bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C9: Human melanoma metastasis in NSG mice correlates with clinical outcome in patients
Authors: Piskounova Elena , Quintana Elsa , Shackleton Mark , Johnson Timothy M. , Morrison Sean J. 
Published: August 2014

Abstract
Although metastasis is the leading cause of cancer-related deaths, little is known about the molecular mechanisms that enable tumor cells to metastasize. We have recently developed a model in which for the first time human melanomas readily engraft in nonobese diabetic/severe combined immunodeficient interleukin-2 receptor-g chain null (NSG) mice. Melanomas from 25 patients exhibit reproducible differences in the rate of spontaneous metastasis after transplantation into NSG mice. Importantly metastasis in mice is strongly correlated with metastasis, and clinical outcome, in the patients, providing an opportunity to test the mechanisms of metastatic progression of human melanoma in an animal model. In transplanted mice, efficiently metastasizing melanomas have much higher levels of circulating melanoma cells compared to inefficiently metastasizing ones, suggesting that the rate of entry into the blood is one factor that limits the rate of metastasis. In addition, we have profiled both genomic mutations and gene expression in 33 primary human melanomas with varying metastatic potential, in order to gain insight into the key regulatory pathways involved in melanoma metastasis. Using our xenograft model we are currently investigating the role of select genes in enhancing melanoma metastasis, at the level of intravasation into the blood stream, survival in circulation and proliferation in distal organs.
Citation Format: Elena Piskounova, Elsa Quintana, Mark Shackleton, Timothy M. Johnson, Sean J. Morrison. Human melanoma metastasis in NSG mice correlates with clinical outcome in patients. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C9.
Abstract IA20: Deregulation of stem cell self-renewal pathways in cancer
Authors: Clarke Michael 
Published: August 2014

Abstract
Most common cancers, such as cancers of the breast and colon, arise in organs such as the breast that contain a small population of stem cells that constantly replenish the mature cells of the tissue. Stem cells are defined by the ability to divide and give rise to a new stem cell (self-renewal), as well as the ability to give rise to the differentiated cells of an organ, and thus are the only long-lived cell population in many tissues. Extensive molecular and cellular analyses factors that play a role in the self-renewal of normal and malignant epithelial stem cells will be discussed.
Citation Format: Michael Clarke. Deregulation of stem cell self-renewal pathways in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA20.
Abstract PR2: Identification of luminal breast cancers that establish a tumor supportive macroenvironment defined by proangiogenic platelets and bone marrow derived cells
Authors: Marsh Timothy , Kuznetsov Hanna , Markens Beth , Castano Zafira , Greene-Colozzi April , Hay Samantha , Brown Victoria , Richardson Andrea , Signoretti Sabina , Battinelli Elisabeth , McAllister Sandra 
Published: August 2014

Abstract
Breast cancer recurrence rates vary following treatment, suggesting that tumor cells disseminate early from primary sites but remain indolent indefinitely before progressing to symptomatic disease. The reasons why some indolent disseminated tumors erupt into overt disease are unknown. We discovered a novel process by which certain luminal breast cancer cells and patient tumor specimens (LBC “instigators”) establish a systemic macroenvironment that supports outgrowth of otherwise-indolent disseminated tumors (“responders”). Instigating LBCs secrete cytokines that are absorbed by platelets, which are recruited to responding tumor sites where they aid vessel formation. Instigator-activated bone marrow cells (BMCs) enrich responding tumor cell expression of CD24, an adhesion molecule for platelets, and provide a source of VEGFR2+ tumor vessel cells. This cascade results in growth of responder adenocarcinomas and is abolished when platelet activation is inhibited by aspirin. These findings highlight the macroenvironment as an important component of disease progression that can be exploited therapeutically.
This abstract is also presented as Poster B6.
Citation Format: Timothy Marsh, Hanna Kuznetsov, Beth Markens, Zafira Castano, April Greene-Colozzi, Samantha Hay, Victoria Brown, Andrea Richardson, Sabina Signoretti, Elisabeth Battinelli, Sandra McAllister. Identification of luminal breast cancers that establish a tumor supportive macroenvironment defined by proangiogenic platelets and bone marrow derived cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr PR2.
Abstract A34: Splenectomy inhibits tumor development and metastases in murine lung cancer models.
Authors: Levy Liran , Mishalian Inbal , Zolotarov Lida , Bayuh Rachel , Fridlender Zvi Gregorio 
Published: August 2014

