bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2397: Fat soluble vitamin B1 analogue, benfotiamine, prevents colon cancer cell growth and aberrant crypt foci formation in murine models of colon cancer
Authors: Ramana Kota V. , Saxena Ashish , Tammali Ravinder , Reddy Aramati BM , Srivastava Satish K. 
Published: June 2012

Abstract
Chronic inflammatory diseases and oxidative stress are major risk factors of colorectal cancer (CRC), the third most common cause of death among cancer patients. Although several agents such as antioxidants, plant products and nutritional supplements have been shown to have some chemopreventive effects on colon cancer, none are very effective to completely. Recent studies indicate that a fat soluble analogue of vitamin B1, benfotiamine is an excellent antioxidant and anti-inflammatory. However, the chemo-preventive or -therapeutic efficacy of benfotiamine in preventing CRC is not known. Our hypothesis is that benfotiamine through its anti-oxidant and anti-inflammatory properties could be very effective in preventing CRC. We therefore investigated the role of benfotiamine in the prevention of carcinogenic signals leading to CRC in cell culture as well as murine models of CRC. Our results show that treatment of human colon cancer cells (HT-29 and Caco-2) in culture with benfotiamine prevented the cancer cell proliferation. Further, benfotiamine also prevented the growth of human adenocarcinoma cells (SW480) -induced tumor growth in nude mice xenografts. Our studies also indicate that benfotiamine prevented NF-kB-dependent survival signals and activated caspase-3 dependent apoptotic signals in colon cancer cells. Further, benfotiamine supplementation also suppressed azoxymethane (AOM)-induced aberrant crypt foci (ACF) formation in mice and AOM-induced inflammatory changes such as activation of Cox-2 and iNOS, and carcinogenic changes such as expression of cyclin D1 and β-catenin in mice colons. In conclusion, our results indicate that benfotiamine prevents colon cancer cell growth in culture and nude mice xenografts as well as formation of ACF in AOM-treated mice. Thus benfotiamine supplementation could be used as an excellent chemopreventive agent for the treatment of CRC.
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 2397. doi:10.1158/1538-7445.AM2011-2397
Abstract 2405: Identification of PHLPP as a tumour suppressor reveals the role of pathway feedback compensation in PTEN-mutant prostate cancer progression
Authors: Chen Muhan , Pratt Christopher P. , Zeeman Martha E. , Schultz Nicholaus , Taylor Barry S. , O'Neill Audrey , Castillo-Martin Mireia , Nowak Dawid G. , Naguib Adam , Grace Danielle M. , Murn Jernej , Sander Chris , Gerald William L. , Cordon-Cardo Carlos , Newton Alexandra C. , Carver Brett S. , Trotman Lloyd C. 
Published: June 2012

Abstract
Hyper-activation of the PI 3-Kinase/ AKT pathway is common in many cancer types. Tumourigenesis through this pathway is prevented by concerted action of multiple tumour suppressor genes. Most notably, PTEN reverts PI 3-Kinase activity whereas excessive pathway activation triggers the p53-mediated senescence arrest. However, it remains ill defined if and at what stage this response acts in human prostate cancer. Here we identify the AKT-inactivating phosphatase PHLPP as a tumour suppressor and demonstrate how the p53-response can antagonise co-deletion of PTEN and PHLPP to form a barrier against prostate cancer progression. We show that Phlpp-loss causes neoplasia and upon partial Pten-loss, carcinoma in mouse prostate. In this setting, Phlpp-deficiency triggers growth arrest via mTorC1-dependent activation of p53 and we find that co-deletion of Pten and Phlpp selects for spontaneous inactivation of p53 in prostate. Validating this conditional gene inactivation scheme in a comprehensive genomic patient data set we find that co-deletion of PTEN and PHLPP is almost exclusively observed in metastatic prostate cancer and tightly correlated to deletion of TP53. Furthermore, PTEN/ PHLPP expression can be used to predict disease outcome in these patients, comparable to the standard histology based method, but adding actionable information on pathway status. Finally, we show that both known PHLPP isoforms compensate for PTEN-suppression in a novel pathway feedback explaining their co-deletion with PTEN in the metastatic samples. Surprisingly, we find that the feedback surge of these genes is sensitive to some pharmacological inhibitors of the PI 3-Kinase pathway. Collectively, our findings emphasise the need for careful evaluation of PI 3-Kinase target therapy effects in prostate cancer and highlight the value of genetically engineered mouse models in this process.
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 2405. doi:10.1158/1538-7445.AM2011-2405
Abstract 2411: Hurp deficiency causes mitotic infidelity and impairs liver regeneration in mice
Authors: Tsai Ting-Fen , Huang Chiao-Ming , Li Chao-Chin , Kao Cheng-Heng 
Published: June 2012

