bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 723: Distinguishing macrophages by a unique gene signature to measure response to treatment
Authors: Lyons Yasmin A. , Pradeep Sunila , Hansen Jean M. , Previs Rebecca A. , Yao Hui , Baggerly Keith A. , Sood Anil K. 
Published: July 2016

Abstract
Objectives: Tumor-associated macrophage infiltration is associated with poor prognosis, making macrophage depletion an ideal therapy. This study aims to identify a macrophage-specific gene signature to quantify macrophage content and measure response to treatment of high-grade serous cancer (HGSC) with colony stimulating factor-1 receptor (CSF1R) inhibitor.
Methods: 39 murine genes were identified in the literature as being macrophage-specific. Corresponding human orthologous genes were identified using BioMart database. Expression levels (log-transformed normalized RSEM values) of human homologous genes were retrieved from The Cancer Genome Atlas (TCGA) portal. Principal component (PC) and hierarchical clustering (HC) analysis of 305 primary HGSC was performed. Q-PCR was performed on human macrophage cell line, endothelial cell line, and fibroblast cell line. Q-PCR was also performed on tumor tissue obtained from CD57Bl/6 mice injected with murine ovarian cancer and treated with CSF1R inhibitor.
Results: 37 human homologous genes were identified for the macrophage specific murine genes. Of the 37 genes, 12 tracked together tightly and included the top 3 genes with greatest median absolute deviance of RSEM values, thus were chosen for further analysis. Q-PCR using human macrophage cell line revealed high expression in all 12 genes (delta CT &lt;25), with TBXAS, CD14, and FCGR1A being the highest. All 12 genes showed greater expression in macrophages versus fibroblasts and endothelial cells, to varying degrees. Expression of CD14, TLR7, FCGR2C, and FCGR1B was significantly higher (p&lt;0.0001) in macrophages compared to both fibroblasts and endothelial cells. Of these 12 human genes, 4 had homologous murine genes. These genes were used for Q-PCR on murine tumor tissue treated with CSF1R inhibitor. There was a statistically significant decrease in the level of CSF3R (p = 0.005), FCGR (p = 0.02), and PON3 (p = 0.002) between the control group and the group treated with CSF1R inhibitor.
Conclusions: These data suggest that macrophage specific genes could be useful for quantifying macrophage content in tumor samples to monitor therapy-related changes.
Citation Format: Yasmin A. Lyons, Sunila Pradeep, Jean M. Hansen, Rebecca A. Previs, Hui Yao, Keith A. Baggerly, Anil K. Sood. Distinguishing macrophages by a unique gene signature to measure response to treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 723.
Abstract 724: MicroRNA-100/mTOR/IL-1ra signaling maintains TAMs phenotype and enhances tumor cell stemness property in mouse breast cancer
Authors: Wang Wei , Liu Yan , Guo Jian , He Huiwen , Xie Junling , Chen Chong , Luo Yunping 
Published: July 2016

Abstract
Tumor-associated macrophages(TAMs),the main part of immune cells in tumor microenvironment(TME),play a potent role in promoting tumorigenesis. MicroRNAs (miRs) are considered to be crucial regulators in tumor progression. However, the role that miRs play in TAMs phenotype regulation still remains unclear.
In this study, we demonstrated that miR-100 played an important role in maintaining TAMs phenotype and enhancing tumor stemness properties. First, miRNome of TAMs isolated from mouse breast tumor was performed. Compared with macrophages from normal spleen, 40 miRs candidates, in 150 TAMs-high and 169 TAMs-low expressed miRs which were selected from miRNome, were further identified by real-time PCR. Importantly, miR-100 was found with TAMs-high expression pattern(about 70 folds changes). Moreover, we found that miR-100 overexpressed RAW264.7 cells and peritoneal macrophages gained M2 phenotype such as CD206+ cells percentage. Mechanism study demonstrated that miR-100 up-regulated IL-1ra expression detected by cytokine array. Furthermore we found that IL-1ra could enhance 4T1 breast cancer cell stemness properties including increasing tumor cell sphere formation and drug resistance in vitro.
Taken together, our results demonstrate that TAMs-high expressed miR-100 could function to maintain the phenotype of TAMs via targeting mTOR pathway, and promote tumorigenesis by enhancing IL-1ra secretion, which would also serve as a promising therapy target to remodel TME and tumor metastasis.
Citation Format: Wei Wang, Yan Liu, Jian Guo, Huiwen He, Junling Xie, Chong Chen, Yunping Luo. MicroRNA-100/mTOR/IL-1ra signaling maintains TAMs phenotype and enhances tumor cell stemness property in mouse breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 724.
Abstract 726: Involvement of proinflammatory chemokines in triple-negative breast cancer (TNBC)
Authors: Ignacio Rosa Mistica C. , Gibbs Carla , Lee Eun-Sook , Son Deok-Soo 
Published: July 2016