Abstract
Introduction & Aims: It has been shown that inhibitors of the immune system (e.g. myeloid derived suppressor cells, MDSC) reside in the spleen and inhibit the endogenous anti-tumor effects of the immune system. We hypothesized that excision of the spleen (splenectomy) can inhibit growth of relatively big tumors, and reduce metastases by modulating systemic inhibition of the immune system. Our long-term goal is to implement mechanisms elucidated in these studies into future clinical trials.
Methods: The clinical effect of splenectomy was evaluated in several murine lung cancer models - flank and metastatic. We compared immunological properties of blood and tumor after splenectomy or sham operation in tumor-bearing mice, using FACS analysis, RT-PCR and specific depletion studies.
Results: We found that splenectomy reduces tumor growth, can induce their regression, and decreases metastases. These effects disappeared in NOD/SCID mice. No significant changes in cell types were found in the blood. Splenectomy increased the percentage out of total tumor cells of neutrophils (2.4% vs. 4.9%, p=0.012), and macrophages (10.9% vs. 14.4%, p=0.014). The tumor macrophages tended to be less immune-inhibitory (non-M2/M2 macrophages ratio increased from 3.4 to 12.1, p=0.04). We further noted a tendency to increased activation of CD8+ CTL (19.2% vs. 30%, p=0.09). Tumor microenvironment was found to be more pro-inflammatory following splenectomy (e.g. upregulation of MIG, TNF-alpha, and IFN-gamma. Using specific depletion of cells we evaluated the role of each cell in the effect described. These experiments demonstrated the importance of myeloid derived suppressor cells (MDSC) in the effect of splenectomy.
Conclusions: Splenectomy inhibits the development of tumors and metastases in murine models of lung cancer, by changing the amount and characteristics of myeloid cells, and reducing activation of CD8+ T-cells.
Citation Format: Liran Levy, Inbal Mishalian, Lida Zolotarov, Rachel Bayuh, Zvi Gregorio Fridlender. Splenectomy inhibits tumor development and metastases in murine lung cancer models. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A34.
Abstract A65: Toll-like receptor 3 signaling in ovarian cancer.
Authors: Muccioli Maria , Pate Michelle , Benencia Fabian 
Published: August 2014