Abstract
Aberrant expression of hepatoma up-regulated protein, HURP, was found in hepatocellular carcinoma (HCC). Recent studies revealed that HURP is an essential factor during mitosis. However, the function of HURP in an in vivo context has not been well studied. In this study, we have concentrated our efforts on the pathological effects of Hurp deficiency during liver regeneration. We generated Hurp knockout (KO) mice to investigate the function of Hurp involved in hepatocyte cell cycle progression; we used the in vivo model of two-third partial-hepatectomy (PH) to induce synchronous cell cycle entry in liver. Our results revealed striking phenotypes of mitotic errors and chromosome instability in the Hurp KO livers. These phenotypes include impaired cell cycle progression as revealed by delayed entry of S-phase and M-phase of hepatocytes post-PH; mitotic infidelity as revealed by lagging chromosomes, multi-polar segregation and unequal segregation; aberrant nuclei of micro-nucleus, multi-nucleus and atypical nuclear morphology were frequently observed in the Hurp KO livers. Mechanistically, these abnormalities caused by Hurp deficiency did not turn on the spindle checkpoint machinery, such as BubR1 and Mad2, but up-regulated p21 expression to delay the cell cycle progression in liver. As an evidence of chronic liver damage, we observed continuously elevated serum ALT levels in Hurp KO mice post-PH. Together, these phenotypes in liver indicated that Hurp deficiency interferes spindle checkpoint (directly or indirectly), leading to mitotic infidelities, and possibly causes DNA breakage during chromatin segregation; this DNA breakage can further induce p21 to delay cell cycle during liver regeneration which is accompanying by chronic liver damages. All of these abnormalities may further lead to enhanced carcinogenesis in liver, which is currently under investigation.
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 2411. doi:10.1158/1538-7445.AM2011-2411
Abstract 2412: Molecular characterization of hepatocellular carcinoma (HCC) patient-derived explant models
Authors: Zhang Lan , Zhang Jingchuan , Xie Liang , Xie Xiaoying , Guo Qiuli , Lv Jing , Gao Zeren , Qian Ziliang , Yin Xiaolu , Zheng Li , Zhu Guanshan , Ji Qunsheng , Ren Zhenggang 
Published: June 2012

Abstract
Recent evidence suggested that cancer patient-derived explant mouse models can maintain certain pathological and molecular features of the original diseases/patients, which offers potential opportunities for testing “personalized medicine” preclinically. We have established over 20 HCC explant models by directly implanting fresh tumor tissues derived from HCC patients into immunodeficient mice. To assess whether these HCC models would represent HCC clinical characteristics and individual patient diversity, we have compared the molecular profiles of these xenografts with their corresponding patient tissues (F0). This included gene copy variation by aCGH, mRNA expression by Affymetrix and gene mutations as well as protein expressions by immunohistochemistry. In addition, we also assessed the stability of the molecular profiles of various models by comparing different passages (F1-F10). Analysis of the data revealed that the xenograft tumors maintain fundamental genotypic features of the original patients, which recapitulate the genetic diversity of the HCC. The assessment on the stability of molecular profiles of individual model based on Pearson correlation coefficient (r) of aCGH data from different passages (F1-F10) suggests that those HCC models are very stable across passages (r &gt; 0.8). In addition, no dramatic changes of the known molecular and histological features were observed throughout serial passages. AFP mRNA expressions of various models by Affymetrix are very different and mirror patient clinical data very well. Amplification of myc and cycline D1 and deletion of DLC1 and FHIT were detected in different individual models, as well as in corresponding patient HCC tissues, and those aberrations are consistent throughout the passages within various individual model. Furthermore, passages of the tumors in successive cohorts of mice did not change their sensitivity to sorafenib. In summary, we have developed preclinical HCC patient-derived explant models that can be used to further understand the disease and develop mechanism-based anti-cancer drugs for treatment of HCC patients.
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 2412. doi:10.1158/1538-7445.AM2011-2412
Abstract 2414: In vitro profiling of gastric and liver cancer cell lines developed from Asian cancer patients
Authors: Kelter Gerhard , Maier Armin , Krumbach Rebekka , Schüler Julia , Fiebig Heinz-Herbert , Beckers Thomas 
Published: June 2012

