bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1536: Neurropilin-1 high monocytes play an important role in trastuzumab mediated antibody-dependent cellular cytotoxicity in HER2 positive breast cancer cell lines.
Authors: Kawaguchi Kosuke , Suzuki Eiji , Sugie Tomoharu , Sato Fumiaki , Toi Masakazu 
Published: August 2014

Abstract
Purpose
Neuropilin-1 (NRP-1) was initially characterized as a neuronal receptor for specific secreted members of the semaphorin family involved in axon repulsion. However, it was recently reported to play an important role in the immune system. This study aimed to investigate the role of NRP-1 expression on monocytes in trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) targeting the HER2-positive human breast cell line SKBR3.
Methods
Peripheral blood mononuclear cells (PBMCs) from healthy volunteers were prepared using Lymphoprep. The cells were stained with fluorescein isothiocyanate (FITC)-conjugated anti-CD14 and allophycocyanin (APC)-conjugated anti-NRP-1 antibodies, and an NRP-1high and NRP-1low monocyte subset was sorted using FACSAria. These cells were used as effector cells in a conventional ADCC assay using SKBR3 as target cells and trastuzumab as an antibody. Target cell cytotoxicity was measured using the LDH cytotoxic test kit. A CD107a degranulation assay was also used to determine the role of NRP-1 expression on monocytes in ADCC. PBMCs were co-cultured with target SKBR3 cells and trastuzumab for 2 h, stained with APC-conjugated anti-NRP-1 and PE-Cy5-conjugated anti-CD107a antibodies, and analyzed by flow cytometry.
Results
The LDH cytotoxic test revealed significantly higher target cancer cell cytotoxicity in sorted NRP-1 high monocytes (12%) than in NRP-1 low monocytes (4%). Interestingly, microscopic findings showed that most NRP-1 high monocytes covered trastuzumab-treated target cancer cells (showing higher cellular cytotoxicity) while NRP-1 low monocytes did not cover the target cells but changed their morphology from a round to a dendritic shape (showing less cellular cytotoxicity) during ADCC. Moreover, the degranulation assay showed a higher expression of CD107a in NRP-1 high monocytes (17.4%) than in NRP-1 low monocytes (1.16%). Mean fluorescence intensity of CD107a in NRP-1 high and NRP-1 low monocytes was 92.6 and 26.3, respectively.
Conclusions
These data suggest that NRP-1 high monocytes exhibit higher trastuzumab-mediated ADCC than NRP-1 low monocytes in HER2-positive breast cancer cell lines. It may therefore be possible to differentiate HER2-positive breast cancer patients for whom trastuzumab will be less effective by testing for monocyte NRP-1 expression levels.
Citation Format: Kosuke Kawaguchi, Eiji Suzuki, Tomoharu Sugie, Fumiaki Sato, Masakazu Toi. Neurropilin-1 high monocytes play an important role in trastuzumab mediated antibody-dependent cellular cytotoxicity in HER2 positive breast cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1536. doi:10.1158/1538-7445.AM2013-1536
Abstract 1537: Characterization of tumor-infiltrating macrophages in humanized mouse model of prostate cancer.
