bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A19: Inhibition of MK2 reduces chronic inflammation and regresses tumors in a mouse model of colorectal cancer
Authors: Ray Anita L. , Castillo Eliseo F. , Nofchissey Robert A. , Beswick Ellen J. 
Published: October 2016

Abstract
Chronic inflammation is a known risk factor for colorectal cancer (CRC). Cancers in patients with increased inflammatory cytokines in tumor tissue are associated with increased drug resistance, metastasis, and mortality. We have identified mitogen-activated protein kinase-activated protein kinase 2 (MK2) as a regulator of pro-inflammatory cytokines and promoter of proliferation in CRC progression. MK2 signaling induces IL-1, IL-6, and TNF-alpha production, which have been associated with CRC development and progression. We investigated this pathway in an inflammation-related model of CRC. This model relies on an initial dose of the carcinogen azoxymethane, followed by administration of dextran sodium sulfate to model chronic inflammation. C57BL/6 mice were found to develop colon tumors by day 54 in this model. Thus, we treated mice with MK2 inhibitors starting at this time point, 3 times a week for 3 weeks. At day 80, neoplasm number and size were measured, as well as pro-inflammatory cytokines and immune cell profiles in the colon using flow cytometry and multiplex bead-based arrays. MK2 inhibition drastically reduced colon pro-inflammatory cytokines, influx of immune cells, and tumor burden compared to vehicle control treated mice. Upon testing two separate MK2 inhibitors, 6/7 and 5/7 mice were completely free of tumors after treatment. We conclude that this pathway is an important contributor to CRC and could be a promising therapeutic target.
Citation Format: Anita L. Ray, Eliseo F. Castillo, Robert A. Nofchissey, Ellen J. Beswick. Inhibition of MK2 reduces chronic inflammation and regresses tumors in a mouse model of colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A19.
Abstract A22: In situ image-based monitoring of extracellular matrix mechanics in 3D pancreatic tumor-stroma co-culture models to inform therapeutic development
Authors: Jones Dustin P. , Hanna William , Cramer Gwendolyn M. , El-Hamidi Hamid , Celli Jonathan P. 
Published: October 2016

Abstract
A number of compelling studies have shown that the mechanical landscape of the tumor microenvironment contributes significantly to regulation of growth behavior, phenotype, and therapeutic response. These findings could be particularly relevant to pancreatic tumors, which are associated with a profound desmolastic reaction. The exceptional abundance of rigid, fibrotic stroma encasing these lethal malignancies has been implicated in obstructing drug delivery and playing multiple tumor-promoting roles. In this context, we use in vitro 3D tumor models with customized stromal composition, combined with in situ quantitative measurements of extracellular matrix (ECM) rigidity via optical microrheology, as a platform for evaluation of therapeutics targeting biomechanical interactions with the microenvironment. Using ECM formulations of calibrated rheological properties (rigidity) in conjunction with optical measurements that provide readouts of dynamic changes provides a window into both sides of a mechanoregulatory dialogue, in which ECM rigidity influences tumor growth and, in turn, cancer cells and stromal fibroblasts remodel their mechanical environment. Here we examine differential therapeutic response to selected chemotherapy agents and photodynamic therapy (PDT) in culture conditions that lead to fibrosis (increasing mechanical strength) as well invasive behavior (local breakdown of ECM). The methodology used here could be more broadly applied to directly quantify impact of stromal depletion therapies and altered ECM remodeling concomitant with therapy.
Citation Format: Dustin P. Jones, William Hanna, Gwendolyn M. Cramer, Hamid El-Hamidi, Jonathan P. Celli. In situ image-based monitoring of extracellular matrix mechanics in 3D pancreatic tumor-stroma co-culture models to inform therapeutic development. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A22.
Abstract A23: Characterization of diverging molecular and phenotypic responses under changing extracellular matrix stiffness in MCF10A cells
Authors: Liu Sonya , Bainer Russell , Yui Yoshihiro , Flinders Colin , Mallick Parag , Weaver Valerie , Mumenthaler Shannon 
Published: October 2016

