bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-357: Efficient identification of tumor of unknown primary origin by its microRNA profile
Authors: Søkilde Rolf , Møller Anne K. , Vincent Martin , Nielsen Boye S. , Hansen Alastair , Daugaard Gedske , Møller Søren , Litman Thomas 
Published: February 2011

Abstract
Background: Carcinomas of unknown primary origin (CUP) constitute 3-5% of all newly diagnosed metastatic cancers, the primary source of which is hard to classify with current histological methods, often because CUPs are poorly differentiated. Since effective cancer treatment depends on early and proper identification of the tumor, CUP patients have poor prognosis and short survival rates. Increasing evidence suggests that microRNAs play an important role in the initiation and progression of cancer, and because the expression of microRNAs is highly tissue specific, the microRNA profile of an unknown tumor can be used to identify its tissue of origin. Here, we present a microRNA based classifier, which based on a sample's microRNA profile, can predict its tissue origin with high accuracy.
Methods: Total RNA was extracted from 1115 formalin fixed paraffin embedded (FFPE) samples, and subjected to expression analysis on an LNA (Locked Nucleic Acid) enhanced microarray platform, which allows for very sensitive and specific detection of 2090 microRNAs. Based on the microRNA expression profiles, we tested and cross-validated several classification algorithms, including KNN (K nearest neighbors), LDA (linear discriminant analysis), SVM (support vector machines) and LASSO (least absolute shrinkage and selection operator) to assess, which method is best suited for the current multiclass classification task.
Results: The currently best classifier for tumors of unknown primary origin is based on the LASSO algorithm, which consistently is able to identify 15 different tumor histologies with 90% or higher accuracy based on a small set of microRNAs. We are currently assessing the classifier's performance on true unknown primary tumors, where the correct diagnosis has been obtained at autopsy.
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 LB-357.
Abstract LB-359: Plasma microRNAs as novel biomarkers for lung cancer
Authors: Zheng Dali , Wang Michael X. 
Published: February 2011

Abstract
Objective: Lung cancer is the leading cause of cancer-related deaths in both men and women. Since there is no validated population-based screening procedure, most patients with lung cancer are diagnosed at advanced stages with an overall five-year survival rate of only 15%. Therefore, diagnosis of lung cancer at an early stage is important for improving the outcome of patients. MicroRNAs (miRNAs), a family of 19- to 25-nucleotide and noncoding small RNAs that primarily function as gene regulators at post-transcriptional level, are frequently dysregulated in cancer. Recent studies demonstrate that the miRNAs in blood are present in notably stabile form and are readily detectible by various sensitive methods. This new finding has raised a concept that circulating miRNAs could be novel non-invasive biomarkers for cancer detection. The objective of this study is to investigate the potential of circulating microRNAs for lung cancer detection.
Methods: First, we searched the miRNA microarray data of lung cancer from published literature, and selected 15 of miRNAs (miR-17, 21, 24, 106a, 125b, 128, 155, 182, 183, 197, 199b, 203, 205, 210 and 221) that were most frequently up-regulated in lung cancer tissues. Total RNA including miRNAs were isolated with mirVana PARIS kit (Ambion, TX), then polyadenylated and reverse-transcribed with a poly(T) adapter into cDNAs for real-time PCR using the miRNA-specific forward primer and the sequence complementary to the poly(T) adapter as the reverse primer. The levels of miRNAs were determined in 28 plasma samples from lung cancer patients and 16 of controls.
Results: We found that the levels of miR-155, miR-182 and miR-197 in plasma of lung cancer patients were significantly elevated compared with controls. MiR-155 yielded an AUC (the areas under the ROC curve) of 0.8739 (95% CI:0.7489 to 0.9989, P&lt;0.001), miR-182 yielded an AUC of 0.8426 (95% CI:0.7239 to 0.9614, P&lt;0.001) and miR-197 yielded an AUC of 0.8037 (95% CI:0.6705 to 0.9369, P&lt;0.001) in discriminating lung cancer from controls.
Conclusions: MiR-155, miR-182 and miR-197 are significantly elevated in patient plasma with lung cancer and can be a potential non-invasive molecular biomarker for lung cancer screening and clinical follow-up.
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 LB-359.
Abstract LB-360: Fluorescence-based co-registration with protein markers reveals distinct cellular compartments for altered microRNA expression in solid tumors
Authors: Sempere Lorenzo F. , Preis Meir , Yezefski Todd , Ouyang Haoxu , Suriawinata Arief A. , Silahtaroglu Asli , Conejo-Garcia Jose R. , Kauppinen Sakari , Wells Wendy , Korc Murray 
Published: February 2011

