bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3966: Targeting integrin αvβ3-expressing cancer stem cells to manipulate tumor-associated macrophages
Authors: Wettersten Hiromi I. , Minami Toshiyuki , Kaneda Megan M. , Seguin Laetitia , Varner Judith A. , Weis Sara M. , Cheresh David A. 
Published: July 2017

Abstract
Tumor associated macrophages are involved in regulation of cancer growth and aggressiveness. Whereas M1 macrophages trigger an inflammatory response and inhibit tumor growth, M2 macrophages secrete pro-tumor cytokines into the microenvironment to support tumor progression. A macrophage switch from M1 to M2 has been associated with lung cancer progression, and cancer stem cells have been implicated as a driver of this reprogramming.
We recently reported that integrin αvβ3 expression is induced on lung adenocarcinoma cells during drug resistance and is both necessary and sufficient to reprogram these tumors to a stem-like state. Given the role that cancer stem cells play in switching M1 to M2 macrophages, we asked whether αvβ3 expression on lung adenocarcinoma cells account for this macrophage conversion. The M1/M2 macrophage ratio in αvβ3-positive tumors was markedly decreased relative to tumors lacking αvβ3. We next treated mice bearing αvβ3-positive tumors with a monoclonal antibody (LM609) targeting this receptor to assess its ability to alter the macrophage phenotype within these tumors. LM609 was able to selectively eliminate the αvβ3-positive cancer stem cells via antibody-dependent cell-mediated cytotoxicity (ADCC), and this not only increased the M1 macrophage population, but also markedly enhanced the sensitivity of these tumors to the effects of therapy.
These findings reveal that αvβ3-expressing cancer stem cells favor the pro-tumor M2 macrophage phenotype. Eliminating αvβ3-positive cancer stem cells via ADCC serves to both increase pro-inflammatory macrophages within the tumor microenvironment and prolong tumor sensitivity to therapy.
Citation Format: Hiromi I. Wettersten, Toshiyuki Minami, Megan M. Kaneda, Laetitia Seguin, Judith A. Varner, Sara M. Weis, David A. Cheresh. Targeting integrin αvβ3-expressing cancer stem cells to manipulate tumor-associated macrophages [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 3966. doi:10.1158/1538-7445.AM2017-3966
Abstract 3968: Canonical NFkB signaling in myeloid cells is required for the glioblastoma growth
Authors: Achyut Bhagelu R. , Bradford Jennifer , Angara Kartik , Rashid Mohammad , Jain Meenu , Borin Thaiz , Iskander ASM , Ara Roxan , Arbab Ali 
Published: July 2017

Abstract
Glioblastoma (GBM) development and therapeutic resistance has been accompanying with the tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). TAMs are heterogeneous cell populations of immune regulatory myeloid-derived suppressor cells (MDSCs) and polarization of anti-tumor macrophages (M1) into pro-tumor macrophages (M2). We investigated the role of myeloid cell NF-κB signaling in orthotopic GBM model using immune deficient and immune competent hosts. Interestingly, conditional deletion of canonical NF-κB signaling (p65) with Lysm-Cre (p65 KO) in myeloid cells, significantly inhibited syngeneic GL261 tumor growth in immune-competent mice compared to control mice. We studied the TAMs recruitment to the tumor and their polarization under the influence of TME. P65 KO mice displayed decreasing trend of immune cell infiltration (CD45), which phenotyped as decreased F4/80+, CD68+, CD206+ (M2) and Gr1+CD11b+ (MDSCs) macrophages, compared to control mice. This was associated with the increased CD80+ (M1) macrophages, increasing trend of CD4+ and CD8+ cytotoxic T cells, and decreased CD44+ mesenchymal cancer stem cells (CSCs) populations in the TME. Cytokine array data indicated that loss of canonical NF-κB signaling within the TAMs was implicated in increased production of IFNγ, IGF1, MCP1, MIP1α, and TNFα cytokines. Co-culture of T cells with p65 KO or control MDSCs identified increased proliferation of T cells with p65 KO MDSCs compared to control MDSCs. Conversely, GBM patient-derived xenografts and U251 GBM cell line-derived tumors showed increasing trend of growth in immune-deficient mice, following the transplantation of p65 KO bone marrow (BM) compared to control BM. Pro-tumor macrophages and CSCs were increased and T cell populations were decreased in human tumors grown in immune deficient mice transplanted with p65 KO BM, compared with control BM. In addition, analysis of human data set revealed higher expression of p65 subunit of NF-κB complex in brain tumor stroma compared to the tumor cells. The study suggests that canonical NF-κB signaling in TAMs is required for the tumor-promoting macrophage polarization and GBM growth in immunocompetent host compared to immune deficient host. Therefore, targeting myeloid-specific NFκB signaling in GBM could inhibit the immune suppressive TAMs and improve the anti-tumor immunity.
Citation Format: Bhagelu R. Achyut, Jennifer Bradford, Kartik Angara, Mohammad Rashid, Meenu Jain, Thaiz Borin, ASM Iskander, Roxan Ara, Ali Arbab. Canonical NFkB signaling in myeloid cells is required for the glioblastoma growth [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 3968. doi:10.1158/1538-7445.AM2017-3968
Abstract 397: Whole genome copy number variation analysis using a SNP-focused targeted sequencing panel for tumor analysis
Authors: Wang Jiashi , Giorda Kristina , Lai Zhongwu , Stetson Daniel , Jarosz Mirna 
Published: July 2017