Abstract
Tissue stiffness has emerged as an important regulator in the maintenance of normal cellular processes. In general, solid tumors are known to be much stiffer than normal tissue, with increased extracellular matrix (ECM) density being indicative of a higher risk for many cancers, including those of the breast. Over the course of breast cancer progression, the ECM becomes increasingly stiffer, a phenomenon which is known to be a driver of malignancy. In a 3D culture system using self-assembling peptide (SAP) gels, we grew MCF10A acini under a dynamic range of stiffness environments (140-5800 Pa). Under normal breast tissue elasticity, mammary epithelial cells form rounded, polarized acini with cleared lumens. However, in tumor-like stiffnesses, the same cells form non-polarized, collapsed structures that invade into the gel. To investigate the specific genes and pathways affected by stiffness, we have conducted tandem mass spectrometry to identify protein expression changes in MCF10A cells grown on SAP gels of increasing stiffness. Interestingly, the resulting analysis showed that cells grown on higher stiffnesses exhibit greater variation in protein expression. These divergent force-regulated molecular pathways are involved in a variety of cellular functions, including cell adhesion and migration, metabolism, and the immune response, among others. This study underscores the significance of mechanical forces exerted by the ECM, and signifies the first large-scale proteomic screen carried out to analyze heterogeneous cellular responses to changing stiffness environments.
Citation Format: Sonya Liu, Russell Bainer, Yoshihiro Yui, Colin Flinders, Parag Mallick, Valerie Weaver, Shannon Mumenthaler. Characterization of diverging molecular and phenotypic responses under changing extracellular matrix stiffness in MCF10A cells. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A23.
Abstract A25: Transcriptional control of inflammatory signaling in the megakaryocyte and erythroid lineages
Authors: Trinh Bon Q. , Barengo Nicolas , Kim Sang Bae , Lee Ju-Seog , Zweidler-McKay Patrick A. , Naora Honami 
Published: October 2016

Abstract
Thrombocytosis, characterized by high platelet counts, and anemia, caused by low numbers of red blood cells, are associated with poor outcomes in solid tumors and occur in several types of myeloid disorders. The megakaryocyte and erythroid lineages give rise to platelets and red blood cells, respectively, but the mechanisms that cause increased megakaryopoiesis and concurrently decreased erythropoiesis are poorly understood. In this study, we identified that expression of DLX4, a transcription factor encoded by a homeobox gene, increases during megakaryopoiesis and decreases during erythropoiesis. Overexpression and knockdown experiments using normal CD34+ stem/progenitor cells and bipotent K562 cells demonstrated that DLX4 induces lineage markers and morphologic features of megakaryocytes, and concomitantly represses erythroid marker expression and hemoglobin levels. Gene Ontology and Gene Set Enrichment Analyses of genome-wide changes in gene expression induced by DLX4 showed that DLX4 induces a megakaryocytic transcriptional program and inhibits an erythroid transcriptional program. Bioinformatic analysis also revealed that DLX4 induces gene signatures that are associated with NF-kappaB signaling. The ability of DLX4 to promote megakaryocyte development and to inhibit erythroid differentiation was diminished by blocking NF-kappaB activity or by repressing IL1B, a transcriptional target of DLX4. These findings indicate that DLX4 promotes megakaryocyte development at the expense of erythroid generation in part by inducing inflammatory signaling. Studies are ongoing to investigate the transcriptional control by homeobox genes of inflammatory signaling in thrombocytosis and anemia that are associated with solid tumors and myeloproliferative diseases.
Citation Format: Bon Q. Trinh, Nicolas Barengo, Sang Bae Kim, Ju-Seog Lee, Patrick A. Zweidler-McKay, Honami Naora. Transcriptional control of inflammatory signaling in the megakaryocyte and erythroid lineages. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A25.
Abstract A45: Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways in triple-negative breast cancer
Authors: Wu Tony J. , Nabet Barzin Y. , Xu Bihui , Boelens Mirjam C. , Jonkers Jos , Minn Andy J. 
Published: October 2016