Abstract
Objective: Triple-negative breast cancer (TNBC) accounts for 12-24% of total breast cancer, and contributes to the more aggressive, therapy-resistant and poorer outcomes. Our analysis based on The Cancer Genome Atlas (TCGA) indicated that basal-like BC subtype representing TNBC has enriched expression profiles for epidermal growth factor receptor 1 (EGFR) and transforming growth factor alpha (TGFá) compared to other subtypes. In addition, TNBC has a higher proinflammatory index compared to non-TNBC. Here we report that the proinflammatory chemokines such as CXCL1-3 and 8 are highly expressed in human TNBC cells and might be potentiated by TGFá-EGFR axis that contributes to cancer progression of TNBC.
Methods: To gauge the role of TGFá-EGFR axis as a proinflammatory driver in TNBC cells, we first checked the expression profiles for EGFR family such as EGFR, HER2, ErbB3, and ErbB4 between TNBC (MCF10A, MB468, MB231, and BT549) and non-TNBC cells (MCF7, T47D). In addition, the expression levels of downstream signaling for EGFR (Akt/Erk) were measured by western blot. To dissect the role of TGFá-EGFR axis in enhancing proinflammatory index in TNBC cells, we utilized a more comprehensive study of the chemokines and chemokine receptors using human chemokine PCR array. Finally, to further confirm the role of TGFá-EGFR axis in inflammatory burden and cancer progression in TNBC, we used EGFR inhibitor and its downstream targets.
Results: TNBC cells expressed more proinflammatory chemokines such as CXCL1-3 and 8 compared to non-TNBC cells. TNBC cells (MB468, MB231, and BT549) showed higher expression of EGFR which led to higher Akt activation as compared to non-TNBC cells. However, Erk is only activated in MB231. To dissect the involvement of Akt, expression of Akt isoforms in TNBC cells was accessed and Akt1 is the predominant isoform expressed in TNBC cells. To further assess the involvement of Akt1 in proinflammatory burden in TNBC cells, we used a commercial siRNA of Akt1 to knockdown Akt1. Knockdown of Akt1 significantly reduced the CXCL2 promoter activity. In addition, afatinib (an EGFR inhibitor) and MK2206 (an Akt inhibitor) significantly reduced the CXCL2 promoter activity.
Conclusion: Thus, higher expression of proinflammatory chemokines CXCL1-3, and 8, via TGFá-EGFR axis-activated Akt, contributes to the inflammatory burden, probably promoting cancer progression, thereby followed by the overall high mortality in TNBC compared to non-TNBC.
Citation Format: Rosa Mistica C. Ignacio, Carla Gibbs, Eun-Sook Lee, Deok-Soo Son. Involvement of proinflammatory chemokines in triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 726.
Abstract 73: Exploring arrayed synthetic CRISPR for functional genomic screening
Authors: Tan Jenille M. , Martin Scott E. 
Published: July 2016

