bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B38: Altered p53 status confers molecular subtype-dependent distinct interactions with fibroblasts in breast cancer
Authors: Sandhu Rupninder , D'Arcy Monica , Troester Melissa A. 
Published: May 2015

Abstract
Different molecular subtypes of breast cancer have distinct interactions with stromal and immune cells in the cancer microenvironment. However, the role of specific somatic mutations in mediating stromal interactions is not well understood. Conversely, the role of stromal interactions in modulating the biological effects of tumor genetic events is understudied. This project hypothesized that (a) p53 mutations may modulate stromal-epithelial interactions, and (b) stromal-epithelial interactions may potentiate the effects of p53 loss. The p53 gene is mutated in 50% of breast cancers, with 84% of basal-like breast cancers harboring p53 mutations, compared to just 12-32% of luminal breast cancers. The influence of p53 loss on stromal-epithelial interactions across different molecular subtypes may have important implications for tumor progression. To study how gene expression of fibroblast-epithelial cocultures differ in luminal vs. basal-like breast cancers as a function of p53 status, we employed RNAi-mediated p53 knockdown (KD) in a panel of four epithelial cell lines (two basal-like, two luminal). Cocultures were carried out with p53-wildtype or KD cell lines maintained in direct physical contact with fibroblasts for 48 hours before RNA isolation. Results of gene expression analysis show that p53 knockdown significantly altered cell-cell interactions in a subtype-specific manner. Comparing cocultures of p53-wildtype to cocultures of p53 KD basal-like cells, we identified 1600 genes whose expression was significantly altered. Among luminal breast cancer cocultures, the impact of p53 loss on gene expression was far more limited, with no genes identified at the same level of significance. Among basal-likes, p53 loss-associated gene expression occurred in immune response pathways, including IL-8 signaling, IL-15 signaling LXR/RXR activation, TREM1 signaling, B cell receptor signaling. In addition, Wnt/β-catenin Signaling was altered in coculture due to p53 loss. Other recent studies have indicated that p53 may modulate Wnt signaling and EMT via a microRNA-dependent mechanism, and these findings suggest that the p53-Wnt axis is also modulated by stromal-epithelial interactions. These observations strongly suggest that the interactions of epithelial cells with fibroblasts are significantly affected by p53 status. Given the high frequency of basal-like tumors with p53 mutations, it is important to understand how stromal-epithelial interactions potentiate the effects of p53 loss.
Citation Format: Rupninder Sandhu, Monica D'Arcy, Melissa A. Troester. Altered p53 status confers molecular subtype-dependent distinct interactions with fibroblasts in breast cancer. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B38. doi:10.1158/1538-7445.CHTME14-B38
Abstract B49: Molecular characterization of breast tumor-associated adipose
Authors: Yarina William C. , Field Lori A. , Deyarmin Brenda , Laar Ryan van , Hooke Jeffrey A. , Shriver Craig D. , Ellsworth Rachel E. 
Published: May 2015

Abstract
Background: Long thought to function only as an inert energy storage depot, the role of adipose tissue in breast tumorigenesis has been largely ignored. In light of increasing rates of obesity and use of breast conserving therapy and autologous fat grafting, improved understanding of the role of adipose in tumor etiology is crucial.
Methods: Adipose adjacent to and distant from invasive breast tumors (n=20), or adjacent to non-malignant diagnoses (n=20) was laser microdissected from post-menopausal women. Gene expression data were generated using microarrays and data analyzed to identify significant patterns of differential expression between adipose groups, at the individual gene and molecular pathway level.
Results: Pathway analysis revealed significant differences in immune response between non-malignant, distant and tumor adjacent adipose, with the highest response in tumor-adjacent and lowest in non-malignant adipose. Adipose from invasive breasts exhibits increased expression in anti-inflammatory genes, such as MARCO and VSIG4, while genes differentially expressed between tumor-adjacent and distant adipose such as SPP1, RRM2 and MMP9, are associated with increased cellular proliferation, invasion, and angiogenesis.
Conclusions: Gene expression levels differ in breast adipose, depending on presence of or proximity to tumor cells. Heightened immunotolerance in adipose from invasive breasts provides a microenvironment favorable to tumorigenesis. In addition, tumor-adjacent adipose demonstrates expression of genes associated with tumor growth and progression. Together, these data suggest that adipose is not an inert component of the breast microenvironment but plays an active role in tumorigenesis.
Citation Format: William C. Yarina, Lori A. Field, Brenda Deyarmin, Ryan van Laar, Jeffrey A. Hooke, Craig D. Shriver, Rachel E. Ellsworth. Molecular characterization of breast tumor-associated adipose. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B49. doi:10.1158/1538-7445.CHTME14-B49
Abstract B50: Visualizing intercellular transfer of hypoxia-induced exosomal miR-210 between breast cancer cells
Authors: Jung Kyung Oh , Kim Young-Hwa , Chung June-Key , Youn Hyewon 
Published: May 2015