Abstract
Accurate genome-wide copy number variation (CNV) analysis is critical for disease and cancer research. Current approaches for CNV analysis include fluorescence in situ hybridization (FISH), array comparative genomic hybridization (array CGH), and SNP arrays. Unfortunately, these methods are not sensitive enough for real world cancer samples because of tumor ploidy, purity and heterogeneity. NGS-based targeted sequencing is increasingly being used for CNV analysis due to throughput, coverage, cost, and sample input requirements. For CNV analysis, detection power is improved by combining both read depth and SNP allele frequency analysis, particularly for copy-neutral events such as loss of heterozygosity. A custom xGen Lockdown CNV backbone panel was developed for broad, uniform genome coverage and to enrich for population-based SNPs. We demonstrate use of the panel as an addition to the xGen Exome Research Panel and a custom cancer focused panel. Downstream analysis incorporates both read depth and observed minor allele frequencies to determine CNVs with enhanced sensitivity. To increase the resolution for large-scale alterations of chromosome 7, a hot-spot for disease-associated CNVs, probe density was increased 6 fold. A known standard, NA12878, was used to validate the panel’s ability to detect heterozygous SNPs with high confidence. In addition, mixtures of cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) were tested with varying levels of background copy-neutral genomic DNA. The sensitivity and specificity of the panel to detect CNV and LOH events with was assessed using deep exome and Affymetrix SNP array data. The ability to detect copy number alterations with high resolution and accuracy would be a valuable resource for disease and cancer research.
Citation Format: Jiashi Wang, Kristina Giorda, Zhongwu Lai, Daniel Stetson, Mirna Jarosz. Whole genome copy number variation analysis using a SNP-focused targeted sequencing panel for tumor analysis [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 397. doi:10.1158/1538-7445.AM2017-397
Abstract 3978: B7-H1/PD-L1 soluble expression in multiple cancer subtypes: High sensitivity measurement by immunoassay
Authors: Haworth Justin , Grant Rainer , Thayer Samuel , Floren Melissa , Steere Nathan , O'Brien Isabel , Younge Paul , Anderson Michael , Wegner Greta , Brumbaugh Kathryn 
Published: July 2017