Abstract
Breast cancer cells can achieve protection from DNA damage both through cell-autonomous mechanisms and intercellular communication with the tumor microenvironment. Previously, we described an Interferon-Related DNA Damage Resistance Signature comprising of a network of interferon-stimulated genes (ISGs) that promotes and clinically predicts chemotherapy and radiation resistance in breast cancer. Here, we examine the heterotypic tumor-stroma interactions that regulate ISGs. We show that STAT1 and other ISGs are induced in breast cancer cells following interaction with stroma. STAT1 induces NOTCH3 expression, explaining a requirement for juxtacrine signaling. Moreover, we report that stroma upregulates ISG expression in breast cancer cells through exosomes. Exosomes transferred from the stroma and ISG induction are both dependent on RAB27B. In mice, targeting these pathways abrogate stroma-mediated resistance and results in long-term tumor-free survival. Analysis of primary human tumors supports the role of anti-viral/NOTCH3 pathways in NOTCH signaling and stroma-mediated resistance. To determine whether these observations can further predict clinical efficacy, cell lines derived from a genetically engineered mouse model for p53-induced breast cancer, K14cre;Brca1F/F;p53F/F, were tested. We show that stroma induces breast cancer ISGs through exosomes, which in turn can induce signaling to activate NOTCH3 and regulate DNA damage resistance.
Citation Format: Tony J. Wu, Barzin Y. Nabet, Bihui Xu, Mirjam C. Boelens, Jos Jonkers, Andy J. Minn. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways in triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A45.
Abstract A47: miR-30c: a TGF beta-regulated miRNA that coordinates vascular-directed fibrinolysis and tumor angiogenesis
Authors: McCann James V. , Xiao Lin , Khan Omar , Kowalski Piotr , Azam Salma , Pecot Chad V. , Anderson Daniel G. , Dudley Andrew C. 
Published: October 2016

Abstract
Tumor-associated endothelial cells (TECs) are dysfunctional and leak fibrin which is resolved (fibrinolysis) and replaced with collagen in a process that closely resembles wound healing. Because degraded perivascular fibrin also promotes angiogenesis and creates scaffolds for invasive cancer cells, vascular-directed fibrinolysis in solid tumors is a fundamental spark during tumor progression. Using a miRNA screen of freshly isolated TECs, we identified a TGF beta-regulated miRNA that controls vascular-mediated fibrinolysis in tumors. miR-30c is increased in TECs relative to normal endothelial cells (NECs) whereas its target PAI-1 (a fibrinolysis inhibitor) is strikingly decreased. TECs secrete less PAI-1 and they rapidly degrade and migrate through fibrin scaffolds resulting in uncoordinated vessel sprouting. However, TGF beta and miR-30c antagomiRs reduce miR-30c expression which re-instates PAI-1 secretion, diminishes vascular-specific fibrinolysis, and “normalizes” TEC sprouting. miR-30c antagomiRs coupled to vascular-tropic nanoparticles reduce TEC migration in fibrin and enforce vascular expression of PAI-1 in vitro and in vivo. Thus, vascular-specific expression of miR-30c in tumors may be manipulated in vivo using this nanoparticle-based strategy. We also show that TGF beta promotes the export of miR-30c in extracellular vesicles (EVs) which are received by recipient stromal cells. TGF beta-mediated extravascular mobilization of miR-30c may down regulate PAI-1 expression in nearby stromal cells or cancer cells thereby programing fibrinolysis in these non-vascular recipients. Taken together, we propose an axis between TGF beta, miR-30c, and PAI-1 in TECs controls the rate of perivascular fibrinolysis and is therefore an important effector of tumor emergence.
Citation Format: James V. McCann, Lin Xiao, Omar Khan, Piotr Kowalski, Salma Azam, Chad V. Pecot, Daniel G. Anderson, Andrew C. Dudley. miR-30c: a TGF beta-regulated miRNA that coordinates vascular-directed fibrinolysis and tumor angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A47.
Abstract B06: Characterizing the effects of hypoxia and hydrostatic pressure on the expression of immunotherapeutic targets in prostate cancer cell lines and donor immune cells in culture
Authors: Adams Bruce A. , Lim James , Chow Tianna , Bernstein Susan , Ryan Charles J. 
Published: October 2016

