bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1106: The tumor immune microenvironment modulates response to chemotherapy in high-grade serous epithelial ovarian cancer
Authors: Koti Madhuri , Edwards Andrew , Squire Jeremy A. 
Published: May 2015

Abstract
Resistance to platinum-based chemotherapy remains a major impediment in the treatment of serous epithelial ovarian cancer. Recent studies have drawn attention to the role of the tumor-microenvironment in mediating chemotherapy resistance, in addition to established mechanisms of tumor progression. This project is investigating the role of the tumor inflammatory microenvironment in facilitating intrinsic chemotherapy resistance using a cohort of 36 high-grade serous epithelial ovarian cancer patient tumor samples. Total RNA from forty-eight, HGSEOC tumor tissue samples was subjected to gene expression profiling using NanoString technology. This type of bar-coded expression profiling has proven to be equally efficient to study gene expression as quantitative real time PCR technique. The gene panel consisted of 184 human genes that are differentially expressed in human inflammation and 6 internal reference genes. The cohort comprised 18 sensitive (PFS &gt;18months) and 18 resistant (PFS&lt;6 months) samples. A multiplex cytokine assay using the bioplex system was also performed on serum samples from a subset of this cohort. The results showed significant differences in expression of some inflammatory cytokines in the serum that were concurrent with the observed gene expression differences in the tumor samples. The results are indicative of a cooperative role of a specific inflammatory gene signature within the tumor microenvironment that may augment pathways leading to differential drug response. These studies need further independent validations to derive non-invasive blood-based biomarkers for use in predicting chemotherapy resistance in serous epithelial ovarian cancer.
Citation Format: Madhuri Koti, Andrew Edwards, Jeremy A. Squire. The tumor immune microenvironment modulates response to chemotherapy in high-grade serous epithelial ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1106. doi:10.1158/1538-7445.AM2014-1106
Abstract 1129: Adenylate kinase 4 promotes metabolic reprogramming and induces EMT in lung cancer through ROS-dependent stabilization of HIF1-α
Authors: Jan Yi-Hua , Hsiao Michael 
Published: May 2015

Abstract
The metabolic alterations that are essential for cancer progression remain largely unknown. Previously, we have identified adenylate kinase 4 (AK4) as a marker for poor clinical outcome that promotes metastasis of lung cancer. However, the molecular mechanism of AK4-induced phenotype remains elusive. By microarray analysis, we found downstream targets of HIF1-α were differentially regulated upon AK4 overexpression in CL1-0 lung cancer cells. Furthermore, AK4 overexpression induces glycolysis and results in accelerated glucose consumption, ATP utilization and lactate production. Overexpression of AK4 also increases the levels of reactive oxygen species (ROS), which exaggerates HIF1-α protein expression under hypoxia and concurrently induces epithelial-to-mesenchymal transition (EMT) in a HIF1-α-dependent manner. IHC analysis showed an inverse correlation between AK4 and E-cadherin and a positive correlation between AK4 and nuclear HIF1-α in lung cancer patients. Moreover, patients with AK4 high/E-Cadherin low showed worse outcome compared to patients with AK4 low/E-cadherin high. Our study indicates that enhanced expression of AK4 is a critical factor to trigger aerobic glycolysis and induced HIF1-α-mediated EMT in lung cancer.
Citation Format: Yi-Hua Jan, Michael Hsiao. Adenylate kinase 4 promotes metabolic reprogramming and induces EMT in lung cancer through ROS-dependent stabilization of HIF1-α. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1129. doi:10.1158/1538-7445.AM2014-1129
Abstract 1130: AKT-mediated phosphorylation is responsible for TWIST1-mediated tumor growth and metastasis
Authors: Ozes Osman N. , Pehivanoglu Suray , Ertosun Gokhan , Gorgisen Gokhan , Erin Nuray , Unal Duygu , Tanriover Gamze 
Published: May 2015