Abstract
Aberrant expression of the B7-H1/PD-L1 immunomodulatory molecule is evident in many forms of cancer. The evidence for increased protein levels of B7-H1/PD-L1 comes largely from immunohistochemistry analysis of surgical and biopsy specimens. While several studies attempt to correlate B7-H1/PD-L1 expression with poor prognosis, there are studies that conclude no correlation based on technical difficulties associated with detecting B7-H1/PD-L1 protein expression on the cell surface. We were able to quantifiably measure soluble B7-H1/PD-L1 in conditioned medium from tumor cell cultures using two new immunoassays, a Quantikine® ELISA and a Simple Plex™ Assay. We show that breast, prostate, glioma, and non-Hodgkin’s lymphoma cells express various levels of B7-H1/PD-L1 which correlate to their PTEN or proliferation status. This is in agreement with previous findings showing that increases in B7-H1/PD-L1 expression levels are frequently coincident with loss of the PTEN tumor suppressor or increased activation of the phosphoinositide 3-kinase (PI 3-K) pathway. The androgen-responsive LNCaP prostate cancer cell line does not exhibit measurable B7-H1/PD-L1 in any instance, while the androgen-independent prostate cancer cell line PC-3 expresses measurable B7-H1/PD-L1 that is further inducible with PMA treatment. In all cell lines included in our study, incubation with PMA increases the level of B7-H1/PD-L1 released into the culture media, while pretreatment with the PI 3-K inhibitor, LY294002, abrogates this increase. Importantly, the Simple Plex platform is able to quantify very low levels of B7-H1/PD-L1 that are below detection by ELISA. Our data suggest that combining the Quantikine ELISA and Simple Plex platforms is a powerful strategy for reliably and quantitatively assessing soluble B7-H1/PD-L1 levels.
Citation Format: Justin Haworth, Rainer Grant, Samuel Thayer, Melissa Floren, Nathan Steere, Isabel O'Brien, Paul Younge, Michael Anderson, Greta Wegner, Kathryn Brumbaugh. B7-H1/PD-L1 soluble expression in multiple cancer subtypes: High sensitivity measurement by immunoassay [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 3978. doi:10.1158/1538-7445.AM2017-3978
Abstract 3980: Ly6G+ neutrophils and polymorphonuclear myeloid derived suppressor cells promote the survival of tumor cells
Authors: Herlihy Sarah , Lin Cindy , Ozeriva Maria , Garfall Alfred , Vogl Dan , Gabrilovich Dmitry , Nefedova Yulia 
Published: July 2017

Abstract
A heterogeneous group of immature myeloid cells which suppress the immune system are termed myeloid derived suppressor cells (MDSC). Collectively a MDSC population is comprised of monocyte-like MDSC and polymorphonuclear MDSC (PMN-MDSC). MDSC are increased in the presence of a number of different tumors. We previously demonstrated that PMN-MDSC represent the majority of MDSC in tumor-bearing mice. In a mouse model of multiple myeloma (MM) depletion of myeloid cells in vivo results in increased survival. Direct co-culture of neutrophils (CD11b+Gr1+ cells from tumor-free mice) or PMN-MDSC (CD11b+Gr1+ cells from tumor-bearing mice) and MM cells increases the survival of the MM cells from chemotherapeutic-induced death. Cell-cell contact is not necessary for the protective effect. Neutrophil and PMN-MDSC supernatants protect MM cells from cell death, suggesting the factor protecting tumor cells is soluble. Results in the mouse were confirmed using human MM cells and replicated on breast cancer cells with neutrophils or PMN-MDSC. Several cytokines and growth factors, such as IL-6 and fibroblast growth factor, are implicated in chemoresistance. The role of these neutrophil and PMN-MDSC soluble factors and the identification of novel contributors to chemoresistance are under investigation.
Citation Format: Sarah Herlihy, Cindy Lin, Maria Ozeriva, Alfred Garfall, Dan Vogl, Dmitry Gabrilovich, Yulia Nefedova. Ly6G+ neutrophils and polymorphonuclear myeloid derived suppressor cells promote the survival of tumor 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 3980. doi:10.1158/1538-7445.AM2017-3980
Abstract 3985: NCoR2 regulates glioblastoma progression and treatment resistance
Authors: Kaushik Shelly , Phillips Joanna J. , Weaver Valerie M. 
Published: July 2017