Abstract
Introduction: Cancer immunotherapy has changed the paradigm of cancer treatment by harnessing the immune system to identify and eradicate tumors leading to significant improvements in the objective response and long term survival of patients. However, more than 50% of patients do not respond to the most advanced immunotherapeutics in clinical trials, suggesting that further research is needed to understand the mechanism of action and resistance to immune-modulating agents in patients. The current hypothesis is that the tumor microenvironment can modulate the reprogramming of stromal cells caused by chronic inflammation, leading to a suppressed immune system that is highlighted by T-cell exhaustion and anergy. Hypoxia and high interstitial fluid pressure within tumors are elements that may contribute to gene and protein expression changes in stromal, immune and tumor cells in the microenvironment to inhibit immune function and promote cancer proliferation and metastasis.
Methods: We have developed a novel primary cell culture bioreactor to modulate both oxygen level (0.1% to 19%) and hydrostatic pressure levels (26 to 260 mmHg / 0.5 psig to 5 psig) to study the effects on gene and protein expression profiles of prostate cancer cell lines and peripheral blood mononuclear cells (PBMCs) derived from donors. We performed high-resolution immunofluorescence imaging and western blot protein expression analysis of primary immuno-therapy targets CTLA-4, PD-1, and PD-L1. In addition, whole transcriptome sequencing was performed on cells across a range of physiologically-relevant culturing conditions to mimic various tumor microenvironments found within the body.
Conclusions: We report that prostate cancer cell lines and PBMCs differentially express immunotherapeutic targets when cultured at physiologically relevant tumor microenvironment conditions, resulting in reduced expression of key targets. Analysis of mRNA-seq data revealed alterations in gene expression profiles of immunotherapeutic and drug-target pathways involving CTLA-4 and AR signaling. In contrast, we observed increased CD47 and CD44 expression at low oxygen and high pressure culturing conditions in cancer cell lines and PBMCs. These data highlight the importance of using physiologically relevant microenvironment conditions that include hypoxia and pressure to identify biomarkers and drug target candidates.
Citation Format: Bruce A. Adams, James Lim, Tianna Chow, Susan Bernstein, Charles J. Ryan. Characterizing the effects of hypoxia and hydrostatic pressure on the expression of immunotherapeutic targets in prostate cancer cell lines and donor immune cells in culture. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B06.
Abstract B19: Vascular normalization suppresses tumor progression and potentiates docetaxel chemotherapy in prostate cancer
Authors: Kang You Hyun , Jin Hyun A , Heo Jun Hyeok , Kim Ki Hong , Han Kyung Seok , Hong Sung Joon 
Published: October 2016

