bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5877: The functional role(s) of serum amyloid A1 (SAA1) polymorphisms in integrin-mediated cell adhesion in nasopharyngeal carcinoma (NPC) cells
Authors: Man On Ying , Lung Hong Lok 
Published: July 2017

Abstract
Serum amyloid A1 (SAA1) was previously identified as a tumor suppressor gene with anti-angiogenic activities in nasopharyngeal carcinoma (NPC). Three SAA1 isoforms (SAA1.1, 1.3, and 1.5) were observed with disproportionate frequencies among the NPC patients and healthy people. SAA1.1 and 1.3 are the functional isoforms to inhibit angiogenesis whereas SAA1.5 was the defective gene. Our immunohistochemical results showed that the loss of SAA1 staining in the metastatic NPC tissues was significantly associated with tumor progression. We aim to investigate the functional roles of the three SAA1 isoforms in NPC metastasis in the present study. We want to investigate whether the functional SAA1.1 and 1.3 isoforms can suppress tumor metastasis by antagonizing the integrin-FAK signaling pathway in the NPC tumor cells. The focal adhesion assay was performed by seeding the tumor cells with or without the integrin alphaVbeta3/beta5 ligand vitronectin. Both the vector-alone control and the SAA1.5-expressing NPC cells began to spread out and adhered to the bottom of the culture dish in the presence of vitronectin from 7 to 9 hours, whereas the SAA1.1 and SAA1.3-cells remained in the round-up morphology with minimal attachment. Interestingly, after 48 hours the SAA1.1 and SAA1.3-expressing cells formed adherents junction among the cells. In order to study the viability of the effects of the three SAA1 isoforms on NPC cells, MTT viability assay was performed. The results showed that the viability of the SAA1.1 and SAA1.3-expressing cells were around 50 % lower than both the vector-alone and the SAA1.5-expressing cells. It is likely that the loss of focal adhesion after seeding of the SAA1.1 and SAA1.3-expressing cells will affect the survival of NPC cells. Furthermore, we found that the presence of the recombinant SAA1.1 and SAA 1.3 proteins could reduce the number of viable NPC cells compared with the solvent control and the SAA1.5 protein. We previously reported that the SAA1 proteins can physically interact with the integrin alphaVbeta3. Taken together, we suggested that the secreted SAA1 proteins from the NPC cells could directly affect the NPC focal adhesion as well as the cell viability by blocking the integrin on the NPC cell surface. We acknowledge the financial support of the General Research Fund (grant number HKBU17115114 to HLL) of the Research Grants Council of the Hong Kong Special Administrative Region.
Citation Format: On Ying Man, Hong Lok Lung. The functional role(s) of serum amyloid A1 (SAA1) polymorphisms in integrin-mediated cell adhesion in nasopharyngeal carcinoma (NPC) cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5877. doi:10.1158/1538-7445.AM2017-5877
Abstract 5880: Acquired chemotherapeutic drug resistance in colorectal cancer is regulated by epithelial-to-mesenchymal transition and altered cellular pathways
Authors: Gangoda Lahiru , Mathew Nidhi , Liem Michael , Keertikumar Shiva , Ang Ching-Seng , Mariadason John , Mathivanan Suresh 
Published: July 2017

Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in the western world. Chemotherapy is the mainstay in the treatment of metastasized CRC. However, cancer cells acquire resistance to treatment by various mechanisms resulting in treatment failure. Even though the molecular mechanisms regulating acquired drug resistance is critical to overcome chemoresistance, it is poorly understood. We developed a panel of seven CRC cells resistant to 5-FU. The parental and 5-FU resistant CRC cells were assayed for proteins known for their involvement in chemotherapeutic resistance. In addition, an unbiased quantitative proteomics and DNA methylation analysis was performed on the panel of seven parental and 5-FU resistant CRC cells. The integrated analysis revealed multiple mechanisms contributing to chemotherapeutic drug resistance including epithelial-to-mesenchymal transition (EMT), deregulation of apoptosis, increased survival autophagy and epigenetic modifications resulting in altered drug metabolite potency. Inhibitors of EMT and autophagy sensitized the 5-FU resistant CRC cells. Furthermore, CRIPSR based gene knockouts of these candidate genes (both up and downregulated) either sensitized the CRC cells or rendered them resistant to 5-FU. As a follow up, PDX mouse models were established and made resistant to 5-FU. Follow up quantitative proteomics and biochemical validations of 5-FU resistant PDX tissue lysates confirmed the role of EMT in acquired chemoresistance. Overall, this project unravelled multiple mechanisms by which CRC cells may become resistant to 5-FU. Importantly, some of these mechanisms are also conserved in many cancer types and hence targeting these mechanisms can overcome chemoresistance and increase patient survival rates.