Abstract
The purpose of this study is to examine the cytokine secretion (in vitro) and leukocyte infiltration profiles (in vivo) in response to Toll-Like Receptor 3 (TLR3) activation in murine epithelial ovarian carcinoma. Ovarian cancer is the most deadly gynecological neoplasm, typically treated with surgery and chemotherapy, and has a less than a 50% 5-year survival rate. Drug resistance develops frequently, and it is necessary to investigate more targeted therapies. Chronic inflammation, which is seen in many cancers, can render an immunosuppressive tumor microenvironment characterized by cytokines that promote leukocyte infiltration, which can potentiate angiogenesis, and subsequent tumor growth and metastasis. Pathways that can generate such inflammation are important to characterize as they may be targeted in the development of novel cancer therapeutics. One regulator of inflammation in some types of epithelial ovarian cancer is TLR3, a protein that senses dsRNA and activates NF-κB, a potent initiator of cytokine secretion. Although typically expressed in immune cells, TLR3 is also present in cancer cells, and may function to direct inflammation at the tumor site towards an immunosuppressive state capable of recruiting pro-angiogenic leukocytes. Using PCR, ELISA, western blot, and microarray experiments on siRNA-generated TLR3-knock-downs and control samples, we are characterizing the cytokine secretion profiles following TLR3 activation with synthetic dsRNA ligands. Furthermore, we will employ this ovarian cancer cell line (ID8) with C57BL/6 mice to generate transplantation tumors and determine the effects of TLR3 signaling on the leukocyte population and presence of angiogenic molecules at the tumor site using flow cytometry and immunohistochemistry. We have determined that treatment of ID8 epithelial ovarian carcinoma cells with TLR3 ligands poly (I:C) or poly (A:U) results in increased secretion of pleiotropic cytokines, such as CCL5 and IL6, that may potentiate leukocyte migration to the tumor site. In vivo studies with C57BL/6 mice will determine whether this TLR3-induced cytokine secretion in the tumor cells translates to the physiological environment and promotes leukocyte infiltration and angiogenesis. By elucidating the contribution of TLR3 to the recruitment of pro-angiogenic leukocytes in ovarian epithelial carcinoma, the results of this project may be useful in the development of anti-angiogenic therapies for certain ovarian tumors.
Citation Format: Maria Muccioli, Michelle Pate, Fabian Benencia. Toll-like receptor 3 signaling in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A65.
Abstract A67: Reconditioning the tumor immune microenvironment for a breast cancer vaccine therapy.
Authors: Huang Yuhui , Yuan Jianping , Righi Elda , Duda Dan G. , Fukumura Dai , Poznansky Mark C. , Jain Rakesh K. 
Published: August 2014

Abstract
The recent approval of a prostate cancer vaccine has re-energized the research on cancer immunotherapy. A critical barrier for immunotherapies remains the immunosuppressive tumor microenvironment, which is due to abnormal tumor vasculature, hypoxia and tumor-infiltrating myeloid suppressors. Judiciously used anti-angiogenic agents have the potential to modulate the tumor immune environment to improve immunotherapy, but they are often used at high doses in the clinic aiming to prune tumor vessels. However, this has been shown to compromise other concurrent therapies, e.g., chemotherapy. Here, we demonstrate that anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody treatment at lower “vascular normalizing” doses – but not high “anti-vascular” doses – results in a more homogeneous distribution of functional tumor vessels and reduces hypoxia. As a result, the lower doses are superior to the high doses at polarizing tumor-associated macrophages from immune inhibitory M2-like towards immune stimulatory M1-like phenotype, and in facilitating CD4+ and CD8+ T cell tumor infiltration. These findings indicate that vascular normalizing doses of anti-VEGFR2 antibody treatment can reprogram the tumor immune microenvironment from suppressive to stimulatory. Based on this mechanism, synchronizing vascular normalization with T cell activation induced by a whole cancer cell vaccine therapy enhanced anti-cancer efficacy in a CD8+ T cell-dependent manner in both immune tolerant and immunogenic murine breast cancer models. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a new strategy to more effectively use anti-angiogenic agents with active immunotherapy and potentially other anti-cancer therapies in a clinical setting.
Citation Format: Yuhui Huang, Jianping Yuan, Elda Righi, Dan G. Duda, Dai Fukumura, Mark C. Poznansky, Rakesh K. Jain. Reconditioning the tumor immune microenvironment for a breast cancer vaccine therapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A67.
Abstract A80: Role of myeloid SOCS3 in prostate cancer progression.
Authors: Yu Hao , Liu Yudong , Benveniste Etty N. , Qin Hongwei 
Published: August 2014

