bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1099: Sorafenib increases numbers and functions of tumor-infiltrated T cells and enhances therapeutic outcomes of adoptive T cell therapy by modifying tumor microenvironment
Authors: Hwang Jeng-Jong , Chuang Hui-Yen , Chang Ya-Fang 
Published: May 2015

Abstract
Purpose: Many chemotherapeutic agents are known to have immunomodulatory activity to improve the effectiveness of adoptive T-cell therapy. We hypothesized that sorafenib could reverse the immunosuppression of tumor microenvironment to enhance T-cell mediated tumor regression.
Experimental design: OVA-specific CD8+ T cells were co-cultured with sorafenib-pretreated OVA-overexpressing E.G7 mouse lymphoma cells to evaluate their function using flow cytometry, 51Cr-release assay, and transwell assay. The underlying mechanism of sorafenib-mediated immunomodulation was also explored by Western blotting. In animal studies, the activation of OVA-specific CD8+ T cells transduced with a granzyme B promoter-driven imaging reporter was monitored by bioluminescence imaging and the levels of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were assessed by flow cytometry.
Results: We found that sorafenib suppressed the expression of critical immunosuppressive components, including TGF-β , IL-10, VEGF, indoleamine 2,3-dioxygenase (IDO) and CCL2/MCP-1, in E.G7 cells through the inhibition of STAT3 signaling pathway and decreased the percentage of Tregs and MDSCs in tumors. Surprisingly, the anti-tumor effect of small numbers of CD8+ T cells was substantially enhanced when combined with sorafenib in vivo.
Citation Format: Jeng-Jong Hwang, Hui-Yen Chuang, Ya-Fang Chang. Sorafenib increases numbers and functions of tumor-infiltrated T cells and enhances therapeutic outcomes of adoptive T cell therapy by modifying tumor microenvironment. [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 1099. doi:10.1158/1538-7445.AM2014-1099
Abstract 1101: Acidosis-induced NF-κB promotes cell invasion in breast cancer
Authors: Gupta Subash C. , Mo Yin-Yuan 
Published: May 2015

Abstract
Although acidic microenvironment has been previously shown to promote breast cancer growth and invasion, the underlying mechanism remains largely unknown. Because inflammation is a major culprit in cancer progression, we hypothesize that pro-inflammatory transcription factor nuclear factor (NF)-κB in the acidic microenvironment plays a major role in the invasion and metastasis of breast cancer. In this study we showed that acidosis (pH 6.6) activates NF-κB but it has no effect on STAT3 activity in breast cancer cells. Mechanistically, the activation of NF-κB is mediated through phosphorylation and degradation of IκBα; nuclear translocation, and phosphorylation of p65, leading to enhanced cell invasion. Upstream to NF-κB signaling, AKT, PDK1, and ERK1/2 are also activated under acidic condition. Moreover, acidosis induces reactive oxygen species (ROS) which can be suppressed by ROS scavengers such as glutathione and N-acetyl-L-cysteine, reversing the acidosis-induced activation of AKT, ERK1/2 and NF-κB, and invasiveness. In addition, the NADPH oxidase (NOX) inhibitor diphenyleneiodonium can suppressed acidosis-induced ROS. Importantly, we observed all of these effects only in cancer cells, but not in non-malignant cells. Together, these results suggest that production of ROS, activation of AKT, ERK1/2 and NF-κB may constitute key acidosis-induced signaling cascades in breast cancer cells.
Citation Format: Subash C. Gupta, Yin-Yuan Mo. Acidosis-induced NF-κB promotes cell invasion in breast 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 1101. doi:10.1158/1538-7445.AM2014-1101
Abstract 1136: p53-induced miR-15a/16-1 and AP4 form a double-negative feedback loop to regulate epithelial-mesenchymal transition and metastasis in colorectal cancer
Authors: Shi Lei , Jackstadt Rene , Siemens Helge , Li Huihui , Kirchner Thomas , Hermeking Heiko 
Published: May 2015