Citation Format: Lahiru Gangoda, Nidhi Mathew, Michael Liem, Shiva Keertikumar, Ching-Seng Ang, John Mariadason, Suresh Mathivanan. Acquired chemotherapeutic drug resistance in colorectal cancer is regulated by epithelial-to-mesenchymal transition and altered cellular pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5880. doi:10.1158/1538-7445.AM2017-5880
Abstract 5892: Induction of stromal fibrosis accelerates tumorigenesis in NeuT mice
Authors: Glazer Robert I. , Yuan Hongyan , Jin Lu 
Published: July 2017

Abstract
Background: One of the central challenges in cancer prevention is the identification of factors in the tumor microenvironment (TME) that increase breast cancer susceptibility. The stromal composition of the breast is largely adipose and fibroblast tissue, and thus it is important to understand how alterations in these constituents affect in the onset of stromal fibrosis (SF) and cancer progression. To address these questions, MMTV-NeuT mice were crossed into the FAT-ATTAC (fat apoptosis through targeted activation of caspase 8) background (NeuT/ATTAC), wherein conditional dimerization of the FKBP-caspase 8 fusion transgene in female mice results in mammary fat ablation and its replacement with fibrotic tissue.
Results: Induction of mammary fat ablation in NeuT/ATTAC mice over 4 weeks resulted in increased ductal proliferation and SF as denoted by increased collagen deposition and expression of Fibroblast Activation Protein and α-smooth muscle actin. Maintaining SF over 3-5 months resulted in a 40% reduction in tumor onset and a 2.5-fold increase in tumor multiplicity, which was associated with increased infiltration by myeloid-derived suppressor cells. Gene expression profiling of tumors from mice with and without SF identified increased expression of the immune-related genes Cxcl1, Ly6d and CD14, as well as acute phase proteins Saa1 and S100a6 in NeuT/ATTAC mice with SF.
Conclusion: Induction of SF in an erbB2-dependent breast cancer model resulted in a tumor microenvironment more conducive to tumor progression and immune tolerance. These results suggest alternative therapeutic approaches that could be taken, eg. chemokine receptor antagonists, to increase the effectiveness of immunotherapy and chemotherapy.
Supported by a grant from the Avon Foundation for Women and Award 1P30CA051008 from the National Cancer Institute, NIH, to the Lombardi Comprehensive Cancer Center.
