bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2820: The mechanism of mesenchymal-to-epithelial transition driven by hepatocytes in prostate cancer.
Authors: Ma Bo , Wells Alan 
Published: August 2014

Abstract
Metastasis of prostate cancer (PCa) almost always leads inexorably to death, but little is known about how cancer cells seed ectopic sites and survive in these inhospitable sites. Our lab has previously shown that carcinoma cells undergo a phenotypic change driven by the metastatic microenvironment, to attain an, at least partial mesenchymal (like)-to-epithelial reverting transition (MET/MErT). This phenotypic plasticity, marked by E-cadherin re-expression, plays a key role in metastatic breast and prostate cancer cell survival in vitro and is though to occur after seeding in the ectopic sites and subsequent treatment with chemotherapeutics. In this study we are seeking the pathway(s) involved in the mesenchymal to epithelial transition and subsequent cell survival. By using hepatocytes co-cultured with prostate cancer cells (DU145 or PC3) we found MET PCa cells displayed more resistance to chemotherapeutics, cell death inducing cytokines, or a combination of both. Moreover, E-cadherin knockdown in PCa cells abolished this survival advantage conferred by hepatocytes. This indicated the key role of E-cadherin in hepatocyted driven PCa cells survival. We focused next on the feedback pathways activated by E-cadherin homotypic binding, the MAP kinases. Our data showed that p38 MAPK regulated E-cadherin expression during DU145 cells MET driven by hepatocytes. By using immunofluorescence, the level of phosphor-p38 was much lower in DU145 cells co-cultured with hepatocytes, and the p38 was only detected in the nucleus, which suggested that hepatocytes suppressed p38 MAPK activity in DU145 cells. When co-cultured with hepatocytes, p38α knockdown DU145 displayed much higher levels of E-cadherin, especially in the rim of cells. Additionally, both p38 inhibitor SB202580 and p38α siRNA transfected cells expressed higher E-cadherin than control in DU145. Taken together, hepatocytes regulate PCa cells to undergo MET via suppressing p38 MAPK activity in the cancer cells.
Citation Format: Bo Ma, Alan Wells. The mechanism of mesenchymal-to-epithelial transition driven by hepatocytes in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2820. doi:10.1158/1538-7445.AM2013-2820
Abstract 2859: Differential effects of specific dietary fat sources on inflammation and intestinal tumorigenesis.
Authors: Doerner Stephanie K. , Leung Elaine S. , Ko Justine S. , Nadeau Joseph H. , Berger Nathan A. 
Published: August 2014

Abstract
Diet-induced obesity (DIO) and metabolic syndrome (MetS) are important factors that contribute to the development and progression of cancer, especially colon cancer. DIO and MetS have reached epidemic proportions in the United States and are heavily influenced by diets high in saturated and omega-6 polyunsaturated fatty acids. Using the ApcMin/+ model of intestinal neoplasia and diets constructed from 58% coconut, corn or olive oils, we demonstrate that high amounts of dietary fats can have differential effects on DIO and MetS, as well as on intestinal tumorigenesis when compared to ApcMin/+ fed corresponding calorically equivalent control diets that contained 10% fat from these same sources. Specific sources of dietary fat lead to more rapid tumor progression, elevated polyp number and mass, as well as increased mortality, thus eliciting a detrimental impact on disease outcome, while others fail to induce an increase in polyp burden and reduce cancer severity in mice with genetic predisposition to intestinal neoplasia. We demonstrate that the tumor promoting effects of different fats are associated with systemic and local intestinal inflammation and that excess nutritional richness from specific sources can increase pro-inflammatory factors such as IL-6, IL-1β, TNFα, COX-2. Adipokines, such as adiponectin and leptin, are differentially modulated in response to different fat sources. Short (3 day) dietary exposure is sufficient to induce inflammation and tumorigenesis before the onset of DIO or MetS, suggesting a potent effect of diet on intestinal immunity. Additionally, we demonstrate a novel mechanism for the innate immunity in diet-induced intestinal cancer. We show that pharmacological and genetic inhibition of innate immunity factors can significantly reduce polyp number and mass in ApcMin/+. These results suggest that nutritional modification may be a useful approach to alter intestinal and systemic inflammation with potential preventative value for use in colon tumorigenesis and that diet, immunity and cancer are intrinsically related.
Citation Format: Stephanie K. Doerner, Elaine S. Leung, Justine S. Ko, Joseph H. Nadeau, Nathan A. Berger. Differential effects of specific dietary fat sources on inflammation and intestinal tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2859. doi:10.1158/1538-7445.AM2013-2859
Abstract 2860: A critical role of bone marrow-derived cells for hedgehog-mediated carcinogenesis.
Authors: Xie Jingwu , Fan Eric Qipeng , Gu Dongsheng , Liu Hailan , Zhang Xiaoli , Kaplan Mark , Yoder Merv 
Published: August 2014