Authors: Ryabov Vladimir , Kim David , Saito Rikka , Alexander Richard B. , Klyushnenkova Elena 
Published: August 2014

Abstract
Macrophage infiltration is observed in many types of human and mouse malignant tumors. Though some studies reported anti-tumor activity of tumor-associated macrophages (TAM) the majority of reports revealed contribution of TAM to tumor growth, invasion and metastasis. The phenotype and functions of TAM in prostate cancer are not well known. However, their abundance in the tumor suggests an important role in the course of malignant progression. In our novel humanized mouse model of prostate cancer, the expression of human HLA-DR*1501 (DR2b) transgene drastically impairs immune response to prostate tumor and induces excessive accumulation of TAM, which predominate in tumor tissue. In parallel, substantial accumulation of CD4+CD25+FOXP3+ T cells is observed in the tumor mass. The initial gene expression profiling of TAM in DR2b+ mice revealed their mixed M1/M2 phenotype since these cells expressed typical M2-associated genes TGFβ, IL10, arginase I, stabilin-1 and M1-associated genes IL1β, TNFα and IL6. Moreover, TAM strongly expressed chemokines CCL2, CCL3, CCL4, CCL5 and CXCL10, which are capable to recruit myeloid, NK and T cells as well as immune checkpoint receptor PDL-1. Interestingly, compared to DR2b- mice, TAM from DR2b+ animals had reduced expression of important NK and T cell survival factor IL15. Immunohistochemical investigation of the tumor tissue revealed that CD68+ TAM co-localized with T cells on the periphery of the tumor and expressed M2-associated marker stabilin-1. Moreover, T cells were found exclusively on the tumor periphery, whereas TAM were observed inside tumor mass. Altogether, present data suggest that TAM in DR2b model of prostate cancer have potential to recruit various immune cells to the tumor mass. However, elevated expression of immunosuppressive factors TGFβ, IL10, arginase I, PDL-1 and close association between TAM and T cells on tumor periphery may impair T cell activation and induce generation of Tregs.
Citation Format: Vladimir Ryabov, David Kim, Rikka Saito, Richard B. Alexander, Elena Klyushnenkova. Characterization of tumor-infiltrating macrophages in humanized mouse model of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1537. doi:10.1158/1538-7445.AM2013-1537
Abstract 1540: TNFRs shed by tumor cells inhibit the migration of macrophages.
Authors: Rego Stephen , Helms Rachel , De Piante Alexander , Kidiyoor Amritha , Lance Amanda , Mukherjee Pinku , Dréau Didier 
Published: August 2014

Abstract
Breast tumor cells transform their microenvironment through the expression of pro-tumor molecules critical to their progression and metastasis. Among the targets of tumor cell secretions are macrophages, which play an essential role in tumor progression. Although macrophages possess tumor cell killing abilities, the tumor-associated macrophages (TAMs) display primarily pro-tumor functions including increasing tumor angiogenesis and promoting tumor cell invasion. Breast tumor cells shed multiple membrane-bound proteins including their tumor necrosis factor (TNF) receptors through TACE/ADAM17 activities. The release of sTNFR1/2 serves a decoy sequestering TNF and preventing TNF-driven apoptosis of tumor cells. Additionally, tumor derived sTNFR1/2 also modulate TNF effects on macrophages including their migration. Here, we investigated whether sTNFRs were shed by cells present within the breast tumor microenvironment and determined their effects on macrophage migration in response to TNF. TNF and sTNFRs concentrations were measured in murine mammary tumor and normal cells including monocytes/macrophages. In addition, the migration of murine monocytes toward TNF in the presence tumor derived soluble factors (TDSFs) was determined by transwell assays. The effects of TDSFs obtained with and without the sheddase inhibitor TAPI-0 treatment on monocyte/macrophage migration were also assessed. No TNF was detected in the TDSFs of tumor cells or secretions from normal epithelial cells. In contrast, stroma cells especially macrophages expressed high levels of TNF (p&lt;0.001). sTNFR2 concentrations were variable in TDSFs and significantly decreased in TDSFs obtained following TAPI-0 treatment (p&lt;0.05). Macrophages migrated toward TNF in a dose-dependent manner (p&lt;0.05). While the addition of TDSFs prevented the macrophage migration toward TNF, the use of TDSFs collected following TAPI-0 treatment had no effects of the macrophage migration toward TNF (p&lt;0.05). These results support the modulatory role of sTNFRs secreted by tumor cells in macrophage responses to TNF.
[This works is supported by grants from the Department of Defense Era of Hope research program (BC044778) and the National Science Foundation EFRI program (CBE0736007)].