Citation Format: Robert I. Glazer, Hongyan Yuan, Lu Jin. Induction of stromal fibrosis accelerates tumorigenesis in NeuT mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5892. doi:10.1158/1538-7445.AM2017-5892
Abstract 59: Engineering glypican-3 targeting immunotoxins for the treatment of liver cancer
Authors: Fleming Bryan D. , Nixon Brittany , Pastan Ira , Ho Mitchell 
Published: July 2017

Abstract
The expression of glypican-3 (GPC3) in hepatocellular carcinoma offers a target with high tissue specificity and cell signaling implications. A human single domain antibody discovered by phage display technology, HN3, was fused to domain II and domain III of Pseudomonas exotoxin A. This protein (HN3-PE38) showed a high level of cytotoxic activity with a IC50 of 0.4 nM on Hep3B cells, but a relatively low maximum tolerated dose of 0.8 mg/kg in mice. In order to produce an immunotoxin with reduced toxicity, a new version was constructed that removed domain II and seven B cell epitopes from the Pseudomonas toxin. This deimmunized immunotoxin (HN3-mPE24) was shown to have a similar IC50 of 0.2 nM on Hep3B cells. To determine if further deimmunization was possible, three new versions have been generated with T cell epitopes or a series of both B and T cell epitopes removed. These include the HN3-T20 immunotoxin which had six T cell epitopes removed, HN3-T19 with 4 B cell, 4 T cell and 2 shared epitopes, and HN3-M11 with 5 B cell, 4 T cell and 2 shared epitopes. A comparative analysis of these immunotoxins was made using in vitro cell proliferation assays using Hep3B. Both the HN3-T20 (IC50 = 0.6 nM) and HN3-T19 (IC50 = 0.8 nM) immunotoxins had similar activity to HN3-mPE24 (IC50 = 0.7 nM) in a side by side comparison. The HN3-M11 variant had poor cytotoxicity and was excluded from in vivo examination. A Hep3B subcutaneous xenograft model was generated in athymic nude mice and was followed by nine rounds of intravenous immunotoxin treatments. The mPE24, T20 and T19 immunotoxins all showed an increase in average survival rate 70 days (mPE24), 76 days (T20) and 72 days (T19) when compared to the 55 days for PE38 and the 41 days for PBS alone. Additionally, the T20 and the T19 showed a maximum tolerated dose that was similar to that of the mPE24 with dosages as high as 10 mg/kg being well tolerated. This data would suggest that the HN3-T19 immunotoxins has potential clinical applications because it represents the most deimmunized immunotoxin to date.
Citation Format: Bryan D. Fleming, Brittany Nixon, Ira Pastan, Mitchell Ho. Engineering glypican-3 targeting immunotoxins for the treatment of liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 59. doi:10.1158/1538-7445.AM2017-59
Abstract 5904: Stiffness of extracellular matrix regulates breast cancer progression by stimulating mesenchymal stem cells
Authors: Ishihara Seiichiro , Inman David R. , Li Wan-Ju , Ponik Suzanne M. , Keely Patricia J. 
Published: July 2017

Abstract
The tumor microenvironment contains cancer cells, non-cancerous cells, and extracellular components such as extracellular matrix (ECM). Previous studies have demonstrated that interactions between the cells and the microenvironment contribute to cancer progression via chemical stimuli, such as growth factors, and mechanical stimuli, such as stiffness of the ECM. Recently, it has been reported that mesenchymal stem cells (MSCs) differentiate into cancer associated fibroblasts (CAFs) in response to chemical stimuli from cancer cells and thereby promote cancer progression. However, the contribution of mechanical stimuli to MSCs in cancer is poorly understood. In this study, we revealed that MSCs showed CAF phenotypes and promote mammary cancer progression in response to mechanical stimuli. On a stiff substrate, MSCs treated with conditioned media from cancer cell culture expressed increased levels of alpha smooth muscle actin (alpha-SMA), a marker of CAFs, compared to the MSCs cultured on a soft substrate. MSCs grown on a stiff substrate displayed higher expression and activity of YAP and increased phosphorylation of myosin light chain (MLC) compared to MSCs grown on a soft substrate. In addition, knockdown of YAP by shRNA decreased the expression of alpha-SMA and phosphorylation of MLC in MSCs on a stiff substrate. Pharmacological inhibition of MLC phosphorylation by H1152 treatment also reduced expression of alpha-SMA and activity of YAP in MSCs. Cell-cell communication between MSCs and carcinoma cells was bi-directional, as conditioned medium from MSCs cultured on a stiff substrate, but not a soft substrate, increased growth of mammary carcinoma cells. The soluble factor prosaposin was highly secreted by the MSCs on a stiff substrate, and the addition of recombinant prosaposin increased proliferation and survival of mammary carcinoma cells. Furthermore, secretion of prosaposin was promoted in YAP-overexpressed MSCs on a soft substrate. Mammary carcinoma cells treated with prosaposin showed increased level of phosphorylation in Akt at T308. In addition, inhibition of phosphorylation of Akt at T308 prevented proliferation and survival in mammary carcinoma cells. These results suggest that increased stiffness of the ECM in the tumor microenvironment induces differentiation of MSCs to CAFs via YAP and actomyosin contractility, secretion of prosaposion from MSCs, and as a result, trigger progression of mammary cancer via phosphorylation of Akt at T308.