Abstract
Over the past decade, RNAi has been the workhorse for loss-of-function genomic screening. Although powerful, RNAi is hampered by a high rate of false positives driven by off-target effects. New screening technologies based on the CRISPR/Cas9 system are being rapidly adopted, and appear to be significantly less prone to off-target effects. CRISPR/Cas9 screens are conducted in pooled formats for positive and negative selection. However, this format is not amenable to many assay types (e.g., protein translocation assays). In an effort to expand and achieve a more comprehensive approach to functional genomics, we explored the use of arrayed CRISPR/Cas9 screening with synthetic CRISPR RNAs. Testing was performed by reverse transfecting synthetic CRISPR reagents into HCT 116 cells stably expressing Cas9, thereby making the workflow analogous to high-throughput siRNA screening. We first explored and optimized the system with reagents targeting genes associated with DNA replication, including geminin (GMNN). Loss of GMNN is known to result in enlarged nuclei due to aberrant DNA replication, which is easily observed and quantitated by automated microscopy. Analysis of individual cells by microscopy also enables the identification of effects that are only observed in a fraction of the population. After optimizing transfection and assay conditions, we observed CRISPR-induced phenotypes similar to siRNA knockdown. Surprisingly, these effects were observed within 72 hours and affected the vast majority of cells. These effects were even more pronounced in some clonal populations of HCT 116 Cas9. Loss of GMNN was confirmed by immunofluorescence, western blot, and enzyme mismatch cleavage assay. We then expanded this approach to other genes with similar success. By testing and validating the utility of synthetic CRISPR on cells already harboring Cas9, we show that arrayed synthetic CRISPR screening can be a valuable new tool for hit validation and screening.
Citation Format: Jenille M. Tan, Scott E. Martin. Exploring arrayed synthetic CRISPR for functional genomic screening. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 73.
Abstract 736: Hypoxia-induced EGFR tyrosine kinase inhibitor resistance is associated with epithelial-mesenchymal transition in NSCLC
Authors: Lu Yuhong , Glazer Peter M. 
Published: July 2016

Abstract
The development of small molecule inhibitors specific for epidermal growth factor receptors (EGFR) with activating mutations has led to a dramatic shift in the treatment of non-small cell lung cancer (NSCLC) patients. Patients with NSCLC carrying such EGFR mutations often show prolonged responses when treated with first or second generation EGFR tyrosine kinase inhibitors (TKIs). However, most patients eventually develop resistance to EGFR TKIs. Hypoxia is a key micro-environmental stress in solid tumors that is associated with poor prognosis. Studies have linked hypoxia to therapy resistance, including radiation therapy and chemotherapy. In this study, we show that long-term, moderate hypoxia induces gefitinib resistance in the NSCLC cell line, HCC827, that harbors an activating EGFR mutation. The hypoxia-induced gefitinib resistance is associated with reduced BIM induction after gefitinib treatment when compared to normoxic HCC827 cells. In addition, in hypoxic HCC827 cells, gefitinib treatment induces N-cadherin expression, a mesenchymal marker, accompanied by downregulation of E-cadherin, an epithelial maker. These results suggest that epithelial-mesenchymal transition (EMT) may be involved in hypoxia induced gefitinib resistance. Wound healing migration assays further support that hypoxia induces HCC827 cell migration after gefitinib treatment. These results suggest that hypoxia may be a driving force for EGFR TKIs resistance potentially through EMT in NSCLC.
Citation Format: Yuhong Lu, Peter M. Glazer. Hypoxia-induced EGFR tyrosine kinase inhibitor resistance is associated with epithelial-mesenchymal transition in NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 736.
Abstract 740: Silica promotes anchorage-independent growth of human bronchial cells via activation of NF-êB1 p50
Authors: Katabami Motoo , Kinoshita Ichiro , Shimizu Yasushi , Takeuchi Satoshi , Dosaka-Akita Hirotoshi 
Published: July 2016