Abstract
Cancer cells show epithelial-mesenchymal transition (EMT) during cell migration, invasion and dissemination. Although it has been shown by numerous publications that the evolutionary conserved basic helix-loop-helix (b-HLH) transcription factor TWIST1 plays pivotal role during EMT the molecular mechanism responsible for TWIST1 function is not fully understood. Here we show that Twist1 binds to and phosphorylated by AKT/protein kinase-B at S42, T121 and S123. While conversion of S42, T121 and S123 to phosphorylation-mimicking Aspartic or glutamic acids created active Twist1, Alanin mutants of the same sites diminished the DNA-binding and transctivating functions of Twist1. In line with this, Glutamic Acids mutants suppressed the expression of E-Cadherin, whose expression is negatively regulated by active TWIST1, Alanin mutants induced the expression of E-Cadherin. Similarly, we tested the impact of above mentioned mutants on cell migration and proliferation. Our results demonstrated that while Glutamic acid mutants accelerated, Alanin mutants suppressed the migration and proliferation of 293T cells. Our in vitro results prompted us to test our mutants under in vivo conditions using breast cancer as a model. We transfected non-metastatic mouse mammary tumor cell line, 67NR, with Glutamic acid mutants, and metastatic mouse mammary tumor cell line, 4T1, with Alanin mutants of mouse TWIST1 and selected the Neo-resistant populations. We injected 1 million 67NR cells over-expressing wild type or Glutamic acid mutants of Twist1, and 100.000 4T1 cells over-expressing wild type or Alanin mutants of Twist1 into the breast tissue of female inbred BalBC mice, and animals were monitored for metastasis. At the end of the 4th week, we sacrifised and examined the animals for tumor growth and metastasis. Although 67NR cells over-expressing wild type Twist1 did not show any metastasis, cells over-expressing 1E (S42E) and 2E (S42E, T121E) mutants of Twist1 showed 15-20 macroscopic metastasis to liver and Lungs. Paralel to this, 4T1 cells expressing 1A (S42A) and 2A (S42A, T121A) mutants of TWIST1 showed no macroscopic metastasis. Our results clearly indicate that phosphorylation of S42 and T121 by AKT is essential for TWIST1-mediated tumor growth and metastasis.
Citation Format: Osman N. Ozes, Suray Pehivanoglu, Gokhan Ertosun, Gokhan Gorgisen, Nuray Erin, Duygu Unal, Gamze Tanriover. AKT-mediated phosphorylation is responsible for TWIST1-mediated tumor growth and metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1130. doi:10.1158/1538-7445.AM2014-1130
Abstract 1146: Up-regulation of integrin β4 promotes epithelial-mesenchymal transition and is a novel prognostic marker in pancreatic cancer
Authors: Masugi Yohei , Yamazaki Ken , Emoto Katsura , Effendi Kathryn , Kitago Minoru , Itano Osamu , Kitagawa Yuko , Sakamoto Michiie 
Published: May 2015

Abstract
Pancreatic cancer is a highly aggressive and lethal malignant tumor. Recent reports have shown that the epithelial-mesenchymal transition (EMT) plays an essential role in cancer invasion and metastasis. We previously reported that EMT was frequently observed in pancreatic ductal adenocarcinoma (PDA) and was related to a high metastatic rate and a poor outcome in patients with PDA (Masugi et al. Hum Pathol. 2010). Further, using cDNA microarray analyses, we identified integrin β4 (ITGB4) as one of the EMT signature genes in 12 patient-derived PDA xenografts. The aim of the current study was to clarify the clinicopathological and functional significance of ITGB4 in PDA. ITGB4 up-regulation in xenografts with high EMT was confirmed by immunohistochemistry. Immunohistochemical analyses of 134 resected PDAs revealed intratumoral heterogeneity with respect to ITGB4 expression and showed that cancer cells undergoing EMT often display diffuse and intense expression of ITGB4. High levels of ITGB4 expression were significantly correlated with the histological hallmarks of EMT (solitary cell infiltration, reduced E-cadherin expression and increased vimentin expression), the grade, and the presence of lymph node metastasis, and showed an independent prognostic effect. Immunocytochemical analyses of PDA cell lines revealed that the distribution of ITGB4 changed from regions of cell-cell contact to a diffuse presence in cytoplasm with occasional localization in filopodia during EMT. Knockdown of ITGB4 by small interfering RNA reduced the migratory and invasive ability of PDA cells. Overexpression of ITGB4 promoted cell scattering and cell motility in combination with down-regulation of E-cadherin and up-regulation of vimentin expression. In conclusion, our study demonstrated the prognostic significance of ITGB4 overexpression in PDA. Moreover, we also identified a potential role for ITGB4 in the regulation of cancer invasion and EMT.
Citation Format: Yohei Masugi, Ken Yamazaki, Katsura Emoto, Kathryn Effendi, Minoru Kitago, Osamu Itano, Yuko Kitagawa, Michiie Sakamoto. Up-regulation of integrin β4 promotes epithelial-mesenchymal transition and is a novel prognostic marker in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1146. doi:10.1158/1538-7445.AM2014-1146
Abstract 1147: CD44s is required for EMT and stemness properties via ZEB1 activation
Authors: Preca Bogdan-Tiberius , Bajdak Karolina , Pfannstiel Jessica , Brabletz Thomas 
Published: May 2015