Citation Format: Seiichiro Ishihara, David R. Inman, Wan-Ju Li, Suzanne M. Ponik, Patricia J. Keely. Stiffness of extracellular matrix regulates breast cancer progression by stimulating mesenchymal stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5904. doi:10.1158/1538-7445.AM2017-5904
Abstract 5909: Microfluidic vertical adhesion-suspension co-culture platform for studying cancer stem cell-fibroblast interactions
Authors: Chen Yu-Chih , Zhang Zhixiong , Cheng Yu-Heng , Yoon Euisik , Wicha Max S. 
Published: July 2017

Abstract
Considerable evidence suggests that cancer-stem-cells (CSCs) play critical roles in tumorigenesis and metastasis .Although surface marker expression or enzymatic activity of CSC has proven useful, variability of expression highlights the need for the development of high throughput functional CSC assays. One such approach utilizes the capability of CSC’s to form single-cell-derived spheres in suspension environments (functional CSCs). Microfluidic tools are suitable for handling and monitoring a large number of single cells in suspension as well as for examining the interaction of these cells with those in the tumor micro-environment including cancer associated fibroblasts (CAF’s).In order to accomplish this, we have developed a high-throughput (10,000-well), simple-to-use, vertical platform for CSC/CAF co-culture. The platform consists of a non-adherent substrate having 10,000 micro wells for single-cell-derived sphere formation and a porous trans well for CAF adherent co-culture. As predicted by Poisson’s distribution, approximately 30% of micro wells capture single cells when T47D breast cancer cells are loaded at a concentration of 200k/ml. After cell seeding, trans wells containing CAFs are placed onto the substrate. 0.4µm pores on the trans well allow for secretion-based cellular interaction while preventing direct CSC/CAF cell contact. This cell separation facilitates sample cell retrieval without cell cross contamination. Utilizing this device, we determined that co-culture of tumor cells with CAF’s doubled the frequency of sphere formation. Spheres derived from individual CSCs were then retrieved and dissociated for single-cell transcriptome analysis utilizing RNA barcoding followed by RNAseq. Molecular analysis revealed significant cellular heterogeneity among sphere derived cells. In addition, principal component analysis of single cell RNAseq, reveled significant differences in gene expression between mono-cultured and CAF co-cultured cells isolated from tumor spheres. These genes represent potential therapeutic targets for interfering with CSC stromal cell interactions in the tumor microenvironment. The vertical adhesion suspension co-culture platform provides a system to identify and evaluate novel CSC targeted therapeutics.
Citation Format: Yu-Chih Chen, Zhixiong Zhang, Yu-Heng Cheng, Euisik Yoon, Max S. Wicha. Microfluidic vertical adhesion-suspension co-culture platform for studying cancer stem cell-fibroblast interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5909. doi:10.1158/1538-7445.AM2017-5909
Abstract 5916: Proton-sensor GPR4 potentiates intestinal inflammation in the DSS-induced colitis mouse model
Authors: Sanderlin Edward J. , Leffler Nancy R. , Lertpiriyapong Kvin , Cai Qi , Hong Heng , Bakthavatchalu Vasudevan , Fox James G. , Oswald Joani Z. , Justus Calvin R. , Krewson Elizabeth A. , O’Rourke Dorcas , Yang Li V. 