Abstract
MicroRNAs (miRNAs) are a class of short non-coding regulatory RNA genes, which have been implicated in the control of developmental, physiological and pathological processes. High-throughput profiling experiments have linked altered expression of miRNAs to different types of cancer. To clarify the clinical significance of these expression changes, we developed a sensitive fluorescence-based in situ hybridization (ISH) method to visualize miRNA accumulation within individual cells in formalin-fixed paraffin-embedded tissues. This ISH method was implemented to be compatible with routine automated clinical immunohistochemical (IHC) assays to enable co-detection with protein markers on the same tissue section for co-localization and functional studies. Here, we utilized this robust and rapid combined ISH/IHC assay to study a subset of commonly highlighted miRNAs including tumor suppressive miRNAs (let-7 and miR-34) and oncogenic miRNAs (miR-21 and miR-155) in a panel of breast, colon, lung, pancreas and prostate carcinomas, which collectively are the leading causes of cancer-related mortality in the United States. Despite the idiosyncrasies of each particular cancer type, general trends emerged that pinpointed to distinct cellular sources of altered miRNA expression. While altered expression of miR-21 and miR-34 was manifested within cancer cells, that of miR-126 and miR-155 was predominantly confined to endothelial cells and immune cells, respectively. These findings suggest a heterogeneous and complex participation of miRNAs in carcinogenesis occurring through cancer cell-autonomous effects as well as through the modulation of stromal, vascular and immune responses. We discuss potential applications of miRNA-based ISH/IHC assays as novel diagnostic and prognostic tools, as well as clinical implications of our findings for miRNA-based therapeutic strategies.
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 LB-360.
Abstract LB-364: Dovitinib (TKI258), a multikinase inhibitor of FGFR, PDGFR, and VEGFR tyrosine kinases, induces growth suppression in mouse models of human hepatocellular carcinoma (HCC)
Authors: Huynh Hung T. , Chow Pierce , Soo Chee Khee , Shi Micheal 
Published: February 2011

Abstract
Background: Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their receptors are over-expressed and involved in the neovascularization, invasiveness, and metastatic potential of HCC. Therefore, suppression of the VEGFR/FGFR/PDGFR by TKI258 may represent a novel approach for treatment of HCC. The aims of this study were 1) to determine the in vivo antineoplastic activity of dovitinib (TKI258), a multikinase inhibitor of FGF, VEGF, and PDGF signaling pathways, and 2) to compare the efficacy of TKI258 with sorafenib in mouse models of human HCC.
Experimental Design: We treated six patient-derived HCC xenografts with i) 50 or 75 mg/kg TKI258 and ii) 50 mg/kg sorafenib. Western blotting was employed to determine pharmacodynamic changes in biomarkers relevant to FGF/VEGF/PDGF signaling pathways. Apoptosis, microvessel density, and cell proliferation were analyzed by immunohistochemistry.
Results: Body weight was maintained up to 75 mg/kg TKI258 and 50 mg/kg sorafenib. TKI258 treatment resulted in suppression of tumor growth in a dose-dependent manner. Potent antitumor activity was observed in all six HCC xenograft lines studied. The T/C ratio's for 50 mg/kg TKI258 and 50 mg/kg sorafenib for xenograft lines 06-0606, 26-0808A, 26-1004, 28-1108, 5-1318, and 25-0705A, were 0.04 and 0.22; 0.11 and 0.18; 0.13 and 0.26; 0.23 and 0.37; 0.14 and 0.30, and 0.28 and 0.19, respectively, suggesting that in general the antitumor effect of TKI258 was greater than that of sorafenib. TKI258-induced growth inhibition was associated with inhibition of angiogenesis and cell proliferation and induction of tumor cell death. Inhibition of p-FGFR, p-PDGFR, p-VEGFR-2, p-ERK1/2, and upregulation of Bim and p-histone H2A-X Ser139 were observed.
Conclusion: TKI258 demonstrated significant antitumor effect in a mouse model of human HCC xenograft. This study provides a strong rationale for clinical investigation of TKI258 in patients with HCC.
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 LB-364.
Abstract LB-366: A role for hNDPK-B in breast cancer metastasis in vivo.
Authors: Yokdang Nucharee 
Published: February 2011

