bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2340: Lactic acidosis triggers starvation response with distinct metabolic profiles by the induction of TXNIP through MondoA
Authors: Chen Julia, Ling-Yu , Merl Daniel , Peterson Chris , Wu Jianli , Liu Patrick Yantyng , West Mike , Ayer Don , Chi Jen-Tsan 
Published: February 2011

Abstract
Although lactic acidosis and other tumor microenvironmental stresses are prominent features in solid tumors, how they influence the phenotypes of cancer cells are not well understood. We compared the transcriptional response of breast cancer cells under three distinct tumor microenvironmental stresses – lactic acidosis, glucose deprivation and hypoxia. We found that lactic acidosis induced gene expression highly similar to glucose deprivation and triggered features of starvation response. In spite of their similar transcriptional response, lactic acidosis had opposite effects on the glucose uptake to glucose deprivation. This discrepancy guided the supervised analysis of expression data to identify TXNIP as the potential regulator for such divergent metabolic effects. TXNIP and its paralogue ARRDC4 were both induced under lactic acidosis and repressed with glucose deprivation. Their expression was also highly correlated with predicted lactic acidosis pathway activities and associated with favorable clinical outcomes in human cancers. These findings are due to the ability of TXNIP to inhibit the tumor glycolytic phenotypes and redirect energy generation toward aerobic respiration. The induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA: Mlx. Lactic acidosis activates the MondoA-TXNIP pathways and contributes to its “anti-Warburg” metabolic effects and anti-tumor properties of cancer cells. These findings illustrate the value of such integrative analysis of transcriptome and metabolic response under various tumor microenvironmental stresses and may lead to important insights on how they influence the phenotypic and metabolic adaptations in human cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2340.
Abstract 235: Desmocollin 2 (DSC2), identified by CAST method, is associated with intestinal phenotype of gastric cancer
Authors: Anami Katsuhiro , Oue Naohide , Sakamoto Naoya , Hayashi Tetsutaro , Ohara Shinya , Sentani Kazuhiro , Noguchi Tsuyoshi , Yasui Wataru 
Published: February 2011

Abstract
Gastric cancer (GC) is one of the most common human cancers. Identification of novel genes encoding secreted or transmembrane proteins expressed specifically in GC is important for the development of ideal biomarkers for cancer diagnosis and therapeutics. In the present study, we tried to identify genes encoding cell surface and secretory proteins in GC using Escherichia coli ampicillin secretion trap (CAST) method. CAST libraries were generated from two GC cell lines, MKN-1 and MKN-28. Ampicillin-resistant 1,440 colonies from each library were sequenced and these sequences were compared to the public databases using BLAST (NCBI). Many genes encoding secreted and transmembrane proteins including some known genes were identified. Quantitative RT-PCR was performed to confirm the overexpression of the candidate genes in GC, and the expressions of several genes are narrowly restricted in GC. Among these genes, we focused on the desmosomal cadherin desmocollin 2 (DSC2). DSC2 is ubiquitously expressed in several normal tissues where desmosomes exist. In cancers, the reduction of DSC2 in sporadic colorectal cancer is reported as desmocollin switching. It is also known that the homeodomain transcription factors Cdx1 and Cdx2 regulate DSC2 expression in colon cancer cells. Quantitative RT-PCR analyses with 14 kinds of normal tissues and 9 GC cases showed that DSC2 is highly expressed in GCs. In normal tissues, the expression was seen in the heart and pancreas at the lower levels, but not in the stomach. Overexpression of DSC2 was observed in 13 (31%) of 41 GC cases. Immunohistochemical analyses revealed that DSC2 was preferentially expressed in the cases with mucosal or submucosal invasion. DSC2 expression was significantly associated with the well differentiated cases. There were no correlations between DSC2 expression and lymph node metastasis, pathological stage, or overall survival. Additionally, DSC2 was significantly associated in GCs positive for MUC2 and CDX2. Cell invasion assay and MTT assay revealed that knockdown for DSC2 of GC cell lines by siRNA did not inhibit either cell growth or invasion ability. These findings suggest that DSC2 is involved in GC with intestinal differentiation. DSC2 is a good biomarker of intestinal type GC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 235.
Abstract 2351: Evaluation of KRAS and BRAF mutation analysis in primary metastatic colorectal cancers versus matched syn- and metachronous metastases
Authors: Dietmaier Wolfgang , Kiesl Alexander , Lang-Schwarz Corinna , Ruemmele Petra , Groeschl Benedikt , Hofstaedter Ferdinand 
Published: February 2011