Abstract
Invasion and metastasis of carcinomas are often promoted by the aberrant epithelial to mesenchymal transition (EMT) program at the invasive front of the tumor. The transcription factor ZEB1 is a crucial promotor of metastasis formation by inducing EMT and tumor initiating capacity. CD44, a cell surface protein, is used as marker to identify tumor initiating cells in many cancer types. It is involved in cell-cell interactions, cell adhesion and migration. Through alternative splicing, controlled by the epithelial splicing factor ESRP1, CD44 is differentially regulated during EMT, resulting in a switch from the variable exon-containing CD44v isoforms to the standard isoform CD44s, which is devoid of all CD44 variable exons.
We examine the reciprocal interaction of CD44s and ZEB1 in their function as tumor initiation markers. CD44s and ZEB1 are co-expressed in poorly differentiated human cancer cells.Transient down regulation of CD44s results in decrease of ZEB1, which in turn leads to reduced sphere formation ability. Likewise, inhibition of CD44s increases ESRP1. Knockdown of ESRP1 decreases expression of CD44v isoforms, increases CD44s and ZEB1 and the sphere forming capacity. Additional knockdown of CD44s reduces the sphere formation. Furthermore, ZEB1 inhibits ESRP1 expression, which leads to upregulation of CD44s.
In summary we identified a positive feedback loop maintaining stemness and mesenchymal features in cancer cells: CD44s activates expression of ZEB1, which suppresses transcription of the splicing factor ESRP1, resulting in further increase in CD44s expression.
Citation Format: Bogdan-Tiberius Preca, Karolina Bajdak, Jessica Pfannstiel, Thomas Brabletz. CD44s is required for EMT and stemness properties via ZEB1 activation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1147. doi:10.1158/1538-7445.AM2014-1147
Abstract 1152: Gene profiling of multiple myeloma: MAPK pathway deregulation, which is regulated by PIM-1 and MOS, is associated with relapse within 6 months after autoSCT in MM patients
Authors: Jung Woo June , Ahn Kwang-Sung , Lee Chansu , Koh Youngil , Lee Hyun Jung , Kim Hyo Jung , Yoon Hwi-Joong , Yoon Sung-Soo 
Published: May 2015

