistant to several clinically-relevant chemotherapeutic agents in combination or in a single regimen compared to CD45+CD19+ cells. The drug resistance of MCL-ICs was largely due to quiescent properties with enriched ABC transporters. In conclusion, designing novel therapies to kill MCL-ICs may prevent relapse and increase patient survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3400. doi:10.1158/1538-7445.AM2011-3400
Abstract 3422: Requirement of the histone demethylase LSD1 in Snail-mediated transcriptional repression during epithelial-mesenchymal transition
Authors: Lin Tong , Ponn Alison , Lu Jianrong 
Published: June 2012

Abstract
Cellular transitions between epithelial and mesenchymal states have crucial roles in embryonic development and tumor metastasis. Members of the Snai1 family of zinc finger transcription factors have emerged as key regulators of epithelial-mesenchymal transition (EMT) and induce EMT in part by directly repressing epithelial markers such as E-cadherin, a gate keeper of the epithelial phenotype. However, the mechanisms underlying Snai1-mediated transcriptional repression remains incompletely understood. Our study shows Snai1 physically interacts with histone demethylase LSD1 (KDM1A) via the repressive SNAG domain located at the N-terminus. Stable over-expression of Snai1 in human mammary epithelial cell MCF10A recruits LSD1 to the E-cadherin promoter and reduce the level of dimethylation of lysine 4 in histone 3 (H3K4m2), a covalent histone modification commonly associated with active promoters. LSD1 is essential for Snai1-mediated transcriptional repression and for maintenance of the silenced state of Snai1 target genes in invasive cancer cells. In the absence of LSD1, Snai1 fails to repress E-cadherin. In cancer cells in which E-cadherin is silenced, depletion of LSD1 results in partial de-repression of epithelial genes and elevated H3K4m2 levels at the E-cadherin promoter, These results underline the critical role of LSD1 in Snai1-dependent transcriptional repression of epithelial markers and suggest that the LSD1 complex could be a potential therapeutic target for prevention of Snai1-dependent EMT and tumor invasion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3422. doi:10.1158/1538-7445.AM2011-3422
Abstract 3423: The role of PGC1-α and KLF4 in inhibiting the progression of human hepatoma cells
Authors: Chi Chin-Wen , Sung Ming-Ta , Ho Ann-Tin , Lee Chin-Chun , Tu Wei-Shan , Yin Peng-Nein , Yin Pen-Hui , Lee Hsin-Chen , Lui Wing-Yiu 
Published: June 2012

Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers with high mortality worldwide. Hypoxia is considered as a driving force to trigger the progression of malignancy, such as epithelial-mesenchymal transition (EMT) process, tumor metastasis, and recurrence. Because of the high recurrence rate caused by frequent metastasis and the lack of effective systemic treatment, development of new biomarkers and therapeutic targets for HCC treatment is urgently needed. Loss of E-cadherin is an early and critical step in EMT process and tumor metastasis. Consequently, modulation of the expression of E-cadherin may be a potential way to prevent tumor metastasis. Recently, we have demonstrated that overexpression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) not only down-regulated the cyclin D1 expression and inhibited growth of hepatoma HepG2 cells, but also up-regulated the E-cadherin expression and concomitantly down-regulated the mesenchymal marker, and decreased the vimentin expression as well as the migration of HepG2 cells. In this study, we observed a significant increase in the expression level of Kruppel-like factor 4 (KLF4) in HepG2 cells when PGC-1α was overexpressed by adenovirus mediated gene transfer. Using wound healing assay and Western blotting, we further observed increased cell migration and decreased expression of KLF4 in HepG2, Hep3B, and HA22T/VGH hepatoma cell lines under hypoxia condition. Moreover, the KLF4 expression level in HepG2 cells under hypoxia and combined with drug treatment was also examined. We found that treatment of sodium nitroprusside, a nitric oxide donor, can protect HepG2 cells from hypoxia- and glucose depletion-induced cytotoxicity through repressing the KLF4 and Bip/Grp78 expression. After treatment with a cytotoxic dose (1 μM) of doxorubicin, the KLF4 expression of HepG2 cells was decreased under normoxia while it was increased under hypoxia. These results together suggest that PGC-1α may regulate the expression of E-cadherin via KLF4, and the KLF4 expression correlated with the response of HepG2 cells to doxorubicin under hypoxia. PGC-1α and KLF4 may serve as potential targets to inhibit the growth and metastasis of hepatoma cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3423. doi:10.1158/1538-7445.AM2011-3423