Abstract
Background: The KRAS mutation status was shown in recent studies to be a predictive biomarker for anti-EGFR monoclonal antibody (mAB) therapy in metastatic colorectal cancer (mCRC). Patients without KRAS mutations (wild type KRAS) did benefit from anti-EGFR-mAB therapy whereas patients with tumors bearing a KRAS mutation did not benefit from this targeted therapy. KRAS mutation analysis is thus required before anti-EGFR-mAB treatment in all mCRCs. As published in the clinical studies, primary tumors are commonly used as the standard tissue. However, KRAS mutation analysis is often complicated because primary tumors are being discarded by many institutes of pathology years after diagnosis. Instead recent metastases are available and are used for KRAS mutation analysis. However the question is raised if primary tumors and metastases are equally informative regarding the KRAS and BRAF mutation status especially when considering the multiple steps during tumor cell dissemination and metastatic processes. So far only little and heterogeneous data are available about this issue. Patients and methods: To address this question we performed a KRAS mutation analysis (codons 12, 13, 61) in 111 colorectal cancers and 171 matched metastases in lymph nodes, liver, lung, ovary, peritoneum, brain, urinary bladder and bone. Additionally, BRAF mutation analysis was done in all KRAS wild type tumors. In addition, multiple (&gt;=2) matched synchronous or metachronous metastases and corresponding primary tumors were analysed in 44 cases. KRAS and BRAF mutation analysis was done using pyrosequencing technology. Tumor cells were gained either by microscopically controlled manual microdissection or by laser assisted microdissection. Results: Primary tumors and matched metastases with initially discrepantly appearing KRAS mutation status were re-analysed using laser-microdissection. By means of laser microdissection we finally did not find any discrepancies in the KRAS and BRAF mutation status in primary tumors versus matched syn- or metachronous metastases. Conclusion: KRAS and BRAF mutation analysis in metastases appears to be as valid as in primary tumors and should serve as reliable specimens in cases where primary tumors are not available to predict response to therapies with anti-EGFR targeted monoclonal antibodies in metastatic colorectal cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2351.
Abstract 2366: Reduced ecto-5′-nucleotidase CD73 expression and altered purine nucleotide metabolism in colorectal cancer cells robustly causing liver metastases
Authors: Matsuyama Masahiro , Wakui Masatoshi , Monnai Makoto , Mizushima Tomoko , NIshime Chiyoko , Kawai Kenji , Suemizu Hiroshi , Hishiki Takako , Suematsu Makoto , Murata Mitsuru , Chijiwa Tusyoshi , Furukawa Daisuke , Ogoshi Kyoji , Makuuchi HIroyasu , Nakamura Masato 
Published: February 2011