Abstract
In East Asia stomach and liver cancer are the 2nd and 3rd most common malignancies and there is a high medical need to develop new drugs. However, well characterized in vitro and in vivo models developed from Asian cancer patients are rare. The Oncotest tumor xenograft and cell line repository used for profiling of anticancer compounds comprised mainly models established from patients with a Caucasian origin. Now the Oncotest tumor repository was extended by 8 gastric and 12 liver cancer cell lines of Asian origin obtained from KCLB (Korean Cell Line Bank) and JCRB (Japanese Collection of Research Bioresources). Additionally, 2 head & neck cancer cell lines from KCLB and the gastric cell line GXA 3011L established at Oncotest from a Korean patient-derived tumor xenograft were added to the panel.
Among these 23 cell lines, 6 currently grow subcutaneously as solid tumor xenografts in nude mice. Gene expression profiles (Affymetrix chip HG-U133 plus 2.0 consisting of 38,500 genes) have been determined for all cell lines and respective xenografts. Doubling times as determined for all cell lines were in the range of 23 h (MKN45) to 76 h (SNU-423).
In vitro chemosensitivity to standard of care (e.g. 5-FU, doxorubicin, oxaliplatin, paclitaxel) and selected targeted drugs (everolimus, lapatinib) was assessed by a fluorescence based monolayer cytotoxicity assay as well as by the ex-vivo clonogenic assay. The drugs showed diverse patterns of selectivity and potency in both assays. As an example, the mTor inhibitor everolimus exhibited pronounced activity with IC50 values in the low nanomolar range towards the liver cancer cell lines SNU-398, SNU-475, SNU-878 and SNU-886 in the monolayer as well as in the clonogenic assay. In contrast, towards gastric cancer cell lines no or only marginal activity was detected for everolimus in the monolayer assay. The HER2 / EGFR kinase selective inhibitor lapatinib showed selective activity towards the gastric cancer cell line NUGC-4 (IC50=0.16µM), the liver cancer cell line JHH-4 (IC50=0.56µM) and the H&N cancer cell line SNU-1076 (IC50=0.54µM). Overall, in vitro activity profiles for 12 SOC drugs and correlations with molecular alterations, target expression and pathway activation will be presented.
This collection of cell lines is of high relevance for the development of drugs against the most widely occurring cancers in East Asia, by providing models for the study of the biology and response to novel anticancer drugs.
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 2414. doi:10.1158/1538-7445.AM2011-2414
Abstract 2422: Epithelial interleukin-4 receptor promotes metastasis of mammary tumor cells
Authors: Hwang Daniel G. , Dozier Ashley , Carter Kathy J. , Fingleton Barbara 
Published: June 2012