Abstract
Although crystalline silica (hereafter silica) was judged as carcinogen by IARC, the mechanism of silica-induced carcinogenesis remains elusive. As limited studies have been reported to support the direct carcinogenic effect of silica on human lung epithelial cells, silica-induced inflammatory microenvironment may be postulated to facilitate lung neoplastic transformation. To test this hypothesis, we investigate the growth of immortalized human lung bronchial epithelial cell lines NL20, BEAS-2B and 16HBE14o-, following incubation with conditioned media collected 48h after exposed to silica (Silica CM) in each cell line. All cell lines promoted anchorage-independent growth in each Silica CM, compared with those in CM without silica exposure. All the bronchial cell lines in Silica CM increased DNA binding activity of NF-êB1 p50. After incubated with Silica CM, culture supernatants of NL20 and BEAS-2B kept higher concentration of EGF, and those of 16HBE14o- contained higher concentration of TNFá and IGF1, respectively. Recombinant EGF, TNFá and IGF1 are all sufficient to promote anchorage-independent growth of each bronchial cell line, and to increase DNA binding activity of NF-êB1 p50. Neutralizing human EGF and TNFá antibodies dampened the growth of each bronchial cell line. NF-êB inhibitor Bay11-7082 suppressed the growth of all bronchial cell lines incubated with Silica CM. Taken together, silica promoted anchorage-independent growth of human lung epithelial cells via silica-induced secretion of soluble factors, followed by activation of NF-êB1 p50 in an autocrine manner. The present study supports the hypothesis that silica-induced inflammatory microenvironment may be actively involved in the potential carcinogenic effect of silica.
Citation Format: Motoo Katabami, Ichiro Kinoshita, Yasushi Shimizu, Satoshi Takeuchi, Hirotoshi Dosaka-Akita. Silica promotes anchorage-independent growth of human bronchial cells via activation of NF-êB1 p50. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 740.
Abstract 758: Modulating function of tumor associated macrophages by CSF1R inhibitor suppressed tumor growth in hepatocellular carcinoma
Authors: Sun Hui-Chuan , Ao Jian-Yang , Cai Hao , Chai Zong-Tao , Zhu Xiao-Dong 
Published: July 2016

Abstract
Aims: To investigate the effect of colony stimulating factor 1 receptor (CSF1R) inhibitor on macrophages and tumor pathogenesis.
Methods: CSF1 and CSF2 stimulated macrophages were obtained from mouse bone marrow derived monocytes cultured with CSF1 and CSF2. Mouse hepatoma cell line Hepa 1-6, and human hepatoma cell lines, HCCLM3 and HepG2 were used to established a allograft or xenograft tumor models to examine the effect of CSF1R inhibitor on tumor growth and distribution of macrophages. The characteristics of macrophages were determined by flow cytometry, immunohistochemistry, cell motility and Western blotting assays.
Results: CSF1R inhibitor suppressed tumor growth in the tumor models derived from three hepatoma cell lines, and prolonged hosts’ survival, but CSF1R inhibitor did not decreased the number of macrophages in Hepa1-6 allograft tumors. in vitro study showed CSF1R inhibitor suppressed proliferation and motility of CSF1 stimulated macrophages but not CSF2 stimulated macrophages. Furthermore, we found CSF1R inhibitor treatment decreased the ability of THP-1 macrophages to promote migration and invasion of tumor cells.
Conclusions: CSF1R inhibitor suppressed tumor growth in hepatoma animal models by modulating function of tumor associating macrophages.
Citation Format: Hui-Chuan Sun, Jian-Yang Ao, Hao Cai, Zong-Tao Chai, Xiao-Dong Zhu. Modulating function of tumor associated macrophages by CSF1R inhibitor suppressed tumor growth in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 758.
Abstract 766: Control of lung cancer with aspirin-triggered stimulation of resolution
Authors: Gilligan Molly M. , Sulciner Megan L. , Gus-Brautbar Yael , Ramon Sesquile , Colas Romain A. , Huang Sui , Serhan Charles N. , Panigrahy Dipak 
Published: July 2016