Abstract
Glioblastoma Multiforme (GBM, WHO Grade IV glioma) is one of the deadliest adult CNS tumors with a median survival of less than two years. It is largely resistant to aggressive therapeutic regimes, which combine radiation, chemotherapy and surgery. Thus, it is imperative to identify the molecular players and pathways that facilitate GBM resistance and recurrence. Nuclear co-repressor protein NCoR2 is upregulated in GBM and its increased expression correlates with poor prognosis in GBM patients (Alrfaei. Plos one. 2013). NCoR2, through its binding to the histone deacetylase protein HDAC3, mediates transcriptional repression (Zhu et al. Brain Res. 2013). NCoR2 is also involved in maintenance of neural stem cells (Jepson et al. Nature. 2007), which contribute to treatment resistance. Our study employs two distinct lineages of glioma - the less aggressive proneural and the highly aggressive mesenchymal subtypes. We show that NCoR2 is differentially expressed across these subtypes, suggesting a role for NCoR2-mediated transcriptional reprogramming in GBM progression. Moreover, knockdown of NCoR2 leads to phenotypic changes both in vitro and in vivo - including effects on neurosphere formation and proliferation, differential expression of stem-like markers as well as regulation of tumor growth and progression in mice. We also demonstrate that NCoR2 expression is increased upon treatment with temozolomide (used for GBM therapy), indicating a protective pro-tumor role for NCoR2. Finally, we explore the contribution of the GBM microenvironment to GBM progression by varying the three-dimensional properties as well as the rigidity of the extracellular matrix and investigating changes in NCoR2 expression and its regulation of tumor progression. We conclude that NCoR2 regulates GBM progression and resistance to therapy potentially via inducing a stem-like phenotype as well as responding to the tumor-promoting mechanical cues within the GBM microenvironment.
Citation Format: Shelly Kaushik, Joanna J. Phillips, Valerie M. Weaver. NCoR2 regulates glioblastoma progression and treatment resistance [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 3985. doi:10.1158/1538-7445.AM2017-3985
Abstract 4001: Infiltration of neutrophils in the tumor was associated with poor prognosis of patients with gastric cancer
Authors: Tanaka Hiroaki , Hiramatsu Soichiro , Tamura Tatsuro , Nagahara Hisashi , Kimura Kenjiro , Shibutani Masatsune , Ohira Go , Toyokawa Takahiro , Yamazoe Sadaaki , Amano Ryosuke , Muguruma Kazuya , Maeda Kiyoshi , Hirakawa Kosei , Ohira Masaichi 
Published: July 2017

Abstract
Background:Recent evidence shows that neutrophils often migrate into the tumor and are associated with tumor progression. These tumor associated neutrophils (TANs) neutrophils have potential to induce angiogenesis, lymphangiogensesis and immunosuppression by inhibiting cytotoxic T lymphocytes. Immune status is one of the important prognostic factor of gastric cancer. We previously reported that lymphangiogenesis was augmented in the primary tumor of gastric carcinoma.
Aim:The aim of this study was to investigate the correlation between CD15+ TANs and clinicopatological features of patients with gastric cancer.
Materials and Methods: We investigated the association of the density of TANs in primary tumor with clinicopathological features by immunohistochemistry. We used specimens from a total of 143 primary tumor and 497 lymph nodes from 120 patients underwent gastrectomy between 2007 and 2008 in our department. We examined prognostic value of TANs identified as positive CD15 cells in both of the primary tumor and tumor draining lymph nodes.
Results:The median number of TANs in primary tumor and tumor draining lymph nodes were 18.4 and 23 cells/HPF, respectively. High TANs in both of the primary tumor and lymph nodes had correlation with depth of invasion (primary tumor P&lt;0.001, lymph nodes P=0.036) and lymph nodes metastasis (primary tumor P&lt;0.001, lymph nodes P=0.002). Kaplan-Meier analysis showed that patients with high TANs in both primary tumor and lymph nodes had worse prognosis than patients with a low TANs (primary tumor P=0.031, lymph nodes P=0.014). Multivariate analysis revealed that high TANs in lymph nodes were independent prognostic factors. (P=0.038)
Conclusion: Our results showed that patients with high CD15+TANs infiltration in gastric cancer tissues had poorer prognosis because of increasing lymph nodes metastasis. These findings suggested the TANs might have important role of tumor lymphangiogenesis in microenvironment of gastric carcinoma.
Citation Format: Hiroaki Tanaka, Soichiro Hiramatsu, Tatsuro Tamura, Hisashi Nagahara, Kenjiro Kimura, Masatsune Shibutani, Go Ohira, Takahiro Toyokawa, Sadaaki Yamazoe, Ryosuke Amano, Kazuya Muguruma, Kiyoshi Maeda, Kosei Hirakawa, Masaichi Ohira. Infiltration of neutrophils in the tumor was associated with poor prognosis of patients with gastric 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 4001. doi:10.1158/1538-7445.AM2017-4001
Abstract 4004: Rapamycin selectively targets obesity-polarized macrophages in the prostate tumor microenvironment
Authors: Galván Gloria C. , Pham Tommy , Harlow Brittany , Johnson Christian , Patodia Riddhi , Quach Duan , Liss Michael A. , deGraffenried Linda A. 
Published: July 2017