Abstract
Cancer cells promote angiogenesis early in tumorigenesis under mutagenic/hypoxic conditions that drive oncogene expression of pro-angiogenic proteins. Clinical data suggest that by the time women are diagnosed with breast cancer, micrometastases are extant but suppressed by the primary tumor. It is imperative that we discover how to suppress metastases at or before breast biopsy, lumpectomy or mastectomy. We have shown in vitro that human breast cancers secrete nucleoside diphosphate kinase (sNDPK), which generates ATP from ADP locally to act at ATP-P2Y receptors locally to regulate blood flow, cell migration, and vascular permeability consistent with intravasation and extravasation of cancer cells and angiogenic stimulation at the metastatic niche. The ability of ATP-P2 receptor stimulation to transactivate the endothelial VEGF receptor in the absence of VEGF suggests the possibility that cancer cell-secreted NDPK, endothelial P2Y receptors, and VEGF receptors interact as partners in tumor angiogenesis in vitro. Our in vitro data strongly suggest a role for NDPK blockers and P2-receptor antagonists in adjuvant therapy for breast cancer (US Patent No. 10/331,375). We have now extended our studies of purinergic regulation of angiogenesis in vivo in a breast cancer metastasis model in mice carrying luciferase-tagged human breast carcinoma cells (MDA-MB-231Luc+) to permit tracking of primary tumor development and tumor metastases. We hypothesized that orthotopic-human tumors growing in SCID mice modulate extracellular sNDPK-B levels to attract angiogenic growth, development and metastasis. Examination of serum using Western blot and an ELISA assay of our own design revealed that tumors secreted sNDPK-B in large amounts two weeks after subcutaneous injection of cancer cells in the mammary fat pad. There is a correlation between secreted NDPK-B and tumor size. We confirmed the activity of sNDPK-B as a phosphoprotein trans-phosphorylase. PCR studies suggest that in more aggressive tumors, expression of sNDPK-B mRNA is increased (r2=0.97), while there is no correlation between intracellular NDPK-B and extracellular sNDPK-B expression. Differential mRNA expression may be seen between primary and metastatic cells and could underscore the role of sNDPK-B in mediating metastatic tumor development. Studies underway with mice carrying tumors and implanted with osmotic drug-delivery pumps will determine the effect of NDPK-B blockers, purinergic receptor antagonists and combined therapy on tumor burden and metastasis development and regression.
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 LB-366.
Abstract LB-367: Wnt-dependent transcription factor LEF-1 controls endothelial cell invasion through changes of MMP-2 expression
Authors: Planutis Kestutis , Planutiene Marina , Holcombe Randall F. 
Published: February 2011