Abstract
Objective: To establish aspirin-triggered resolvins as a novel treatment to enhance current cancer therapies through the resolution of inflammation and clearance of cancer therapy-induced tumor cell debris. Background: Inflammation in the tumor microenvironment is now recognized as a strong promoter of tumor growth. Substantial epidemiological evidence suggests that aspirin, which suppresses inflammation, also reduces the risk of cancer. However, the mechanism by which aspirin reduces cancer risk and improves survival remains unclear, and toxicity has limited its clinical use. Low-dose aspirin stimulates the endogenous production of aspirin-triggered (AT) resolvins, novel omega-3 fatty acid-derived pro-resolving lipid autacoid mediators. We recently discovered that resolvins have potent anti-tumor activity, making resolvins potential candidates to mediate the anti-cancer activity of aspirin. Thus, we hypothesize that aspirin's anti-cancer activity is mediated in part by AT-resolvins via novel anti-inflammatory and pro-resolution mechanisms. Methods: Flow cytometry confirmed apoptotic and necrotic lung tumor cell debris following chemotherapy (etoposide) or targeted therapy (erlotinib) treatment in vitro. Macrophage phagocytosis was quantified via Relative Fluorescent Units (RFU). Cytokine levels were quantified via ELISA. Results: AT-resolvins counter therapy-induced debris-stimulated tumor growth and spontaneous lung metastases via enhancing endogenous clearance of tumor debris via macrophages and counter-regulating macrophage cytokine production. Pharmacological and genetic antagonism of the AT-resolvin D1 receptor (ALX/FPR2) neutralized aspirin's anti-cancer activity. Conclusions: AT-resolvins may provide a novel pathway and molecular mechanism to explain how aspirin reduces cancer risk so broadly. These anti-inflammatory and pro-resolving lipid autacoid mediators may complement current therapies for lung cancer with minimal toxicity.
Citation Format: Molly M. Gilligan, Megan L. Sulciner, Yael Gus-Brautbar, Sesquile Ramon, Romain A. Colas, Sui Huang, Charles N. Serhan, Dipak Panigrahy. Control of lung cancer with aspirin-triggered stimulation of resolution. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 766.
Abstract 769: Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/â-catenin /STAT3 axis signalling pathway in human non-small cell lung carcinomas
Authors: Huang. Wen-Chien 
Published: July 2016

Abstract
Innate or acquired drug resistance and consequently, tumor relapse in lung cancer patients have been linked to the activities of cancer stem cells (CSCs). Therefore, targeting CSCs is suggested as an effective approach for non-small cell lung cancer (NSCLC) therapy. In this study, we demonstrated that Garcinol, a polyisoprenylated benzophenone isolated from the fruiting bodies of Garcinia indica, possessing anti-inflammatory, antioxidant, acetyltransferase inhibitory and anticancer activities, modulates the activities of lung cancer stem cells (LCSCs) and their associated aggressiveness. Here, we demonstrated the inhibitory effect of Garcinol on LCSC phenotype of human NSCLC cells by using the analytical drug cytotoxicity or cell viability, flow-cytometric and functional assay approach. Garcinol significantly diminished the ability of NSCLC cell lines, H441 and A549 to form spheres. In parallel assays, Garcinol inhibited differentiated lung cancer cell and LCSCs viability in a dose-dependent manner. Consistent with these observations, Flow cytometric data showed that Garcinol reduced putative LCSC pool, evidenced by the dose-dependent decreased proportion of side-population (SP) cells and associated ALDH activity in Garcinol-treated H441 cells, compared to the control group. Additionally, functional assays showed that Garcinol markedly diminished the ability of H441 and A549 cells to form colonies. Mechanistically, Garcinol impaired phosphorylation of LRP6, a co-receptor of Wnt and STAT3. In same assay, Garcinol downregulated â-catenin, Dvl2, Axin2, and Cyclin D1 expressions in NSCLC-generated spheres, suggesting its ability to regulate the Wnt/â-catenin signalling pathway. Put together, we demonstrated here that Garcinol modulates the LCSC phenotype via regulation of the Wnt/â-catenin signalling and inactivation of STAT3, thus, presenting Garcinol as a putative novel anti-LCSC therapeutic agent.
Keywords - Garcinol, non-small cell lung cancer, cancer stem cells, Wnt/â-catenin signalling pathway, anti-cancer therapy, STAT3
Citation Format: Wen-Chien Huang. Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/â-catenin /STAT3 axis signalling pathway in human non-small cell lung carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 769.