Abstract
Interleukin-4 (IL4) is known primarily for its immune system functions where it can stimulate lymphocytes and promote macrophage activation. Various cancer cells, including breast, are now known to express functionally active IL4 receptors, which appear to play a role in cell survival. We believe that blocking IL4 signaling specifically in epithelial cells will attenuate metastasis because of reduced cell survival in secondary sites. To test this hypothesis, we have generated multiple clones of two murine mammary tumor cell lines that show efficient knockdown of an essential component of the IL4 receptor, IL4-receptor [IL4R] alpha. Initial characterization of knockdown and control clones showed a significantly slower growth rate in vitro as assessed both by metabolic (MTT) assays and direct cell counting. Flow cytometric analysis using either annexin V staining or sub G1 measurement showed that clones lacking IL4Ralpha had 2-fold higher basal levels of apoptosis. To test effects in vivo, we have performed experimental and spontaneous metastasis assays using clones of the 4T1 cell line. Both pulmonary and hepatic metastatic lesions were significantly decreased [2.4-fold lower] in mice injected with IL4Ralpha knockdown clones compared to controls. There was however no significant effect on the primary mammary tumors. Together these results suggest that IL4 signaling in epithelial tumor cells is pro-metastatic, and blocking it may be a useful therapeutic approach for preventing metastatic spread.
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 2422. doi:10.1158/1538-7445.AM2011-2422
Abstract 2427: Endothelioma of bone revisited: G-Protein coupled receptor 64 promotes invasiveness and metastasis in Ewing Tumors
Authors: Richter Günther H. , Fasan Annette , Roessler Sabine , Burdach Stefan 
Published: June 2012

Abstract
Metastatic spread in Ewing Tumors (ET) is frequent and hematogenous. Microarray analysis revealed the G-protein coupled receptor 64 (GPR64), an orphan receptor with normal expression restricted to human epididymis, to be over-expressed in ET. Members of this family of receptors have been implicated with vascularization and neuronal development. Inhibition of GPR64 expression by RNA interference impaired endothelial differentiation in vitro and suppressed local tumor growth and metastasis in Rag2-/-γC-/- mice. Microarray analysis of ET after GPR64 knock down revealed a GPR64-mediated suppression of genes involved in differentiation like v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ERBB4), and genes stimulating transcriptional activation including pre-B cell leukemia homeobox 2 (PBX2) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4). Similarly, a GPR64-mediated induction of VEGF receptor 1 ligand placental growth factor (PGF) in ET was observed. PGF itself was induced by EWS-FLI1 in mesenchymal stem cells. The GPR64-mediated induction of placental growth factor (PGF) and repression of PGF resulted in a phenotype similar observed after GPR64 knockdown. GPR64 as well as PGF inhibition was associated with reduced proteolytic activity of Matrix Metalloproteinase (MMP) 1 and invasiveness in vitro. MMP1 knock down abrogated lung metastasis in Rag2-/-γC-/- mice. GPR64 and subsequent up-regulation of PGF and MMP1 orchestrate and promote invasiveness and metastatic spread of this tumor, and provide significant conceptual progress in understanding both the histogenesis of ET in particular and the pathogenesis of metastatic dispersal in general.
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 2427. doi:10.1158/1538-7445.AM2011-2427
Abstract 2433: Hepatitis B virus X protein induces metastasis-associated protein 1 gene expression through promoter methylation
Authors: Lee Min-Ho , Na Hyelin , Lee Mi-Ock 
Published: June 2012

Abstract
Expression of metastasis-associated protein 1 (mta1) gene is well correlated with the degree of invasion and lymphatic metastasis in colorectal, hepatocellular and breast carcinomas. Expression of MTA1 was induced by hepatitis B virus X protein (HBx), however, little is known about transcriptional regulation of mta1 gene expression. Here, we reported that 5′-flanking region of MTA1 promoter contains two CpG islands. CpG island 1 and CpG island 2. The CpG island 1 was highly methylated (32.5%) but CpG island 2 (&lt;1%) was not. Using bisulfite-modified direct sequencing, transient expression of HBx led to an increase in methylation of the CpG island 1 up to 48.8 %. In addition, chromatin immunoprecipitation revealed that HBx recruited DNMT3A to CpG island 1 region of MTA1 promoter. In silico analysis of the CpG island 1 predicted an existence of putative p53 binding sequences. We demonstrated that p53 bound to the CpG island 1 by chromatin immunoprecipitation using specific anti-p53 antibody. Further, p53 was pull-downed by DNA probe encoding the p53 binding sequences. However p53 was not pull-downed by the methylated DNA probe using SssI DNA methyltransferase. These data showed that HBx induced methylation of CpG island 1, which interferes the DNA binding of p53 on the specific DNA region. This result may provide the molecular mechanism of how HBx induces the expression of MTA1 gene.
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 2433. doi:10.1158/1538-7445.AM2011-2433
Abstract 2439: Association of antigen processing machinery components and CD8+ T-cell infiltration in breast cancer brain metastasis
Authors: Liu Yan , Komohara Yoshihiro , Domenick Natalie , Horbinski Craig , Hamilton Ronald , Ferrone Soldano , Okada Hideho 
Published: June 2012