Abstract
Substantial advances have been made in understanding the biology of multiple myeloma (MM) through the study of the bone marrow (BM) microenvironment. Dynamic interplay between bone marrow stromal cells (BMSCs) and MM cells regulated the relapsed MM after autologous bone marrow transplantation (ABMT). In this study, we performed gene expression profiling with microarray data to better dissect the molecular phenotypes and prognoses of relapsed multiple myeloma (MM). Using gene expression and clinical data, we applied gene expression signatures reflecting deregulation of oncogenic pathways to highlight molecular changes in bone marrow aspirate from 28 patients with relapsed MM. The patient subgroups were defined according to relapse-free interval, within 6 months versus more than 6 months. The microarray results revealed that dyregulation of MAPK pathway was associated with relapse within 6 months after ABMT. Among them, the expression of PIM-1 gene and MOS gene was higher in samples from patients with relapsed MM than MM cell lines (p=0.0037; p=0.0021). Also, IL-6, sIL-6R, and HGF expression in patients who relapsed within 6 months after ABMT was higher than the patients whose relapse-free interval were longer than 6 months. Treatment of shRNA PIM-1 gene and shRNA MOS gene in U266 and MOLP8 dramatically led to decreasing IL-6/sIL-6R mediated ERK phosphorylation and HGF-mediated MET phosphorylation. Similar results were noted for cluster genes for PIM-1/MOS. Especially, functional analysis of PIM-1 leads to inactivate the MAPK pathway through regulating p38 mediated signaling and Wnt/β-catenin pathway. Recent studies suggested that p38 activity in myeloma inhibits osteoblast differentiation and bone formation, but also enhances osteoclast maturation and bone resorption. p38 regulated the expression and secretion of the Wnt pathway antagonist DKK-1 and the monocyte chemoattractant MCP-1. Conclusionally, Our analysis suggested that MOS gene and PIM-1, which regulates MAPK pathway, is a noble prognostic marker for relapse of MM. The importance of the PIM-1-MOS-MAPK pathway as a prognostic marker in relapsed MM should be reassessed in the novel therapeutic agent era.
Citation Format: Woo June Jung, Kwang-Sung Ahn, Chansu Lee, Youngil Koh, Hyun Jung Lee, Hyo Jung Kim, Hwi-Joong Yoon, Sung-Soo Yoon. Gene profiling of multiple myeloma: MAPK pathway deregulation, which is regulated by PIM-1 and MOS, is associated with relapse within 6 months after autoSCT in MM patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1152. doi:10.1158/1538-7445.AM2014-1152
Abstract 1156: Shed syndecan-1 downregulates histone acetyltransferase activity and shuttles HGF to the nucleus of tumor and host cells
Authors: Stewart Mark , Ramani Vishnu , Sanderson Ralph 
Published: May 2015

Abstract
The cell surface heparan sulfate proteoglycan syndecan-1 (CD138) is expressed by myeloma tumor cells, is proteolytically shed from the cell surface and accumulates in the serum. High levels of serum syndecan-1 are an independent indicator of poor prognosis. Our lab has demonstrated that shed syndecan-1 drives myeloma tumor progression in vivo, but the mechanism(s) mediating this are not fully understood. The role of heparan sulfate proteoglycans on the cell surface and in the extracellular matrix has been extensively studied, but their presence and function within the nucleus is often overlooked. However, recent findings indicate that nuclear heparan sulfate has important regulatory functions. Based on preliminary findings, we hypothesized that shed syndecan-1 binds to the tumor cell surface and translocates to the nucleus where it regulates gene expression thereby promoting aggressive tumor behavior. We utilized murine myeloma cells which were grown in the presence of medium containing human shed syndecan-1. Strikingly, the shed syndecan-1 was rapidly taken up by these cells and translocated to the nucleus. Additionally, exogenous human shed syndecan-1 added to murine stromal cells also bound to the cell surface and translocated to the nucleus. This is the first demonstration that shed proteoglycans can translocate to the nucleus of cells. When stromal cells were grown in the presence of tumor-derived shed syndecan-1, acetylated histone H3 was decreased. Additionally, tumor cells engineered to express high levels of shed SDC1 have a 58% reduction in histone acetyltransferase activity. This may be due to syndecan-1 directly binding to p300/CBP-associated factor, a HAT enzyme. Moreover, HGF bound to shed syndecan-1 was shuttled to the nucleus of myeloma cells as a complex. Shed syndecan-1 and HGF translocation to the nucleus is dependent on intact heparan sulfate chains present on the syndecan-1 core protein. These data reveal a novel mechanism of tumor-host crosstalk whereby syndecan-1, shed by tumor cells, alters histone acetyltransferase activity and shuttles heparin-binding factors to the nucleus to reprogram cells and alter gene expression. Therapeutic regulation of syndecan-1 shedding, its binding to the cell surface or translocation to the nucleus represent novel strategies to control the progression of myeloma and other cancers.
Citation Format: Mark Stewart, Vishnu Ramani, Ralph Sanderson. Shed syndecan-1 downregulates histone acetyltransferase activity and shuttles HGF to the nucleus of tumor and host cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1156. doi:10.1158/1538-7445.AM2014-1156
Abstract 1164: sHER3 inhibits the proliferation and migration of melanoma-derived cells in a tenascin-dependent manner
Authors: Cai Chunlin , Maihle Nita J. 
Published: May 2015