Citation Format: Stephen Rego, Rachel Helms, Alexander De Piante, Amritha Kidiyoor, Amanda Lance, Pinku Mukherjee, Didier Dréau. TNFRs shed by tumor cells inhibit the migration of macrophages. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1540. doi:10.1158/1538-7445.AM2013-1540
Abstract 1541: M2 macrophages co-cultured with prostate cancer cells promote osteoblast differentiation mediated by BMP-2 and BMP-7.
Authors: Wang Lihui , Huang Xin , Wang Jianhua , Lu Yi 
Published: August 2014

Abstract
Prostate cancers frequently metastasize to bone and cause predominantly osteoblastic lesions. When tumor cells metastasize to bone, they interact with the bone microenvironment. Bidirectional interactions between prostate cancer cells and bone microenvironment increase expression of cytokines, chemokines and adhesion molecules. These factors can be produced by tumor cells as well as bone marrow cells including osteoclasts, osteoblasts/stromal cells and macrophages. It has been demonstrated that M2 macropahge enhanced tumor growth, survival and metastasis. However, whether M2 macropahges play roles in prostate cancer-induced osteoblastic lesions, specifically in osteoblast differentiation is unknown. We initially isolated M2 macrophages from primary murine bone marrow cells culturing with IL-4 and IL-13. Then M2 macrophages were co-cultured with or without prostate cancer C4-2B or LNCaP cells at ratio 5:1. Then the conditioned media (CM) from M2 co-cultures were collected. We incubated murine bone marrow cells or MC3T3 E1 cells with different concentrations of the CM and performed Von Kossa Staining. We found that the co-cultured CM, but not the CM collected from either macrophages or prostate cancer cells, significantly induced bone marrow cells or MC3T3 E1 mineralization in vitro. This induction was partially blocked by anti-BMP-2 and anti-BMP-7 neutralizing antibodies. We further observed that the co-cultured CM significantly induced alkaline phosphatase (ALP) and osteocalcin (OCN) production. Finally, we determined the cytokine productions from the co-cultured CM by using ELISA. The production of BMP-2 and BMP-7 were detected. The conditioned media collected from M1 macrophage were used as corresponding and negative controls throughout the whole study. We concluded that M2 macrophages co-cultured with prostate cancer cells promote osteoblast differentiation mediated by BMP-2 and BMP-7. Supported by NSF projects 81171993 and 81272415; NSF key project 81130046; 973 Grant (2009CB918902); Guangxi projects 201201ZD004 and 2012GXNSFCB53004.
Citation Format: Lihui Wang, Xin Huang, Jianhua Wang, Yi Lu. M2 macrophages co-cultured with prostate cancer cells promote osteoblast differentiation mediated by BMP-2 and BMP-7. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1541. doi:10.1158/1538-7445.AM2013-1541
Abstract 1549: Diet-induced obesity increases tumor levels of MCP-1, macrophage infiltration and microvessel density in a murine model of breast cancer.