Published: July 2017

Abstract
Inflammation and tissue acidosis are two factors that co-exist in inflammatory bowel disease (IBD) and can contribute to increased risk of colorectal cancer (CRC) development. GPR4 is a proton-sensing G protein-coupled receptor that can be activated by extracellular acidosis through several histidine residues and subsequently signal through downstream G-protein pathways. Recently, GPR4 has been shown to be activated by acidosis and can increase the expression of numerous inflammatory and stress response genes in vascular endothelial cells (ECs) and has functionally increased EC-leukocyte adhesion. Subsequently, genetic and small molecule approaches for the inhibition of GPR4 activity have reduced endothelial cell inflammation. In this study, we examined the role of GPR4 in intestinal inflammation using a dextran sulfate sodium (DSS)-induced colitis mouse model. We observed that GPR4 mRNA expression was increased in mouse and human IBD tissues when compared to control intestinal tissues. To determine the function of GPR4 in intestinal inflammation, wild-type and GPR4-deficient mice were treated with 3% DSS for acute and chronic time points for the induction of colitis. Our results showed that the severity of colitis was decreased in GPR4-deficient DSS-treated mice in comparison to wild-type DSS-treated mice. Clinical parameters, macroscopic disease indicators, and histopathological features were less severe in the DSS-treated GPR4-deficient mice than the DSS-treated wild-type mice. Inflammatory gene expression, endothelial adhesion molecule expression, leukocyte infiltration, and isolated lymphoid follicle (ILF) formation were reduced in intestinal tissues of DSS-treated GPR4-null mice. In summary, our results suggest GPR4 potentiates intestinal inflammation as the absence of GPR4 ameliorates intestinal inflammation in the DSS-induced colitis mouse model. Use of GPR4 inhibitors could prove a valuable therapeutic in the reduction of intestinal inflammation and subsequent CRC development.
Note: This abstract was not presented at the meeting.
Citation Format: Edward J. Sanderlin, Nancy R. Leffler, Kvin Lertpiriyapong, Qi Cai, Heng Hong, Vasudevan Bakthavatchalu, James G. Fox, Joani Z. Oswald, Calvin R. Justus, Elizabeth A. Krewson, Dorcas O’Rourke, Li V. Yang. Proton-sensor GPR4 potentiates intestinal inflammation in the DSS-induced colitis mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5916. doi:10.1158/1538-7445.AM2017-5916
Abstract 5922: Cellular interaction between pancreatic cancer cells and MSC as tumor microenvironment
Authors: Kondo Eisaku , Saito Ken 
Published: July 2017

Abstract
Tumor microenvironment such as neoangiogenesis, stroma and tumor immunity has recently gained much attention because it is significantly involved in tumor progression. Pancreatic adenocarcinoma (PAC; pancreatic invasive ductal carcinoma) is recognized as one of the most intractable malignancies and required to disclose a key biological characteristics to provide a clue for its diagnosis and therapeutics. Here we focus on the biological role of bone marrow-derived human mesenchymal stem cells (MSCs) in PAC, which were reported to be accumulated in various cancer tissues such as colon, breast cancers.
We detected small numbers of MSCs in the stroma of PAC in human pathological tissues using double immunofluorescence in combination with several MSC markers including CD73, 105, 34, 45, SMA and so on. Then, in in vitro coculture system, we found that MSCs significantly facilitated invasion of BxPC3 cells, a human PAC cell line, in comparison with the culture of BxPC3 cell alone by transwell chamber assay. Proteome profiling of the cocultured supernatant revealed augmented production of soluble molecules including CXCL7, CCL7 as a cytokine, integrin beta1, transferrin R, ALCAM, and Amphiregulin (AREG) as a soluble receptor and ligand, metalloprotease (MMP), ADAMTS-1 as a soluble protease-related molecule, all which were significantly increased comparing to the culture sup. of BxPC3 alone or MSC alone.
Based on the result of proteome profiling, we further examined mRNA upreguttion on the cells of each culture by real-time PCR (qPCR) to identify which molecule would be more specifically upregulated by the coculture sample of PAC cells and MSCs.
Consequently, upregutaion of AREG and MMP-3, in addition to downregulation of MMP-9 was observed by qPCR, and knockdown of AREG using the specific siRNA on the cocultured cells corroborated marked decrease of PAC invasion in transwell chamber assay. Interestingly, AREG expression on the tumor cells of tissue specimens of the patient with PAC was observed especially on the cells at invasive front, which suggests stromal MSCs may interact with PAC cells and facilitate invasion of cancer cells by regulating expression of the specific genes such as AREG and MMPs.
Note: This abstract was not presented at the meeting.
Citation Format: Eisaku Kondo, Ken Saito. Cellular interaction between pancreatic cancer cells and MSC as tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5922. doi:10.1158/1538-7445.AM2017-5922