Abstract
Liver metastases are frequently inoperative and severely impact the prognoses of patients with cancers. Colorectal cancers as well as pancreatic cancers most commonly metastasize to the liver, although there are some patients with colorectal cancers presenting liver metastases operative contrary to the cases of pancreatic cancers. Through liver metastasis models using NOD/SCID/IL-2Rγcnull (NOG) mice, we have previously established and examined a highly liver-metastatic human pancreatic cancer cell subline, which was derived from the poorly liver-metastatic parental line, identifying a key molecular regulator of liver metastasis. In the present study, we established a highly liver-metastatic human colorectal cancer cell subline SW48LM2 through the serial intrasplenic transfer of cells derived from poor but visible hepatic tumor foci formed by parental SW48 cells transferred to NOG mice. The growth both under monolayer-culture conditions and during formation of the subcutaneous tumors was similar between the two cell lines, although there were morphological differences in the in vitro spheroid formation. Of 41 molecules reportedly associated positively or negatively with tumor progression, four were overexpressed and four were underexpressed in SW48LM2 cells. Most strikingly, this liver-metastatic cell subline exhibited strongly reduced expression of the ecto-5′ -nucleotidase CD73 as well as altered metabolism of purine nucleotides. Contrary to previous studies showing a positive correlation between CD73 expression and metastatic cancer phenotypes, reduced CD73 expression on tumor cells may contribute to the potential of liver metastases. The present study highlights the need for interpretative caution when investigating metastasis-associated molecules for the diagnostic and therapeutic applications, providing insights into the mechanisms of liver metastases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2366.
Abstract 2367: RSK2 promotes head and neck cancer cell invasion through direct phosphorylation of Hsp27 to regulate actin filaments
Authors: Elf Shannon , Lythgoe Katherine , Hitosugi Taro , Taunton Jack , Zhou Wei , Xiong Li , Wang Dongsheng , Muller Susan , Fan Songqing , Sun Shi-Yong , Chen Zhuo (Georgia) , Khuri Fadlo R. , Chen Jing , Shin Dong M. , Kang Sumin 
Published: February 2011

Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancers and frequently metastasizes to lymph nodes. We found that the protein expression pattern of p90 ribosomal S6 kinase 2 (RSK2) correlates with the invasive ability of diverse HNSCC cell lines, and with human head and neck cancer progression. Continued RSK2 expression is vital for maintenance of the invasive and metastatic potential of HNSCC cells in vitro and in vivo, respectively. In a phospho-antibody microarray-based study, we identified pro-metastatic protein factors that are phosphorylated and activated by RSK2, including the previously identified CREB and a newly identified RSK2 substrate Hsp27, which are important for the RSK2-mediated pro-invasive ability of HNSCC cells.
Hsp27 has been found to be overexpressed in many types of cancers, and its overexpression is associated aggressive tumor behavior. Here we found that RSK2 promotes stabilization of actin filaments in HNSCC cells through phosphorylation and activation of Hsp27 RNAi-mediated knockdown of Hsp27 significantly attenuated HNSCC Tu212 cell invasion conferred by exogenous expression of RSK2. In an in vitro kinase assay using purified recombinant Hsp27 WT and individual S15A, S78A or S82A mutant proteins incubated with active recombinant RSK2, we found that RSK2 directly phosphorylates Hsp27 at S78 and S82, but not S15. Moreover, stable expression of phospho-mimetic Hsp27 S78D/S82D double mutant led to further significantly enhanced cell invasion of poorly invasive HNSCC Tu212 and 686LN cells, compared to exogenous expression of Hsp27 WT. Stable expression of Hsp27 S78D/S82D mutant, but not WT or S78A/S82A mutant, rescued the cell invasion and tumor metastasis attenuated by stable knockdown of RSK2 in highly invasive HNSCC M4e cells in vitro and in vivo using xenograft mice, respectively.
Hsp27 regulates actin dynamics and apoptosis. Actin immunofluorescent staining showed that RNAi-mediated stable knockdown of RSK2 resulted in disruption of actin filaments in 212LN and M4e cells. However, stable expression of the Hsp27 phospho-mimetic mutant S78D/S82D, but not WT or the phospho-deficient S78A/S82A mutant, rescued the formation of actin filaments.
Our findings demonstrate that RSK2 signals through Hsp27 to regulate actin filaments and cell invasion via direct phosphorylation of Hsp27 at Ser78 and Ser82. This may represent a transcription-independent mechanism underlying RSK2-mediated pro-metastatic signaling in HNSCC cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2367.
Abstract 2368: Autotaxin/Enpp2 controls of bone metastasis formation through osteoclast function
Authors: David Marion , Wannecq Estelle , Jansen Sylvia , Deux Blandine , Ribeiro Johnny , Serre Claire-Marie , Grès Sandra , Bendriss-Vermare Nathalie , Bollen Mathieu , Saulnier-Blache Jean-Sébastien , Clézardin Philippe , Peyruchaud Olivier 
Published: February 2011