Authors: Ngan Emily , Pacilli Alessandra , Marshall Eva , Cutlip Kirstie , Coad James , Ammer Amanda , Vona-Davis Linda 
Published: August 2014

Abstract
Epidemiological studies indicate that obesity is associated with poor outcomes in breast cancer. In our previous work, we demonstrated that a chronic consumption of a high fat diet increases solid tumor growth and metastasis in a spontaneous mammary cancer mouse model. In addition to higher tumor burdens and rates of metastases, mice fed a high fat diet showed elevated levels of adipocyte derived monocyte chemoattractant protein-1 (MCP-1) in the blood. We hypothesized that diet-induced obesity promotes mammary carcinogenesis by inducing an inflammatory and tumor-supportive microenvironment. We further compared chow fed lean MMTV(PyMT) mice with those fed 45.0% (w/w) high fat (HF) to investigate the impact of body adiposity and dietary nutrient overload on levels of MCP-1 in tissue, tumor associated macrophages (TAMs) and for the degree of microvessel density. We analyzed early and late carcinoma stage tumors together with adipose tissue from mice fed HF and control diets in order to identify possible sources of MCP-1 production. MCP-1 levels in tumors of mice differed significantly by cancer stage and diet, with late stage tumors showing more MCP-1 (P&lt;0.05). Moreover, MCP-1 production was elevated in adipose tissue of obese mice compared to lean mice. Tumors and adjacent adipose were stained with CD68 and the numbers of TAMs were quantified. Significantly more TAMs (P&lt;0.05) were found within tumor beds and more crown-like structures were evident in adipose tissue from obese mice at both early and late stage carcinoma. Tumor beds also showed increased microvessel density when stained with CD31. In summary, diet-induced obesity increased levels of MCP-1 in tumors and adipose with more macrophage infiltration and greater vascular density evident in mammary tumor beds. Taken together, these findings suggest that high body adiposity caused by diet-induced changes promote an inflammatory and tumor-supportive microenvironment in breast cancer. NIH P20 RR016440, P30 R032138/GM103488, and P20 RR016477
Citation Format: Emily Ngan, Alessandra Pacilli, Eva Marshall, Kirstie Cutlip, James Coad, Amanda Ammer, Linda Vona-Davis. Diet-induced obesity increases tumor levels of MCP-1, macrophage infiltration and microvessel density in a murine model of breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1549. doi:10.1158/1538-7445.AM2013-1549
Abstract 1551: Irradiation enhances tumor-homing ability of monocytes as cellular carrier.
Authors: Yu Ching-Fang , Woo Christopher W. , Lo Shao-Hua , Yen Chia-Yi , Hong Ji-Hong , Chiang Chi-Shiun 
Published: August 2014

Abstract
Tumor-homing ability of monocytes renders them as potential cellular delivery system for alternative cancer therapy, but the migration ability is reduced after reagents are up-taken. Approaches that can enhance monocyte tumor homing and migration abilities will facilitate the clinical value of using monocytes as cellular carrier. Previous studies have shown that irradiation (IR) could promote macrophage aggregation into the hypoxic regions. To investigate whether IR could enhance the infiltration of bone marrow-derived monocytes (BMDMs) into tumors, the infiltration of BMDMs prepared from GFP-transgenic mice were examined by fluorescence microscopy in murine prostate adenocarinoma TRAMP-C1 model. The results showed that IR did not increase the initial infiltration number of BMDMs, but enhanced the retention of monocytes within IR-treated tumors up to 2 weeks. This study also showed that BMDMs were able to uptake various imaging or therapeutic agents, but their mobility was decreased as the load was increased. However, when BMDMs were differentiated in IR-treated tumor condition medium (IR-CM), the nanoparticles-loaded migration loss was recovered in both in vitro and in vivo models. The prolong retention of monocytes within irradiated tumor tissues and the ability of IR-CM to enhance the migration ability of cargo-loaded BMDMs suggest that pre-conditioned monocytes could be a potential cellular carrier for target therapy following conventional RT. (This study is supported by NHRI-EX101-10132BI and NSC101-2627-M-007-001 grants)
Citation Format: Ching-Fang Yu, Christopher W. Woo, Shao-Hua Lo, Chia-Yi Yen, Ji-Hong Hong, Chi-Shiun Chiang. Irradiation enhances tumor-homing ability of monocytes as cellular carrier. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1551. doi:10.1158/1538-7445.AM2013-1551
Abstract 1555: Use of a mouse model of constitutive mTOR inhibition to identify molecular modulators of acquired resistance.