Abstract
Amounting evidence indicate that the tissue microenvironment in a developing tumor is created by the tumor to orchestrates molecular and cellular interactions. As a major pathway involved in tumorigenesis, Hedgehog (Hh) signaling is known to regulate tumor microenvironment, but the underlying molecular mechanisms in hedgehog-driven tumors remain unclear. Here we show that smoothened (SMO)-mediated tumor development is accompanied by TGFβ activation in a variety of cell types of the tumor microenvironment, such as keratinocytes, fibroblasts and myeloid-derived suppressor cells. To determine the role of TGFβ signaling for SMO-mediated tumor development, we generated cell type specific TGFβR2flp/flp mice in which SmoM2 expression is accompanied by TGFβR2 knocking out. We found that while K14cre-mediated TGFβRII knockout promoted tumor development, Mx-1cre-mediated TGFβRII knockout suppressed tumor development, indicating a tumor promoting effect of stromal TGFβ signaling. Using EGFP expressing mice for bone marrow transplantation, we determined that most stromal cells with TGFβ signaling activation are derived from bone marrow. To further determine the role of stromal TGFβ signaling for hedgehog signaling-mediated tumor development, we performed bone marrow transplantation experiments in mice that can be induced to develop basal cell carcinomas (BCC). We found that bone marrow cells with TGFβR2 knockout, but not the wild type cells, inhibited tumor development and reduced the size of developed tumors. Reduction of tumor development was associated with decreased expression of multiple inflammation stimulatory cytokines as well as the number of myeloid-derived suppressor cells (MDSCs). The tumor promoting effect of TGFβ signaling is not limited to BCC because tumor growth of B16-F10 cells was also affected by TGFβRII elimination in bone marrow-derived cells. Our data indicate that TGFβ signaling in the tumor microenvironment, not in the keratinocytes, is critical for maintaining the tumor microenvironment to foster tumor development and growth.
Citation Format: Jingwu Xie, Eric Qipeng Fan, Dongsheng Gu, Hailan Liu, Xiaoli Zhang, Mark Kaplan, Merv Yoder. A critical role of bone marrow-derived cells for hedgehog-mediated carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2860. doi:10.1158/1538-7445.AM2013-2860
Abstract 2863: RNase-L modulates the immune response to intestinal damage and ameliorates murine colitis and colitis-associated cancer.
Authors: Long Tiha M. , Chakrabarti Arindam , Ezelle Heather , Brennan-Laun Sarah , Raufman Jean-Pierre , Polyakova Irina , Silverman Robert , Hassel Bret 
Published: August 2014