Abstract
Background: Wnt signaling is involved in many events including embryogenesis, stem cell regulation, morphogenesis, cell fate determination, and oncogenesis. The role of Wnt pathway in angiogenesis is proposed, however the mechanism is still unclear. Most cancers express elevated levels of different Wnts when compared to normal cells. LEF-1 is a participant in and a target gene of the Wnt/ -catenin pathway. LEF-1 increases the in vitro invasiveness of cancer cells.
Hypothesis: We suggest that LEF-1 controls the invasion also in endothelial cells. We hypothesize further that cancer affects local tumor angiogenesis via Wnt pathway-dependent up-regulation of LEF-1 in endothelial cells (EC).
Methods: To test this hypothesis we construct a model system: endothelial cell line EaHy926 treated with Wnt3a (mostly known as a canonical Wnt signal) conditioned medium or grown in co-culture with L-cells producing Wnt3a.
Results: Wnt3a increases nuclear ß-catenin in human endothelial cell line, and up-regulates LEF/TCF-dependent promoter activity. Wnt3a augments its target gene's LEF-1 promoter activity and LEF-1 mRNA concentration, demonstrating involvement of some transcription factors with E-tails. Both Wnt3a treatment and LEF-1 overexpression elevate MMP-2 mRNA level. Elimination of Wnt-dependent induction of MMP-2 gene expression by LEF-1 siRNA confirms the LEF-1 role in the MMP-2 control mechanism. Loosening up the extracellular matrix MMPs allows the cells to move around. These enzymes are integral part of invasion process. Indeed, LEF-1 up-regulates endothelial cells invasiveness in Matrigel matrix. LEF-1 increases also EC proliferation, in agreement with published data for parental primary endothelial culture HUVEC.
Conclusions: In endothelial cells canonical (ß-catenin) Wnt signaling enhances invasiveness of EC via LEF-1 - dependent regulation of MMP-2 expression. There is a number of similarities between primary cells HUVEC, studied by others, and cell line EAhy926 in their response to Wnt3a. This indicates that EAhy926 cell line conserves many components of angiogenesis control by Wnt/β-catenin pathway and could serve as a simplified model to study this regulation, replacing primary endothelial 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 LB-367.
Abstract LB-371: Altered vascular endothelial growth factor mRNA stability may lead to cancer development following immunosuppressive therapy
Authors: Basu Aninda , Datta Dipak , Pal Soumitro 
Published: February 2011

Abstract
The development of cancer is an increasing and major problem in immunosuppressed patients, particularly after solid organ transplantation. In part, the increased cancer risk is associated with the use of immunosuppressive agents, especially calcineurin inhibitors (CNIs). The CNIs are used to prevent inflammatory diseases and allograft rejection. However, little is known about the mechanism(s) underlying their ability to promote the development and recurrence of cancer. We have recently demonstrated that CNI can mediate the transcriptional activation of the angiogenic cytokine vascular endothelial growth factor (VEGF) and promote a rapid progression of human renal cancer. In contrast, the mTOR inhibitor rapamycin (RAPA), which is thought to have anti-cancer effects, has been reported to decrease VEGF expression. Here, we investigated whether the CNI cyclosporine (CsA) and RAPA could alter the mRNA stability of VEGF in 786-0 and Caki-1 renal cancer cells. By using actinomycin-D, we observed that CsA increased, while RAPA decreased the VEGF mRNA stability as observed by real time PCR. It is established that the mRNA-binding protein HuR may play a critical role in VEGF mRNA stability. By using HuR-siRNA, we found that the knockdown of HuR significantly decreased the CNI-induced VEGF mRNA stability. By Western blot analysis, it has been observed that CNI treatment induced the translocation of HuR from the nucleus to the cytoplasm; CNI also induced the association between HuR and protein kinase C (PKC)-δ, and promoted the phosphorylation of HuR. Interestingly, there was no significant change in the cytoplasmic translocation of HuR following RAPA treatment. Finally, we found that the inhibition of PKC-δ using a dominant-negative plasmid significantly decreased the CsA-induced cytoplasmic translocation of HuR and the VEGF mRNA stability. Together, we suggest that targeting the pathways that promote the transcription as well as the mRNA stability (post-transcriptional modification) of VEGF in response to CNI might serve as novel therapeutics for the prevention and treatment of cancer in immunosuppressed patients.
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 LB-371.
Abstract LB-372: Activation of focal adhesion kinase in cancer cells is regulated by crosstalk between PKCα and MDA-9/syntenin
Authors: Hwangbo Cheol , Lee Suhyun , Lee Jeongmin , Kang Jungwon , Lee Jeong-Hyung 
Published: February 2011