Authors: Gary Joy , Xu Jinfei , Simmons John , Kovalchuk Alexander , Dubois Wendy , Testa Joseph , Mock Beverly 
Published: August 2014

Abstract
The AKT/PI3K/mTOR signaling pathway is hyperactivated in cancers, including both solid tumors and hematologic malignancies. This hyperactivation is often due to an overexpression or mutation in PI3K, which is upstream of AKT, or a down regulation of PTEN, an inhibitor of the PI3K pathway. mTOR is a central downstream target of this pathway and is a critical modulator of cell cycle, size, proliferation and metabolism. Resistance to mTOR inhibition has been reported in many tumors as well as in certain cell lines, resulting in decreased efficacy of cancer therapy involving this class of inhibitor. In these studies, mice (Mtortm1.1Lgm) with constitutive reduction in mTOR protein level were crossed to mice (Lck-MyrAkt2) that spontaneously develop thymic lymphomas due to constitutive AKT activation to simulate mTOR inhibitor treatment of thymic lymphoma development. The Lck-MyrAkt2 mice spontaneously develop thymic lymphomas at 10-20 weeks of age, and frequently harbor a 14;15 translocation that leads to the apposition of the TCRalpha and Myc genes. Tumor formation was significantly delayed in the mTOR knockdown x Lck-MyrAkt2 cohort, and the mice had a median survival of 181 days compared to 88 days in mice with normal mTOR expression. A similar t(14;15) translocation frequency was observed in thymic lymphomas of mice from both groups. To evaluate potential mTOR resistance mechanisms, gene expression profiling (GEP) of tumors arising from both groups of mice was performed. Molecular and functional enrichment analysis of the genes differentially expressed in the tumors arising despite mTOR inhibition was performed. Increased expression of an oncogenic transcription factor was observed, and is the subject of on-going investigation.
Citation Format: Joy Gary, Jinfei Xu, John Simmons, Alexander Kovalchuk, Wendy Dubois, Joseph Testa, Beverly Mock. Use of a mouse model of constitutive mTOR inhibition to identify molecular modulators of acquired resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1555. doi:10.1158/1538-7445.AM2013-1555
Abstract 1561: An evaluation of the use of genetically modified mouse models in human cancer risk assessment.
Authors: Eastmond David A. , Vulimiri Suryanarayana V. , French John E. , Sonawane Babasaheb 
Published: August 2014

Abstract
The development of short-term or accelerated cancer bioassays using genetically modified (GM) animals that exhibit high sensitivity to chemically induced cancers and that act through mode(s) of action relevant to humans continues to be an important focus of research. However, to date only a few GM mouse models such as the Trp53+/−, the Tg.AC and the rasH2 models have effectively been evaluated to substitute for the two-year rodent cancer bioassays. Whether these models provide an acceptable replacement for the conventional rodent cancer bioassay for assessing human cancer risks is the subject of ongoing debate. The objective of this study was to evaluate the current status of the use of GM mice for accelerated cancer bioassays in assessing the potential human health risks associated with exposure to carcinogenic agents. We compared the published data from the GM bioassays with results obtained using the National Toxicology Program's conventional 2-year mouse cancer bioassay presently used in human cancer risk assessment. The results demonstrate a moderate success for these GM models to distinguish carcinogens from non-carcinogens. Although the GM models are less efficient in detecting rodent carcinogens, they are more consistent in identifying non-carcinogens. Our analysis also shows that there continue to be concerns about the assay design and protocols used for the GM models, including issues related to sample size, study duration, genetic instability, and reproducibility. Additional issues of concern include specific toxicity pathway-dependent effects, and differences in the potential carcinogenic mechanisms operating in GM and non-GM animals, topics that still need to be investigated. In addition, the dose-responses of the GM models can vary substantially from those seen in conventional cancer bioassays. Overall, we conclude that the existing GM mouse models are of value for hazard identification, but are of limited use for dose-response analysis with currently used study designs. Hence, until these models are thoroughly validated using more robust study designs and the dose-response issues adequately addressed, caution should be exercised when using the current GM models to assess the carcinogenic risks of chemicals to humans.
Disclaimer: The views expressed in this abstract are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency or the National Institute of Environmental Health Sciences.
Citation Format: David A. Eastmond, Suryanarayana V. Vulimiri, John E. French, Babasaheb Sonawane. An evaluation of the use of genetically modified mouse models in human cancer risk assessment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1561. doi:10.1158/1538-7445.AM2013-1561