Abstract
The transcription factor AP4 mediates epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC) but its control in this setting is not fully understood. Here we report the definition of a double-negative feedback loop involving AP4 and miR-15a/16-1 that regulates EMT and metastatic progression. In CRC cells, AP4 was downregulated by DNA damage in a p53-dependent manner. AP4 downregulation by p53 was mediated indirectly by the tumor suppressive microRNAs miR-15a and miR-16-1, which targeted the 3′-UTR of AP4 mRNA, induced mesenchymal-epithelial transition (MET) and inhibited CRC cell migration and invasion. The downregulation of AP4 was necessary for MET induction by miR-15a/16-1. In tumor xenoplants, ectopic miR-15a/16-1 suppressed formation of lung metastases. Furthermore, AP4 directly suppressed expression of miR-15a/16-1. In clinical specimens of colorectal cancer, miR-15a levels inversely correlated with AP4 protein levels shown previously to correlate with distant metastasis and poor survival. In summary, our results define a double-negative feedback loop involving miR-15a/16-1 and AP4 that stabilizes epithelial and mesenchymal states, respectively, that may determine metastatic prowess.
Citation Format: Lei Shi, Rene Jackstadt, Helge Siemens, Huihui Li, Thomas Kirchner, Heiko Hermeking. p53-induced miR-15a/16-1 and AP4 form a double-negative feedback loop to regulate epithelial-mesenchymal transition and metastasis in colorectal 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 1136. doi:10.1158/1538-7445.AM2014-1136
Abstract 1141: p53-dependent regulation of epithelial-to-mescenchymal transition by nf-κb in head and neck squamous cell carcinoma
Authors: Lin Yuan , Luo Jie , Abemayor Elliot , Sharma Sherven , Dubinett Steven , John Maie S. 
Published: May 2015

Abstract
PURPOSE:
In head and neck squamous cell carcinoma (HNSCC), mutations of p53 usually coexist with aberrant activation of NF-kappaB (NF-κB) and other transcription factors which promote tumor pathogenesis. However, how these factors mediate oncogenesis and metastasis is not fully understood. Herein we investigate the mechanisms by which p53 and NF-κB contribute to Epithelial-Mesenchymal Transition (EMT) in HNSCC.
EXPERIMENTAL DESIGN:
We evaluated the effects of p65 mutation on the molecular events of EMT in surgical specimens and HNSCC cell lines. We examined the correlation with tumor histologic features.
RESULTS:
In HNSCC cell lines with mutant p53, p65 knockdown promotes EMT. In contrast, in normal oral epithelial cells or HNSCC cells with WT p53, p65 over-expression, instead of knockdown, promotes EMT. Ablation of p53 in normal oral epithelial cells blocks p65 induced EMT. These findings are functionally corroborated herein in three-dimensional cell culture, anchorage-independent growth assays, and tumor cell migration assays.
CONCLUSIONS:
This is the first report indicating the role of p53 status in the NF-κB -induced promotion of EMT in HNSCC. Bortezomib-based regimens have been shown to have minimal activity in recurrent or metastatic head and neck cancer. Our new findings are important in understanding a possible basis for these clinical findings as well as defining important implications for targeted chemoprevention and therapy.
Citation Format: Yuan Lin, Jie Luo, Elliot Abemayor, Sherven Sharma, Steven Dubinett, Maie St John. p53-dependent regulation of epithelial-to-mescenchymal transition by nf-κb in head and neck squamous cell carcinoma. [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 1141. doi:10.1158/1538-7445.AM2014-1141
Abstract 1143: Induction of epithelial-mesenchymal transition (EMT) in human gastric cancer cell lines induced by Tipα of H. pylori mediated through surface nucleolin
Authors: Fujiki Hirota , Watanabe Tatsuro , Takahashi Atsushi , Suzuki Kaori , Kurusu-Kanno Miki , Yamaguchi Kensei , Suganuma Masami 
Published: May 2015