Abstract
mda-9/Syntenin, a tandem PDZ-domain containing adaptor protein, functions as a positive regulator of cancer cell progression in several human cancers. Protein kinase Cα (PKCα) is a key intermediate between integrins and focal adhesion kinase (FAK) signaling in response to fibronectin (FN), but the molecular mechanism by which PKCα regulates FN-induced FAK activation remains unclear. Here, we report that mda-9/syntenin links FN-induced activation of FAK and PKCα in human breast cancer and melanoma cells. FN induced mda-9/syntenin expression and PKCα activation in a similar manner prior to FAK activation. PKCα inhibition resulted in the suppression of the endogenous and FN-induced mda-9/syntenin expression, as well as mda-9/syntenin-induced cell migration and invasion toward FN. mda-9/Syntenin expression and PKCα activation was interdependently regulated; e.g., inhibition of mda-9/syntenin suppressed both FN-induced and endogenous phosphorylation of PKCα at Thr638/641, and inhibition of PKCα suppressed both FN-induced and endogenous expression of mda-9/syntenin. Moreover, inhibition of either mda-9/syntenin or PKCα suppressed the FN-induced association of integrin- 1/FAK/c-Src signaling complexes. Consistently, suppression of either mda-9/syntenin or PKCα significantly inhibited FN-induced phosphorylation of FAK at Tyr397 and c-Src at Tyr416, activation of downstream signaling molecules such p38 and ERK mitogen-activated protein kinases (MAPKs), Cdc42 GTPase, and nuclear factor-κB (NF-κB). These findings demonstrate that PKC -dependent mda-9/syntenin up regulation could play a critical role in FN-induced activation of FAK, and mda-9/syntenin may act as a molecular adaptor that links PKCα and FAK during adhesion to FN in human breast cancer and melanoma cells.
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 LB-372.
Abstract LB-378: Establishment of hepatic metastases in a steatotic microenvironment is enhanced by stromal derived MMP-12
Authors: VanSaun Michael N. , Mendonsa Alisha , Lee In Kyu , Matrisian Lynn M. , Gorden Lee 
Published: February 2011

Abstract
Non-alcoholic fatty liver disease (NAFLD), encompassing steatosis and progression to non-alcoholic steatohepatitis (NASH) are liver disorders of increasing clinical significance. We have shown that hepatic steatosis establishes a permissive microenvironment for metastatic seeding and tumor progression in the liver. We have identified MMP-12 (macrophage metalloelastase) as an important molecular component associated with hepatic steatosis and steatohepatitis. Wildtype mice in the C57Bl/6 background were fed a 42% fat diet for three months to induce hepatic steatosis. Affymetrix microarray analysis was performed on steatotic vs. normal murine livers to determine candidate genes altered between these liver microenvironments. Our results noted 715 significant changes in gene expression, of which matrix metalloproteinase 12 was among the most significantly up regulated genes in the steatotic microenvironment. Importantly, we have detected an upregulation of MMP-12 in human steatotic and steatohepatitis samples. MMP-12 deficient mice gained weight and developed diet-induced hepatic steatosis similar to wildtype mice. To determine whether MMP-12 affected metastasis, normal and steatotic MMP-12 deficient mice were tested with an experimental metastasis model via splenic injection of MC38 tumor cells. The number of resultant tumors per unit of tissue area in wildtype steatotic livers showed a 25 fold increase compared to tumors in MMP-12 deficient mice. Comparison of tumors between regular diet livers in wildtype and MMP12−/−mice was not significant. Immunohistochemical staining for F4/80 showed a reduction in the number of positive cells in MMP-12 deficient steatotic livers.
Conclusions: Modulation of host factors is known to be important in tissue/site specific susceptibility to cancer metastases. MMP-12 can influence immune-mediated injury response by processing latent TNF alpha and regulating macrophage recruitment. Upregulation of matrix metalloproteinase 12 suggest a role for this protease in inflammatory mediated events in the distinct microenvironments of steatosis and steatohepatitis. The molecular mechanisms underlying the decreased establishment of metastatic tumors in MMP-12 deficient mice requires further investigation.
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 LB-378.