Abstract
The endoribonuclease RNase-L is a Type-I interferon (IFN)-regulated component of the innate immune response that functions in antiviral and antibacterial activities. Here we identify a protective role for RNase-L in the inflammatory response to gastrointestinal (GI) injury and commensal bacteria. In a dextran sulphate sodium (DSS)-induced model of ulcerative colitis RNase-L-/- mice exhibited a more severe clinical score and increased mortality compared to wild type animals. The enhanced sensitivity to GI damage was accompanied by delayed leukocyte infiltration and reduced expression of the proinflammatory cytokines IFNβ, TNFα, IL-1β and IL-18 at early times post-DSS exposure. This impaired innate immune response corresponded with increased inflammation and a decreased capacity to recover from GI injury at later times. Consistent with the established role of inflammation as a risk factor for colorectal cancer, in a model of colitis-associated cancer DSS treated RNase-L-/- mice displayed an increased carcinogen-induced tumor burden and mortality. A potential mechanism by which RNase-L functions in the response to GI damage and commensal bacteria is via the production of RNA agonists of RIG-I-like receptors (RLRs), sensors of cytosolic pathogen-associated RNAs that initiate signaling to induce proinflammatory cytokines important to GI homeostasis. Indeed, we found that bacterial RNA triggers IFNβ induction in macrophages in an RNase-L-dependent manner. Together, these results support a model in which the protective role for RNase-L in experimental colitis and colitis-associated cancer occurs through RNase-L-dependent RLR signaling and IFNβ induction.
Citation Format: Tiha M. Long, Arindam Chakrabarti, Heather Ezelle, Sarah Brennan-Laun, Jean-Pierre Raufman, Irina Polyakova, Robert Silverman, Bret Hassel. RNase-L modulates the immune response to intestinal damage and ameliorates murine colitis and colitis-associated cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2863. doi:10.1158/1538-7445.AM2013-2863
Abstract 2869: Interaction between a COX2 polymorphism and ER status in relation to risk for early events in breast cancer patients.
Authors: Markkula Andrea , Simonsson Maria , Ingvar Christian , Rose Carsten , Jernström Helena C. 
Published: August 2014

Abstract
Background. Cyclooxygenase-2 (COX2) polymorphisms are associated with cancer in the lung, colorectum, and breast. In several studies, the COX2 rs5277 variant has been implicated in cancers associated with inflammation. COX-2 is the rate-limiting enzyme in the production of the pro-inflammatory prostaglandin, which activates CYP19 transcription and increases CYP19 (aromatase) levels, the key enzyme in androgen to estrogen conversion. The aim of this study was to investigate whether associations between the COX2 rs5277 polymorphism and early breast cancer events vary according to ER-status. Methods. COX2 rs5277 (306G&gt;C, V102V) was genotyped with PCR based methods in 634 breast cancer patients in a population-based ongoing cohort from southern Sweden. Clinical data were obtained from patient charts and pathology reports. Rs5277 was examined in relation to patient, tumor characteristics and early events. Results. Minor allele frequency was 16.1%. Rs5277 was not associated with patient or tumor characteristics. Median follow-up was 4.92 years in patients with invasive tumors. Overall, increasing number of C-alleles was not associated with early events (Log Rank 1df; p=0.35). However, after stratification according to ER status, increasing number of C-alleles was associated with a fewer early events in the 73 patients with ER-negative tumors (Log Rank 1df; p=0.029) and borderline associated with more early events among the among the 497 patients with ER-positive tumors (Log Rank 1df; p=0.081). The interaction between ER-status and COX2 rs5277 on early events was significant (pinteraction=0.010). In a multivariate model among patients with ER-positive tumors, a CC genotype predicted an increased risk for early events (HR 4.25; 95 %CI 1.18-15.29; p=0.027), adjusted for tumor size (pT), nodal involvement, age, and histological grade. None of the patients with a CC genotype and an ER-negative tumor had a breast cancer event during the follow-up. Conclusion. The results indicate that the association between the COX2 rs5277 polymorphism and early breast cancer events varies according to ER-status. Information on rs5277 genotype may provide additional prognostic information for individual breast cancer patients.
Citation Format: Andrea Markkula, Maria Simonsson, Christian Ingvar, Carsten Rose, Helena C. Jernström. Interaction between a COX2 polymorphism and ER status in relation to risk for early events in breast cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2869. doi:10.1158/1538-7445.AM2013-2869
Abstract 2896: Genomic determinants and signature of MET-targeted therapy in glioblastoma.
Authors: Xie Qian , Johnson Jennifer , Ascierto Maria Libera , Kang Liang , Bradley Robert , Mittal Sandeep , Furge Kyle , Briggs Michael , Tanner Kirk , Berens Michael E. , Marincola Francesco M. , Vande Woude George F. 
Published: August 2014