Abstract
The expression of HER3 receptor tyrosine kinase, a member of the EGFR/HER family of cellular oncogenes, is common in both primary and metastatic melanoma, and high levels of HER3 expression are correlated with poor patient survival. However, no one has demonstrated the mechanistic basis for HER3 as a poor prognostic determinant in melanoma patients, even though these tumors poorly express other members of the EGFR/HER receptor family. In this study we present evidence demonstrating that 13 of 14 melanoma cell lines tested express HER3, supporting previous reports regarding the frequency of expression of this gene product in melanoma samples. We further report that a soluble isoform of HER3 (sHER3) that we previously have shown to be a potent inhibitor of neuregulin mediated, Akt-dependent breast cancer cell growth strongly inhibits the growth of HER3 expressing melanoma cells. Interestingly, however, the phosphorylation of Akt, a known mediator of ligand-dependent HER3 signaling, is not reduced in melanoma cells growth inhibited by sHER3. To explore alternative mechanisms of HER3 signaling in melanoma, we identified sHER3 interacting partners using a mass spectrometry proteomic approach. Only one prominent sHER3 binding partner was identified in melanoma cell conditioned media: tenascin. This was an unexpected finding since ligand-dependent HER3 signaling has not previously been linked to tenascin. Interestingly, tenascin expression has independently been identified as another negative prognostic indicator in melanoma. Our initial studies to test the functional relationship between HER3 and tenascin suggest that tenascin expression is correlated with both HER3 expression and migration in all of the melanoma lines tested. Moreover, sHER3 inhibition of melanoma migration was dependent on the level of tenascin present. Treatment of melanoma cells with purified sHER3 inhibits the migration only in the presence of high levels of tenascin. These results suggest the existence of an unanticipated tenascin- and HER3-dependent signaling pathway in melanoma cells, and suggest that this pathway is functionally correlated with melanoma cell migratory potential and poor patient survival. (This work was supported by the Harry J. Lloyd Charitable Trust Foundation.)
Citation Format: Chunlin Cai, Nita J. Maihle. sHER3 inhibits the proliferation and migration of melanoma-derived cells in a tenascin-dependent manner. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1164. doi:10.1158/1538-7445.AM2014-1164
Abstract 1181: The Apoptosis repressor with a CARD domain (ARC) is a direct HIF1 target gene and promotes survival and proliferation of VHL deficient renal cancer cells
Authors: Razorenova Olga V. , Castellini Laura , Colavitti Renata , Edgington Laura E. , Nicolau Monica , Huang Xin , Bedogni Barbara , Mills Edward M. , Bogyo Matthew , Giaccia Amato J. 
Published: May 2015

Abstract
The induction of hypoxia inducible factors (HIFs) is essential for the adaptation of tumor cells to a low oxygen environment. We found that the expression of the apoptosis inhibitor ARC was induced by hypoxia in a variety of cancer cell types and its induction is primarily HIF1 dependent. Chromatin immunoprecipitation (ChIP) and reporter assays also indicate that the ARC gene is regulated by direct binding of HIF1 to a hypoxia response element (HRE) located at -190 bp upstream of the transcription start site. HIFs play an essential role in the pathogenesis of renal cell carcinoma (RCC) under normoxic conditions, through the loss of the Von Hippel Lindau (VHL) gene. Accordingly, our results show that ARC is not expressed in normal renal tissue, but is highly expressed in 65% of RCC tumors, which also express high levels of Carbonic Anhydrase IX (CAIX), a HIF1-dependent gene. Compared to controls, ARC-deficient RCCs exhibited decreased colony formation and increased apoptosis in vitro. In addition, loss of ARC resulted in a dramatic reduction of RCC tumor growth in SCID mice in vivo. Thus, HIF-mediated increased expression of ARC in RCC can explain how loss of VHL can promote survival early in tumor formation.
Citation Format: Olga V. Razorenova, Laura Castellini, Renata Colavitti, Laura E. Edgington, Monica Nicolau, Xin Huang, Barbara Bedogni, Edward M. Mills, Matthew Bogyo, Amato J. Giaccia. The Apoptosis repressor with a CARD domain (ARC) is a direct HIF1 target gene and promotes survival and proliferation of VHL deficient renal cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1181. doi:10.1158/1538-7445.AM2014-1181