Abstract
Autotaxin (ATX, NPP-2) is a secreted protein with both an oncogenic action on mouse breast tissue and metastatic properties on breast cancer cells. Due to its lysophospholipase D activity, ATX generates lysophosphatidic acid (LPA) from lysophosphatidylcholine and controls LPA levels in the blood. We have recently showed that platelet-derived LPA promotes the progression of osteolytic bone metastases of breast cancer cells. However, how LPA is produced at the metastatic site and the role of ATX by cancer cells in this metastasis process are still unknown. Here, we found that in vitro, forced expression of ATX in human breast cancer MDA-B02 cells (MDA-B02/ATX) increased invasiness, proliferation and enhanced their pro-osteoclastic function. In vivo, intravenous injection of MDA-B02/ATX cells to inmmunodeficiency BALB/C nude mice enhanced osteolytic bone metastasis formation, as judged by increased bone loss and tumor burden, and higher active osteoclast number at the bone metastatic site. Mouse 4T1 breast cancer cells induced the formation of osteolytic bone metastases after intracardiac injection in immunocompetent BALB/C mice. We found that 4T1 cells expressed active ATX. In vitro, silencing ATX[O1] expression inhibited invasion but not proliferation of 4T1-siATX cells. In vivo, silencing ATX expression inhibited the extent of osteolytic bone lesions and decreased the number of active osteoclasts at bone the metastatic site. Altogether, these results demonstrated that expression of ATX by cancer cells controls bone metastasis formation and that targeting ATX in patients might contribute to the development of additional therapies against bone metastases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2368.
Abstract 2371: Arid4b is a potential breast cancer progression modifier gene
Authors: Winter Scott F. , Lukes Luanne , Hunter Kent W. 
Published: February 2011

Abstract
Our laboratory's research focuses on the role of host genetics in breast cancer metastasis. The MMTV-PyMT mouse model exhibits varying metastatic efficiency to the lungs when transgenic mice in an FVB background are bred to other strains such as DBA and AKR. Combining quantitative measurement of metastasis with genetic mapping studies of the AKXD recombinant inbred panel of mice has allowed us to determine quantitative trait loci (QTLs) that affect metastatic efficiency. My work has focused on the potential role of Arid4b in breast cancer tumorigenesis and metastasis. Arid4b is a component of the mSin3a histone deacetylase complex that has a known role in breast cancer progression and is a candidate gene underlying a metastasis QTL peak we have identified on mouse chromosome 13. In two independent mouse breast cancer cell lines, Met-1 and PyMT-luc, stable expression of the AKR (high metastatic strain) allele caused significantly larger primary tumor growth than the DBA (low metastatic strain) allele following orthotopic implantation into the mammary fat pads of syngeneic hosts. In Met-1 cells we detected lung surface metastases in the AKR cohort but not in the DBA cohort. We are in the process of performing functional analyses to determine a mechanism of action whereby Arid4b polymorphisms influence tumorigenesis and metastasis. Sequencing has revealed a high density of non-synonymous SNPs between the AKR and DBA alleles in exon 22, which encodes a C-terminal region of the Arid4b protein that is known to mediate interaction with the mSin3a HDAC complex. We are currently using co-IPs and proteomics strategies, such as tandem affinity purification, to identify proteins that bind differentially to the AKR or DBA Arid4b proteins. Arid4b is also alternately spliced and cells ectopically expressing the shorter isoform 2 formed significantly larger tumors in our orthotopic model compared to cells expressing the full-length isoform 1. Interestingly, the alternately spliced exon encodes part of a conserved Chromodomain, which is known to mediate binding of other Chromodomain containing proteins such as HP1 to modified histone tails. Western blots using an Ab specific for dimethylated histone H3 lysine 27 suggest a potential role of Arid4b in modifying chromatin structure. It is likely that both the alternate splicing of the Chromo domain and the allelic variation in the C-terminal domain modulate the epigenetic influence of Arid4b on tumorigenesis and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2371.
Abstract 2375: Nodal regulates the angiogenic switch in breast cancer
Authors: Quail Daniela , Zhang Guihua , Postovit Lynne-Marie 
Published: February 2011