Abstract
Purpose: Defects in human leukocyte antigen (HLA) class I antigen processing machinery (APM) component expression can have a negative impact on the clinical course of tumors and the response to T cell-based immunotherapy. Since brain metastases of breast cancer are of increasing clinical significance and only scant information is available about the expression of APM component abnormalities in these lesions, the APM component expression and CD8+ T cell infiltration pattern was analyzed in primary breast and metastatic brain lesions of breast cancer.
Experimental design: Immunohistochemistry was performed to evaluate the expression of APM components HLA class I heavy chain, β2-microglobulin, tapasin, antigen peptide transporter (TAP)1, TAP2, LMP2 and calnexin.
Results: Comparison of unpaired 50 primary and 33 brain metastases showed lower expression of β2-microglobulin, TAP1, TAP2 and calnexin in the brain lesions. Although no significant differences were found in APM component scores between primary breast and brain lesions in 15 paired cases, primary breast lesions of which patients eventually developed brain metastases showed lower levels of β2-microglobulin, TAP1 and calnexin compared with newly diagnosed breast lesions without brain metastases. Furthermore, the extent of CD8+ T cell infiltration was significantly higher in the newly diagnosed breast lesions compared with the ones of which the patients developed brain metastases, and was positively associated with the expression of TAP1 and calnexin.
Conclusions: Our data suggest that patients with low or defective TAP1 or calnexin in the primary breast cancers may be at higher risks for developing brain metastases due to the reduced immunosurveillance.
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 2439. doi:10.1158/1538-7445.AM2011-2439
Abstract 2458: MicroRNA miR-34 as a natural regulator and potential therapeutic for pancreatic cancer stem cells
Authors: Meng Xiaojie , Ji Qing , Hao Xinbao , Tang Wenhua , Xu Liang 
Published: June 2012

Abstract
MicroRNAs (miRNAs) have been implicated in cancer initiation and progression and are involved in cancer stem cell dysregulation. We show that miR-34 directly regulates Notch and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer stem cells. We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines and the potential link to cancer stem cells. Restoration of miR-34 expression in the cancer cells downregulated Bcl-2 and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and G2/M arrest in cell cycle, and sensitized the cancer cells to chemotherapy and radiation. We identified that CD44+/CD133+ cancer cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to significant reduction of the tumor-initiating cell population, accompanied by inhibition of tumorsphere growth in vitro and tumor-initiation in vivo. Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function of the p53 in p53-deficient human pancreatic cancer. Our data support that miR-34 may be involved in cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch, implying that miR-34 may play an important role in cancer stem cell self-renewal and/or cell fate determination. Currently, we are exploring the nanoparticle-targeted delivery of miR-34 to cancer stem cells as a novel molecular therapy for human pancreatic cancer, based on our patented nanobiotechnology which has been approved by FDA for clinical trials. Taken together, our results demonstrate that restoration of miR-34 may hold significant promise as a novel molecular therapy for human pancreatic cancer with loss of p53-miR34, potentially via inhibiting cancer stem cells. Molecularly targeted miRNA therapy could be a powerful tool to correct the cancer stem cell dysregulation. Supported in part by NIH grants CA121830(S1) and CA134655.
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 2458. doi:10.1158/1538-7445.AM2011-2458