Abstract
Glioblastoma (GBM) is one of the most devastating cancers, because the intrinsic capability of single tumor cells to invade normal brain impedes surgical eradication, predictably resulting in early local recurrence and death. The goal of this study is to develop therapeutic strategies for treating GBM patients by identifying and targeting the molecular mechanisms of GBM invasiveness through inhibiting MET signaling pathway. Overexpression of hepatocyte growth factor (HGF) and its receptor MET are associated with poor prognosis of GBM. Genomic analysis of primary GBM tumors indicates that MET is overexpressed in tumors of the mesenchymal phenotype, which is more invasive and results in short patient survival. More recently, MET activation was found to contribute to recurrence in GBM patients after bevacizumab treatment, further highlighting the utility of blocking the MET pathway in this disease. With MET inhibitors’ entering clinical trials, there is increased need to find the molecular determinants of MET sensitivity. Because GBM is a heterogeneous disease in which drug response in the individual patient can be regulated by different mechanisms, approaches for understanding and predicting treatment outcomes based on the molecular features of individual tumor will be of a high value. Based on our previous finding that HGF-autocrine activation predicts sensitivity to MET inhibition, we have developed a two-step methodology using microarray technology and bioinformatics analysis to identify and test genomic determinants in order to effectively deploy MET-targeted therapy in GBM patients. By analyzing the data sets from The Cancer Genome Atlas Network (TCGA) and those from GBM xenograft models sensitive and insensitive to MET inhibitors, a 25-gene signature highly associated with HGF-autocrine activation is identified. When performing validation analysis, the signature scored 40 human GBM xenograft models by HGF expression level, providing a good rationale for further testing its predictive value in identifying tumors sensitive to MET inhibitors. We conclude that HGF-autocrine activation can result in oncogene addiction to MET signaling in GBM. Via a unique panel of signature genes we may be able to identify a subset of patients vulnerable to anti-MET drugs.
Citation Format: Qian Xie, Jennifer Johnson, Maria Libera Ascierto, Liang Kang, Robert Bradley, Sandeep Mittal, Kyle Furge, Michael Briggs, Kirk Tanner, Michael E. Berens, Francesco M. Marincola, George F. Vande Woude. Genomic determinants and signature of MET-targeted therapy in glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2896. doi:10.1158/1538-7445.AM2013-2896
Abstract 291: ERK1/2 pathway activation controls epithelial-mesenchymal transition in NSCLC cells.
Authors: Buonato Janine M. , Lazzara Matthew J. 
Published: August 2014

Abstract
Understanding and overcoming the cellular mechanisms that underlie de novo and acquired therapy resistance remains a challenge in treating many cancers including non-small cell lung cancer (NSCLC). Despite the prevalence of epidermal growth factor receptor (EGFR) over-activation in NSCLC and other cancers, most patients are resistant to EGFR inhibitors. A number of studies have linked mesenchymal cellular phenotypes and epithelial-mesenchymal transition (EMT) with resistance to chemotherapeutics and EGFR inhibitors across cancer types. Here, we demonstrate in NSCLC cells that MAPK/ERK signaling plays a key role in determining mesenchymal cellular characteristics and response to the EGFR inhibitor gefitinib. In cultured NSCLC cell lines, pharmacological inhibition of MEK pushed cells toward a more epithelial phenotype and prevented EMT induction by exogenous transforming growth factor beta. In addition, chronic MEK inhibition synergistically enhanced cellular sensitivity to gefitinib in a reversible manner and slowed cell migration in wound healing assays in NSCLC cell lines with both de novo and acquired resistance to gefitinib. Importantly, our results demonstrate that the observed cell phenotypic changes occur on a time scale corresponding to that with which epithelial and mesenchymal marker expression change in response to ERK inhibition. This time scale is much larger than that for changes in ERK activity itself, reflecting the need for downstream ERK-dependent processes to affect phenotypic changes. Changes in the same cellular phenotypes and associated changes in epithelial and mesenchymal markers also occurred as a result of KRAS mutant expression in a MEK-dependent manner. Overall, this study draws a strong connection between ERK pathway activation and mesenchymal characteristics in NSCLC and suggests potential new opportunities for expanding the efficacy of currently available EGFR inhibitors.
Citation Format: Janine M. Buonato, Matthew J. Lazzara. ERK1/2 pathway activation controls epithelial-mesenchymal transition in NSCLC cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 291. doi:10.1158/1538-7445.AM2013-291
Abstract 2957: Cellular level of HSP27 phosphorylation plays a key switch from cell survival to death induced by TRAIL or gemcitabine.
Authors: Kang Dongxu , Choi Hye J. , Kim Jina , Kim Joo-Hang , Song Jae Jin 
Published: August 2014