Abstract
Background: Tumor requires excessive oxygen and nutrients due to their rapid growth. Tumor is generally vascular but the vasculature is not physiologic but leaky, dilated, and tortuous. The inefficiency of tumor vessels induces hypoxic stress that makes the tumor more aggressive. Here, we investigated the role of normalizing tumor vasculature on tumor progression and treatment efficacy of conventional chemotherapy in prostate cancer.
Methods: Human vascular endothelial cell (HUVEC) was used to evaluate the effects of SAC-1004 on endothelial cells. Immunofluorescent confocal imaging with immunocytochemistry was performed for E-cadherin expression in HUVECs. MTS assay was performed to assess cell proliferation of HUVECs and PC-3 cells after SAC-1004 treatment. Immunohistochemical staining with anti-CD31 and anti-SMA antibodies was performed to assess vasculature in vivo. PC-3 subcutaneous xenografts were developed to evaluate the effects of SAC-1004 on tumor vasculature and tumor growth in prostate cancer. Magnetic resonance images were taken to assess vascular perfusion in xenografts. SAC-1004 was administrated via tail vein once a day for 7 days. Docetaxel was administrated intravenously once a week.
Results: SAC-1004 restored junction protein E-cadherin in vitro in endothelial cells and significantly reduced VEGF-induced retinal vascular leakage. SAC-1004 promoted proliferation of HUVECs in vitro in a dose-dependent manner. However, proliferation of cancer cells was not significantly affected by SAC-1004 treatment. Reduced vascular leakiness and improved hypoxia were found in PC-3 xenografts treated with SAC-1004 treatment and magnetic resonance imaging after SAC-1004 treatment for 7 days confirmed improved perfusion in the PC-3 xenografts treated with SAC-1004 compared with control. Interestingly, SAC-1004 treatment suppressed tumor growth in PC-3 xenografts but SAC-1004 followed by intravenous docetaxel treatment showed the most potent tumor suppression compared with control in PC-3 xenografts.
Conclusions: SAC-1004 improves hypoxic tumor microenvironment and restores abnormal leak vasculature of tumor by restoring endothelial cell junction in prostate cancer. Vascular normalization induced tumor regression and docetaxel combination following vascular normalization sensitized prostate cancer to docetaxel treatment.
Citation Format: You Hyun Kang, Hyun A Jin, Jun Hyeok Heo, Ki Hong Kim, Kyung Seok Han, Sung Joon Hong. Vascular normalization suppresses tumor progression and potentiates docetaxel chemotherapy in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B19.
Abstract B20: Obesity-induced Nlrc4 inflammasome promotes angiogenesis in breast cancer
Authors: Kolb Ryan , Phan Liem , Borcherding Nicholas , Liu Yinghong , Yuan Fang , Janowski Ann M. , Xie Qing , Markan Kathleen R. , Li Wei , Potthoff Matthew J. , Fuentes-Mattei Enrique , Ellies Leslie G. , Knudson Michael , Lee Mong-Hong , Yeung Sai-Ching Jim , Cassel Suzanne L. , Sutterwala Fayyaz S. , Zhang Weizhou 
Published: October 2016

Abstract
Obesity, which impacts 36% of adults in the U.S., is associated with an increased risk of ER-positive breast cancer in postmenopausal women, increased incidence of the more aggressive triple negative breast cancer, increased risk of developing invasive ductal carcinoma (IDC) versus ductal carcinoma in situ (DCIS; non-invasive) and a worse clinical outcome. There have been many hypotheses to explain this link between obesity and breast cancer, but a causal mechanism is still largely missing. Here, using two syngeneic orthotopic transplant models in C57Bl/6 mice, we examined the role of obesity-associated inflammasome activation/IL-1 signaling in obesity-driven breast cancer progression. Our results show that the tumor microenvironment under the conditions of obesity promotes Nlrc4 inflammasome activation in tumor-infiltrating myeloid cells, which in turn leads to IL-1β activation which promotes tumor progression. Further studies show that obesity-induced Nlrc4 inflammasome activation/IL-1β promotes increased angiogenesis and upregulation of Vegfa, primarily in adipocytes. Finally, treatment of mice with Metformin inhibited obesity-associated angiogenesis and breast cancer progression. This data provides evidence for obesity-induced Nlrc4 inflammasome mediated activation of IL-1β as a causal mechanism for obesity-driven breast cancer progression and a rationale for blockade of IL-1 signaling, the use of anti-angiogenesis therapies, or treatment with metformin in obese breast cancer patients.
Citation Format: Ryan Kolb, Liem Phan, Nicholas Borcherding, Yinghong Liu, Fang Yuan, Ann M. Janowski, Qing Xie, Kathleen R. Markan, Wei Li, Matthew J. Potthoff, Enrique Fuentes-Mattei, Leslie G. Ellies, Michael Knudson, Mong-Hong Lee, Sai-Ching Jim Yeung, Suzanne L. Cassel, Fayyaz S. Sutterwala, Weizhou Zhang. Obesity-induced Nlrc4 inflammasome promotes angiogenesis in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B20.