Abstract
Highly aggressive breast tumours undergo dedifferentiation, by displaying tissue-nonspecific gene expression patterns and stem cell-like phenotypes. Nodal is an embryonic morphogen responsible for maintaining plasticity in embryonic stem cells, and is aberrantly expressed in aggressive cancers. The current study reveals a positive correlation between Nodal and aggressive breast cancer phenotypes. Specifically, Nodal promotes self-renewal through single-cell non-adherent spheroid formation, anchorage-independent growth on soft agar, and tube formation by endothelial cells in vitro. Additionally, Nodal promotes angiogenesis in vivo. Similar to its role in embryonic morphogenesis, Nodal may be responsible for promoting the dedifferentiated phenotype of breast cancer, and subsequent angiogenic switch. Since the angiogenic switch is a precursor to metastasis, Nodal may be useful as a prognostic marker or therapeutic target for metastatic disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2375.
Abstract 2380: Carcinoembryonic antigen (CEA) directly activates endothelial cells, thereby inducing (tumor)-angiogenesis
Authors: Bramswig Kira H. , Poettler Marina , Kalinowska Waclawa , Binder Bernd R. , Zielinski Christoph C. , Prager Gerald W. 
Published: February 2011

Abstract
Angiogenesis has become a major target in treatment of a varietly of cancers, whereby the major angiogenic growth factor VEGF is currently in focus for therapeutic interventions. Nevertheless, the use of VEGF-targeting drugs has been shown to be of limited efficacy, which might lie in the fact that tumor angiogenesis is not only induced by VEGF, but also by a variety of other factors.
In this study, we report that the human carcinoembryonic antigen (CEA), a GPI-anchored cell surface adhesion molecule, which is shedded by 70% of human cancers, directly binds to endothelial cells, thereby inducing angiogenic endothelial cell behavior in vitro and in vivo:
Overexpressing CEA in endogenous negative renal cell cancer (RCC) cell line or in the sarcoma cell line MethA led to an enhanced tumor angiogenesis and an increase in tumor growth in vivo, effects which were reverted by downregulation of the CEA receptor in endothelial cells via a lentiviral shRNA construct. Furthermore, targeting CEA by CEA mimotope immunized BALB/c mice, led to a breakdown In tumor vascularization, which was reflected by retarded tumor growth. We found that CEA, by binding to its receptor, led to an increase in integrin activation state, leading to enhanced endothelial cell adhesion, followed by amplified adhesion-induced signal transduction, which involved c-src-activation, focal adhesion kinase (FAK) and ERK phosphorylation, as well as PI3kinase/Akt activation. As a consequence, pro-angiogenic endothelial cell behavior, such as migration and invasion or proliferation were induced. Whenever integrin beta-3 were blocked, CEA was effect less in endothelial cells.
These results show that the tumor marker CEA might bear hitherto undescribed biological significance in promoting tumor-angiogenesis. Thus, CEA-mediated signaling may offer a potential novel therapeutic target for the treatment of cancer.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2380.