Abstract
TRAIL-induced activation of Akt catalytic activity and phosphorylation were highly correlated with p38/HSP27 phosphorylation, whereas the phosphorylation of p38/HSP27 increased further during incubation with curcumin and TRAIL, which caused significant apoptotic cell death in DU-145 cells. Next, we investigated whether the cellular level of HSP27 phosphorylation acts as a determinant of cell fate: from cell survival to cell death by biphasic way using another anticancer agent, gemcitabine an antitumor drug currently used for the treatment of advanced pancreatic cancer. We have observed that gemcitabine induced p38/HSP27 phosphorylation and acquired resistance at lower concentration as TRAIL did. After the acquisition of TRAIL or gemcitabine resistance, cancer cells (DU-145 or Mia-PaCa) with acquired resistance to these drugs expressed higher amount of vimentin as well as various MMPs. However, the expression level of these proteins even in TRAIL or gemcitabine-resistant cells was significantly decreased by the incorporation of constitutively phospho-mimic HSP27 with concurrent cell death, providing a new potential strategy to overcome the drug resistance and ultimate metastasis.
Citation Format: Dongxu Kang, Hye J. Choi, Jina Kim, Joo-Hang Kim, Jae Jin Song. Cellular level of HSP27 phosphorylation plays a key switch from cell survival to death induced by TRAIL or gemcitabine. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2957. doi:10.1158/1538-7445.AM2013-2957
Abstract 3018A: A novel type of oncogene SWAP-70.
Authors: Shu Chung-Li , Lai Jing-Yang , Su LIang-Cheng , Chuu Chih-Pin , Fukui Yasuhisa 
Published: August 2014

Abstract
SWAP-70 is a protein that has been suggested to be involved in regulation of actin rearrangement. Having found that an artificial mutant of SWAP-70 can transform mouse embryo fibroblasts, we searched for mutations of the SWAP-70 gene, finding listings for several on the Web at www.sanger.ac.uk/genetics/CGP/cosmic/, including three mutations in ovarian cancers. (The number of such mutations has now reached seven.) We made expression vectors for the mutant SWAP-70 proteins and introduced into NIH3T3 cells. The cells expressing the mutant SWAP-70 exhibited faster growth than the parental or wild type SWAP-70-expressing cells. That these cells grew in soft agar suggests they may be malignant tumor cell lines. They were sensitive to nutrient starvation, supporting the idea that they are transformed cells. However, they failed to pile up and showed contact inhibition, unlike usual transformed cells. Upon expression of human SWAP-70 genes, MEK was activated. This activation appeared to contribute to the saturation density of the cells. Because SWAP-70 has been shown to be the last protein to receive signals from cytokines, it is likely that there is a feedback signaling pathway and that disorder of this signaling pathway can transform the cells.
Citation Format: Chung-Li Shu, Jing-Yang Lai, LIang-Cheng Su, Chih-Pin Chuu, Yasuhisa Fukui. A novel type of oncogene SWAP-70. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3018A. doi:10.1158/1538-7445.AM2013-3018A