Abstract
Background: Obesity is associated with prostate cancer progression and mortality. Previous studies in our laboratory suggest that obesity drives prostate cancer progression in part by increasing macrophage recruitment and by polarizing macrophages in the tumor microenvironment into a tumor promoting M2/TAM phenotype. Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has been used for several decades in transplant patients, and in the last several years has been shown to be an effective disease suppressor in certain cancer types. Intriguingly, mTOR has been shown to be especially important for M2 polarization and stabilization.
Hypothesis: Based upon published data and our preliminary studies, we hypothesize that rapamycin will selectively target obesity-polarized macrophages and will provide a survival benefit to the obese prostate cancer patient. Methods: To address this hypothesis, we used our in vitro model of obesity-induced macrophage polarization that includes two different prostate cancer cell lines, macrophages, and sera from obese and non-obese men. qPCR was used to measure expression levels of markers associated with an M2/TAM phenotype. MTT assays were conducted to measure cell viability, and flow cytometry and Western blot analyses were used to determine cell cycle status and apoptosis.
Results: Obese conditions increased expression of M2/TAM markers in macrophages and rapamycin selectively decreased viability of obesity-activated M2/TAMs compared to M1 macrophages.
Conclusions: Our in vitro study suggests that obesity promotes a tumor-associated phenotype in macrophages and that the mTOR pathway is involved in the survival of M2/TAM macrophages. This study offers a novel mechanistic approach to treat obese patients with prostate cancer.
Citation Format: Gloria C. Galván, Tommy Pham, Brittany Harlow, Christian Johnson, Riddhi Patodia, Duan Quach, Michael A. Liss, Linda A. deGraffenried. Rapamycin selectively targets obesity-polarized macrophages in the prostate 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 4004. doi:10.1158/1538-7445.AM2017-4004
Abstract 4007: Differential macrophage programming is associated with the aggressiveness of gliomas
Authors: Yao Nai-Wei , Liao Fang , Chang Chen , Chen Joanne Jeou-Yuan 
Published: July 2017

Abstract
Tumor-associated macrophages (TAMs), a major component of immune cells in the tumor microenvironment, have been shown to be associated with enhanced malignancy of gliomas. The polarization of macrophages toward a pro-inflammatory phenotype M1 or an anti-inflammatory phenotype M2 governed by niche factors in the tumor microenvironment may dictate the malignant outcome of gliomas. In this study, we examined the effects of differential programming of TAMs on the development of C6 gliomas in different host microenvironment using SD and Wistar rats. Using multi-parametric MRI measurements, we show that C6 cells implanted into SD rats developed larger tumors as compared to those in Wistar rats (p = 0.0199), which was accompanied with a shorter survival of SD rats (p = 1.06×10-9). The increased tumor growth in SD rats was associated with increased angiogenesis and higher levels of VEGF and VEGFR2 expression. We also observed a significantly increased ratio of M2/M1 in the tumors of SD rats while a decreased ratio of M2/M1 in those of Wistar rats, suggesting that the milieu of C6 gliomas in SD rats favors for the polarization of macrophages toward the pro-tumorigenic M2 phenotype. Most importantly, Induction of M1 polarization by IFNγ treatment greatly reduced tumor burden in SD rats, and induction of M2 polarization by IL-4/IL-10 treatment or blockade of M1 polarization by anti-IL12 treatment significantly promoted tumor growth in Wistar rats. These results demonstrate an important role of TAMs in glioma pathogenesis and the crucial role of microenvironment in dictating the polarization of TAMs into M1 or M2 phenotypes. We conclude that macrophage programming plays an important role in glioma development and that targeting glioma-associated macrophages may serve as a promising therapeutic approach.
Citation Format: Nai-Wei Yao, Fang Liao, Chen Chang, Joanne Jeou-Yuan Chen. Differential macrophage programming is associated with the aggressiveness of gliomas [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 4007. doi:10.1158/1538-7445.AM2017-4007