Abstract
Suppressor Of Cytokine Signaling (SOCS) proteins, negative regulators of the JAK/STAT pathway, have been implicated in having a key protective role in tumor initiation and progression. However, the role of SOCS3 in regulating the differentiation and functions of myeloid-derived suppressor cells (MDSC) is poorly understood. Recent studies show the important role of MDSCs in promoting tumor progression as well as metastasis by regulating immune surveillance. To determine the role of myeloid SOCS3 in tumor progression, Conditional SOCS3 deletion in myeloid cells (LysMCre-SOCS3fl/fl) and SOCS3fl/fl C57BL/6 mice were used as recipients for subcutaneous transplantation of TRAMP-derived mouse prostate tumor cells. Our results indicate that tumor growth is significantly enhanced in myeloid-specific SOCS3-deficient mice, which correlates with elevated levels of Gr1+/CD11b+ cells in both spleen and tumor, and less CD8+ T-cell infiltration in tumors. Tumors from myeloid-specific SOCS3-deficient mice also express high levels of Arginase-1 and have elevated Akt signaling. In vitro, SOCS3-deficient bone-marrow-derived mononuclear cells (BDMC) exhibit heightened STAT3 activation and are subject to differentiation towards the MDSC phenotype. These findings suggest that myeloid cell SOCS3 provides protection from tumor progression by regulating MDSC differentiation.
Citation Format: Hao Yu, Yudong Liu, Etty N. Benveniste, Hongwei Qin. Role of myeloid SOCS3 in prostate cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A80.
Abstract A83: Modifications of the bone marrow microenvironment in the transition from monoclonal gammopathy of undetermined significance to multiple myeloma in Vk*MYC mice.
Authors: Calcinotto Arianna , Grioni Matteo , Bertilaccio Maria Teresa Sabrina , Chesi Marta , Bergsagel Leif , Casorati Giulia , Dellabona Paolo , Bellone Matteo 
Published: August 2014

Abstract
Multiple myeloma (MM) is a neoplastic plasma cell (PC) disorder of the oldster, and it is characterized by clonal proliferation of PC in the bone marrow (BM), monoclonal protein in biological fluids and organ dysfunction. While monoclonal gammopathy of undetermined significance (MGUS) often anticipates MM, the role of the cellular components of the BM microenvironment in the shift from MGUS to MM is unknown. Our aim was to define if the immune system has a role in this process. Thus, clinical signs of disease development and progression were investigated in the peripheral blood, bone marrow, kidney and bone of aging Vk*MYC mice to pinpoint the shift from MGUS to MM. We have also defined by immunohistochemistry and multiparametric flow-cytometry the phenotypic and functional characteristics of tumor infiltrating immune cells in the different phases of disease.
We have found that the BM of Vk*MYC mice is the primary organ of PC accumulation, and accrual of PC in the BM associates with the presence of a measurable M-spike. Based on the frequency of PC in the BM and the quantification of M-spike in serum we were able to segregate MGUS from MM. The transition from MGUS to MM in Vk*MYC mice was characterized by increased vascularization of the BM that associated with local enrichment of proangiogenic molecules such as VEGF-A and IL18. The BM was also enriched in molecules that favor survival and proliferation of myeloma cells, and signs of osteoporosis accompanied these alterations. A comparison between Vk*MYC mice affected by MGUS and age matched wild type C57BL/6 mice revealed precocious alteration of the CD4/CD8 T cell ratio, increased percentage of IL2 and IL4 producing CD4+ T cells, and CD8+ T cells more prone to produce IFNγ in the BM of the former.
In summary, our data suggest that early in disease development, yet unknown factors elicit an inflammatory reaction that significantly modifies the cellular composition of the BM and associates with neoangiogenesis and PC accumulation. Being the pathology in the Vk*MYC mouse similar to the human disease, our data might be relevant to understand the mechanisms of progression from MGUS to MM in humans.
Citation Format: Arianna Calcinotto, Matteo Grioni, Maria Teresa Sabrina Bertilaccio, Marta Chesi, Leif Bergsagel, Giulia Casorati, Paolo Dellabona, Matteo Bellone. Modifications of the bone marrow microenvironment in the transition from monoclonal gammopathy of undetermined significance to multiple myeloma in Vk*MYC mice. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A83.
Abstract A92: Tumor suppressive function of human macrophage-derived ADAM15 exosomes.
Authors: Lee Hee Doo , Kim Yeon Hyang , Kim Doo-Sik 
Published: August 2014