Abstract
(a) Introduction: Tumor necrosis factor-α (TNF-α)-inducing protein (Tipα) of H. pylori acts as a carcinogenic factor in the gastric epithelium: it binds to surface nucleolin on human and mouse gastric cancer cell lines, resulting in cancer progression. We studied various phenotypes of epithelial-mesenchymal transition (EMT) to examine the function of surface nucleolin in gastric cancer cell line.
(b) Experimental procedures :
1) Induction of cell migration and elongation: After human gastric cancer cell line MKN-1 was transfected with nucleolin-targeted siRNAs (siRNA-n), cell migration and elongation induced by Tipα were determined using Transwell assay and cell morphology.
2) Formation of filopodia in MKN-1 cells was determined by staining filamentous actin with AF488-phalloidin.
3) Phosphorylation of 89 cancer-related proteins was determined using Cancer Signaling Phosphoantibody Array.
4) Expression of EMT markers was examined with Western blotting.
5) Cell stiffness was determined from Young's modulus using atomic force microscope (AFM).
(c) A summary of the new data:
1) The transfected cells with siRNA-n showed a reduced amount of surface nucleolin in membrane fraction, but not in cytosol or nuclear fractions. Knockdown of nucleolin inhibited cell migration and elongation induced by Tipα.
2) Tipα induced the formation of filopodia in MKN-1 cells, which suggests the invasive morphological changes.
3) Tipα enhanced the phosphorylation of 11 cancer-related proteins in serine, threonine and tyrosine residues, indicating activation of MEK-ERK signal cascade.
4) Tipα induced the expression of vimentin, a significant marker of EMT, even though down-regulation of E-cadherin was not found in MKN-1 cells.
5) Tipα reduced the Young's modulus of MKN-1 cells as determined by AFM: The results showed that lower cell stiffness and increased cell motility were induced by Tipα.
(d) Conclusions:
This is the first report that Tipα is a new inducer of EMT in human gastric cancer cells, and that EMT was induced through the binding of Tipα to surface nucleolin.
Citation Format: Hirota Fujiki, Tatsuro Watanabe, Atsushi Takahashi, Kaori Suzuki, Miki Kurusu-Kanno, Kensei Yamaguchi, Masami Suganuma. Induction of epithelial-mesenchymal transition (EMT) in human gastric cancer cell lines induced by Tipα of H. pylori mediated through surface nucleolin. [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 1143. doi:10.1158/1538-7445.AM2014-1143
Abstract 1149: The role of the novel Notch1-Sox9 signaling axis in NSCLC progression and EMT
Authors: Capaccione Kathleen M. , Hong Xuehui , Morgan Katherine M. , Allen Thaddeus D. , Miles Gregory D. , Markert Elke K. , Bishop J. Michael , Pine Sharon R. 
Published: May 2015

Abstract
Sox9 plays critical roles in the specification and differentiation of numerous progenitor and differentiated cell types during embryonic and fetal development. Sox9 is overexpressed in 40 - 50% of lung adenocarcinomas and associated with poor prognosis in lung cancer patients. We set out to identify upstream pathways that regulate Sox9 expression in lung cancer, as well as the role of Sox9 in lung adenocarcinoma progression. Several developmental and stem cell pathways are known to induce Sox9 transcription during carcinogenesis, including the TGB-β, Wnt/β-catenin, Sonic Hedgehog, and NF-κB signaling. Sox9 has also been shown to be a transcriptional target of the Notch pathway during mouse development, although the binding sites for Notch within the mouse Sox9 promoter are not conserved in humans. We mined gene expression data from three publicly available datasets and found that Hes1, a known Notch target gene, is co-expressed with Sox9 in lung adenocarcinoma. Furthermore, Sox9 mRNA and protein levels were upregulated over 100-fold as early as 14 days after Notch1 induction in the Notch1-induced mouse model of lung cancer, suggesting that Sox9 overexpression is an early event during lung cancer development. Through a series of in vitro assays, we determined that Sox9 is downstream of Notch1 in lung adenocarcinoma cell lines. By ChIP we determined that Sox9 is a direct target of Notch1 and using luciferase reporter assays, we located the previously unidentified human RBP-Jκ binding site, the principle effector of canonical Notch1 signaling, immediately upstream of the Sox9 transcriptional start site. We also examined TGF-β, a known inducer of epithelial-to-mesenchymal transition (EMT) in lung cancer. We determined that induction of Sox9 expression by Notch1 is independent of TGF-β signaling and that TGF-β and Notch1 cooperate in their regulation of Sox9 expression. Loss of Notch1 expression led to an induced MET phenotype, characterized by decreased cell invasion/migration, MET-like morphological changes, and increased E-cadherin expression, which were rescued by Sox9 overexpression. Our data also demonstrate that Sox9 contributes to Notch1-induced EMT in lung adenocarcinoma. These results establish Sox9 as a key Notch1 target gene mediating Notch1-induced EMT independent of TGF-β, leading to poor survival in lung adenocarcinoma.
Citation Format: Kathleen M. Capaccione, Xuehui Hong, Katherine M. Morgan, Thaddeus D. Allen, Gregory D. Miles, Elke K. Markert, J. Michael Bishop, Sharon R. Pine. The role of the novel Notch1-Sox9 signaling axis in NSCLC progression and EMT. [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 1149. doi:10.1158/1538-7445.AM2014-1149
Abstract 1150: The role of the tumor suppressor gene THY1 in suppression of epithelial-mesenchymal transition (EMT) in nasopharyngeal carcinoma
Authors: Lung Hong Lok , Lung Maria Li 
Published: May 2015

Abstract
Background and aims:
THY1 has been successfully identified as a tumor suppressor gene (TSG) in nasopharyngeal carcinoma (NPC) in our laboratory. The frequency of down-regulated THY1 protein expression was found to be significantly associated with NPC lymph node metastases. However, direct functional evidence is still lacking for THY1 being anti-metastatic in NPC. Epithelial-Mesenchymal Transition (EMT) is well-known as a closely associated process for stem cells as well as tumor cells to invade to other part of the body. We aim to study the association of EMT with the THY1 in NPC.
Methods: Functional analysis of restoration of THY1 expression in the NPC cell lines was studied. The RhoA negative regulator, p190 Rho GTPase-activating protein (p190RhoGAP) and the E-cadherin/beta-catenin cell junction was examined in the THY1-expressing NPC cells.
Results: Both real-time and conventional invasion chamber assays clearly showed that the invasive ability of the THY1 transfectants was consistently lower than vector-alone control. The reverse transcription-polymerase chain reaction (RT-PCR) results show that the gene expression of cell invasion-associated gelatinase MMP-9 was significantly down-regulated in the THY1-transfectants compared with the vector-alone control. The p190RhoGAP was greatly activated by phosphorylation in the THY1 transfectants, when the THY1 gene was switched on in the absence of doxycycline (dox, an analogue of tetracycline). In the presence of dox when THY1 was switched off, the phosphorylation of p190RhoGAP was reduced. It appears that the phosphorylation status of p190RhoGAP is positively regulated by THY1 in NPC cells. The immunofluorescence (IF) confocal microscopy results show that beta-catenin and E-cadherin were much more frequently translocated to the cell-cell junction in the THY1 transfectants than the vector-alone.
Conclusions: These findings suggest that THY1 inhibited NPC cell invasion via the formation of adherens junction and up-regulation of p190RhoGAP. The enhanced formation of cell adherens junction by THY1 is likely to be one of the possible mechanisms to suppress EMT in NPC.
Citation Format: Hong Lok Lung, Maria Li Lung. The role of the tumor suppressor gene THY1 in suppression of epithelial-mesenchymal transition (EMT) in nasopharyngeal carcinoma. [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 1150. doi:10.1158/1538-7445.AM2014-1150
Abstract 1160: Novel CSF-1 receptor ligand IL-34 modulates macrophage-breast cancer cell crosstalk
Authors: Gunawardhana Sandun , Zins Karin , Lucas Trevor , Abraham Dietmar 
Published: May 2015

Abstract
Crosstalk between stromal cells and malignant cells within the tumor microenvironment is important for tumorigenesis. According to current clinical and experimental evidence, tumor associated macrophages (TAMs) play a major role in tumor progression to metastasis in different cancers. In breast cancer, increased number of TAMs is associated with poor prognosis. Previous work in our laboratory has shown that depletion of TAMs by blocking colony-stimulating factor-1 (CSF-1) suppresses tumor growth, matrix metalloprotease production and further recruitment of macrophages in a MCF-7 breast cancer xenograft model. In this study, we aim to investigate Interleukin-34 (IL-34), a novel ligand for the colony stimulating factor-1 receptor (CSF-1R). IL-34 functions as a specific and independent ligand and as an agonist to the CSF-1R. Furthermore it is known to induce proliferation through mitogen activated protein kinase (MAPK) activation in macrophages and cancer cells. To date, nothing is known about the role of IL-34 in breast cancer and its effects on downstream signalling pathway modulation in cancer cell-macrophage crosstalk. Our real-time PCR data shows that in co-cultures with murine macrophages, human MCF-7 and MDA-MB-231 breast cancer cells express increased levels of IL-34. In addition, in vitro migration assays demonstrated that recombinant human and murine IL-34 significantly increases the migration of murine macrophages, MCF-7 and MDA-MB-231 breast cancer cells. IL-34 also increased the proliferation of murine macrophages and breast cancer cells. Experiments on the protein level demonstrated the activation of MAPK/ERK in murine macrophages and breast cancer cells by recombinant IL-34. These preliminary data indicate that TAM-breast cancer cell interactions induce IL-34 production associated with induction of proliferation and the migratory capacity of tumor and stromal cells, which together may influence the invasiveness of the developing tumor. Here we propose IL-34 as a target for the treatment of breast cancer which may affect the accumulation of TAMs and improve breast cancer prognosis.
Citation Format: Sandun Gunawardhana, Karin Zins, Trevor Lucas, Dietmar Abraham. Novel CSF-1 receptor ligand IL-34 modulates macrophage-breast cancer cell crosstalk. [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 1160. doi:10.1158/1538-7445.AM2014-1160
Abstract 1166: CXCR7-mediated signaling axis regulates breast cancer growth and metastasis by modulating tumor microenvironment
Authors: Wani Nissar A. 
Published: May 2015