Abstract
A disintegrin and metalloproteinase (ADAM) 15, the only ADAM protein containing an Arg-Gly-Asp (RGD) motif in its disintegrin-like domain, is a widely expressed, human membrane protein. The present study demonstrates that macrophages derived from monocytes actively release ADAM15 into the extracellular space as an exosomal component. The exosomal ADAM15 release is further elevated by lipopolysaccharide stimulation, indicating that the exosome release is closely associated with immune cell differentiation and activation. ADAM15-rich exosomes display enhanced binding affinity for integrin alpha v beta 3, thereby interfering with the interaction between integrin alpha v beta 3 and vitronectin. ADAM15 exosomes significantly suppress vitronectin- and fibronectin-induced proliferation and migration of various tumor cells as well as tumor growth in vivo. Tumor suppressive function of exosomal ADAM15 is effectively blocked by monoclonal antibody specific for the extracellular domain of ADAM15. Experimental evidence shows that RGD-containing disintegrin-like domain, but not metalloproteinase activity, of ADAM15 is the responsible element for the tumor suppressive activity. Notably, proliferation and migration of macrophages are stimulated by the exosomes, indicating anti-tumor immunity. This work strongly suggests that a novel tumor suppressive mechanism is mediated by macrophage-derived ADAM15 exosomes.
Citation Format: Hee Doo Lee, Yeon Hyang Kim, Doo-Sik Kim. Tumor suppressive function of human macrophage-derived ADAM15 exosomes. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A92.
Abstract B23: DNA damage response in responder lymphocytes reduces vaccine efficacy following alkylating chemotherapy.
Authors: Litterman Adam J. , Zellmer David M. , Grinnen Karen L. , Dudek Arkadiusz Z. , Largaespada David A. , Ohlfest John R. 
Published: August 2014

Abstract
The effect of alkylating chemotherapy on cancer vaccines is controversial, with numerous reports of immune stimulation via Treg depletion following cyclophosphamide and temozolomide treatment. Using a pre-clinical model of a cancer vaccine in both naïve and tumor bearing animals, we observed that the direct anti-proliferative effect of drugs such as temozolomide or cyclophosphamide reduced the quantity of vaccine induced immune responses in a dose dependent manner. Amounts of temozolomide exposure in mice that duplicated human pharmacokinetic exposure and lymphopenia led to lower numbers of CD8 T cells elicited by vaccination with the model antigen ovalbumin. In vitro experiments with purified OT-I CD8 T cells implicated activation of DNA damage responses within strongly proliferating cells as the cause of this diminished immunity. ATM phosphorylation was greater in temozolomide or cyclophosphamide exposed OT-I cells stimulated with the canonical SIINFEKL peptide relative to variant peptides that trigger weaker TCR signaling. In vaccinated mice, this activation of DNA damage response in lymphocytes receiving the highest intensity TCR signals lead to lower avidity of responder cells for cognate antigen and lower effector function. These quantitative and qualitative defects of vaccine driven responses lead to inferior efficacy and loss of survival benefit in murine models. Mice bearing ovalbumin peptide expressing glioma had faster tumor growth and shorter survival following temozolomide and vaccine relative to vaccine only treated mice. Similar defects of vaccine generated responses and a loss of survival benefit relative to controls were observed in response to a neo-antigen vaccine following cyclophosphamide pre-treatment in melanoma bearing mice. The clinical relevance of this finding is demonstrated by a phase II cancer vaccine trial in metastatic melanoma patients where vaccine only patients survived a median of 4.2 years versus less than 8 months in patients treated with low dose cyclophosphamide before vaccine.
Citation Format: Adam J. Litterman, David M. Zellmer, Karen L. Grinnen, Arkadiusz Z. Dudek, David A. Largaespada, John R. Ohlfest. DNA damage response in responder lymphocytes reduces vaccine efficacy following alkylating chemotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B23.