Abstract
Chemokine CXCL12 has been shown to bind chemokine receptor CXCR4 and CXCR7. Although extensive studies have been done to elucidate the role of CXCL12/CXCR4 signalling axis in tumor growth and metastasis, not much is known about the role of CXCL12/CXCR7 signalling axis in regulating breast cancer growth and metastasis. In order to study the role of CXCR7 in breast cancer growth and metastasis, we employed two models-i) 4T1 and CXCR7 downregulated 4T1 (4T1 shRNA-CXCR7) and ii) highly metastatic 4T1.2. First we observed CXCL12 induced and CXCR7 dependent migration of breast cancer cells and CXCL12 induced activation of ERK, STAT3 and cyclin D1, a downstream target of STAT3. In orthotopic syngenic models of breast cancer, we found reduced tumor growth and metastasis of breast cancer cells genetically silenced or pharmacologically inhibited for CXCR7 or its downstream target STAT3. The downregulation or inhibition of CXCR7 or its downstream target reduced tumor proliferation, angiogenesis and macrophage (M2) recruitment to the tumor site. Further analysis revealed the role of CXCR7 in secretion of cytokines (GMCSF, M-CSF and MCP-2), and expression of MMP-9, MMP-2 and VCAM-1. Moreover, we observed that CXCR7 is highly expressed in breast cancer tissues and positively correlates with disease progression from invasive ductal carcinoma (IDC) to metastasis. These observations highlight the importance of the CXCR7 axis in regulating breast cancer growth and metastasis. Blocking the CXCL12/CXCR7/STAT3 axis and macrophage recruitment to the tumor site with CXCR7 or STAT3 inhibitor may lead to the development of novel therapeutic strategies against breast cancer.
Citation Format: Nissar A. Wani. CXCR7-mediated signaling axis regulates breast cancer growth and metastasis by modulating tumor microenvironment. [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 1166. doi:10.1158/1538-7445.AM2014-1166
Abstract 119: Overexpression SOCS-1 may inhibit invasion and metastasis of cervical cancer
Authors: Kim Moon-Hong , Kim Wonwoo , Kang Miae , Seol Hyesil , Jeong Jae-Hoon 
Published: May 2015

Abstract
Purpose: To investigate whether the overexpression of SOCS-1 affects radiosensitivity, invasion, and metastasis in xenograft nude mouse model.
Methods: We established stable SOCS-1-overexpressing ME-180 cell line with pLNCX2-mSOCS1-Myc. Also we established xenograft nude mouse model for tumor growth delay experiment. Immunohistochemistry was employed to elucidate the pattern of expression of VEGF, CD-31, MMP-2, and TUNEL assay for apoptosis in SOCS-1 overexpressing ME-180 cells. Tumor cells were injected to right thigh of mouse to form cancer mass. Lung metastasis assay was performed in day 45 and 60. Metastatic nodules in both lungs were obtained and counted for statistical analysis.
Results: Tumor growth delay after 5 Gy radiation was observed in SOCS overexpressing tumor compared to wild type tumor but the difference did not show the statistical significance (p&gt;0.05, Mann-Whitney U test). Immunohistochemistry showed that decreased MMP-2 expression, decreased VEGF expression, decreased CD-31 expression, and significantly elevated index of apoptotic body in SOCS-1 overexpressing tumor. Lung metastasis assay showed statistically significant decrement of metastatic nodule count in SOCS-1 overexpressing tumor (p&lt;0.05, Mann-Whitney U test).
Conclusion: Decrement of radiosensitivity was statistically insignificant in SOCS-1 overexpressing tumor while invasion, angiogenesis, and metastasis were inhibited. Also apoptosis was increased in SOCS-1 overexpressing tumor.
Citation Format: Moon-Hong Kim, Wonwoo Kim, Miae Kang, Hyesil Seol, Jae-Hoon Jeong. Overexpression SOCS-1 may inhibit invasion and metastasis of cervical 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 119. doi:10.1158/1538-7445.AM2014-119