Abstract
Purpose: Cancer cells actively release exosomes containing many functional proteins, mRNA, and miRNA to communicate with tumor microenvironment, providing a novel mechanism of paracrine signaling between the tumors and surrounding tissues. In this study, we visualized exosome-mediated transfer of miR-210 between breast cancer cells .
Methods: Mouse breast cancer cell lines, 4T1, were transfected with pCMV-luc2/miR-210 reporter vector which was designed to be turned off its luciferase signal by binding of miR-210. Hypoxia was induced by Deferoxamine Mesylate (DFO). Exosomes were characterized by western blot (Alix, CD63, and CD9) and TEM. Exosomes from hypoxic conditions were isolated and treated to normoxic breast cancer cells. Real-time PCR was performed to compare levels of miR-210. Luciferase activity was measured by luciferase activity assay and bioluminescence imaging. Immunohistochemistry was performed with antibodies of HIF-1a, luciferase, and Ephrin-A3.
Results: Amount of isolated exosome from hypoxic condition was 1.4 fold more than that of normoxic condition. Expression of miR-210 was increased in 15.70 and 12.73 fold in hypoxic cells and exosomes, respectively. Luciferase activity and bioluminescence imaging signal intensity of the cells treated with hypoxic exosome were significantly decreased at 0.50 and 0.67 fold compare to that of untreated cells. In xenograft models, luciferase signals of tumor treated hypoxic exosomes were also decreased in 0.56 fold. Luciferase was decreased in the tumor tissues treated with hypoxic exosomes, and the expression of Ephrin-A3, a target of miR-210, was also decreased in tumor tissues treated hypoxic exosome.
Conclusions: Reporter gene imaging system for monitoring hypoxia-induced miR-210 successsfully demonstrated the exosome-mediated intercellular transfer of miR-210 in vitro and in vivo.
Citation Format: Kyung Oh Jung, Young-Hwa Kim, June-Key Chung, Hyewon Youn. Visualizing intercellular transfer of hypoxia-induced exosomal miR-210 between breast cancer cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B50. doi:10.1158/1538-7445.CHTME14-B50
Abstract B51: SOCS3 deficiency in myeloid cells promotes prostate tumor development
Authors: Yu Hao , Liu Yudong , Deshane Jessy , Benveniste Etty (Tika) , Qin Hongwei 
Published: May 2015

Abstract
Suppressor Of Cytokine Signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway, and have been implicated as functioning as tumor suppressors, particularly SOCS3. We have previously demonstrated that specific deletion of SOCS3 in myeloid cell leads to heightened activation of STAT3 and downstream STAT3 target gene expression. STAT3 activation has been strongly implicated in contributing to prostate cancer progression and metastasis. STAT3 signaling in myeloid cells has been demonstrated to attenuate anti-tumor immunity. Thus, we evaluated the impact of SOCS3 deletion in myeloid cells in a murine prostate tumor model. We demonstrate that prostate tumor growth is significantly enhanced in myeloid-specific SOCS3-deficient mice, which correlates with elevated levels of Myeloid Derived Suppressor Cells (MDSC) in both the spleen and tumor microenvironment, and less CD8+ T-cell infiltration in tumors. Furthermore, SOCS3-deficient bone-marrow-derived mononuclear cells exhibit heightened STAT3 activation and are preferentially differentiate into MDSC phenotype. Importantly, we identify granulocyte-colony stimulating factor (G-CSF) as a critical factor secreted by the prostate tumor microenvironment that promotes development of Gr-1+CD11b+ cells via a STAT3-depentent pathway. Abrogation of tumor-derived G-CSF reduced the proliferation and accumulation of Gr-1+CD11b+ cells and inhibited prostate tumor growth. Therefore, the tumor-derived cytokine, G-CSF, is a prospective candidate upstream of the STAT3/SOCS3 pathway in MDSC differentiation from the bone marrow. These findings highlight the critical function of SOCS3 as a negative regulator of MDSC development and function, which may contribute to tumor suppressor attributes of SOCS3.
Citation Format: Hao Yu, Yudong Liu, Jessy Deshane, Etty (Tika) Benveniste, Hongwei Qin. SOCS3 deficiency in myeloid cells promotes prostate tumor development. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B51. doi:10.1158/1538-7445.CHTME14-B51
Abstract B58: Visualization of ERK and PKA activities in the tumor microenvironment comprising of lung-metastasized 4T1 murine breast tumor cells
Authors: Kamioka Yuji , Matsuda Michiyuki 
Published: May 2015

Abstract
Tumor microenvironment comprising of fibroblasts, endothelial cells, immune cells and tumor cells play critical roles in the tumor development. The complexities and dynamic changes of interactions among the constituting cells hampers comprehensive understanding of tumor microenvironment by conventional methods such as immunohistochemistry of tissue or biochemical analyses. Recently, intravital imaging have been providing unprecedented insight into tumor microenvironment. From the perspective of imaging, fluorescent imaging based on the principle of Förster resonance energy transfer (FRET) provides important information about cellular events that cannot be obtained by other methods. Genetically-encoded FRET biosensors have been widely used in biology to visualize the spatiotemporal dynamics of signaling molecules. Despite the increasing multitude of these biosensors, their application has been mostly limited to cultured cells with transient biosensor expression, due to difficulties in stable expression of FRET biosensors. We have recently reported the efficient generation of transgenic mouse lines expressing heritable and functional biosensors for ERK and PKA. These transgenic mice were generated by the cytoplasmic co-injection of Tol2 transposase mRNA and a circular plasmid harboring Tol2 recombination sites. Observation of these transgenic mice by two-photon excitation microscopy enabled us to visualize the activities of ERK and PKA in live tissues. Here, we report the visualization of ERK and PKA activities in 4T1 mammary tumor cells metastasized to lung tissue, which enabled us to observe effect of tumor microenvironment. We have also developed the imaging system to stabilize the live lung tissue to obtain stable images with the reduction of image blurring caused by breathing. We hereby demonstrate the utility of a three-dimensional, intravital FRET imaging technique toward understanding the mechanisms underlying tumor invasion and metastasis.
Citation Format: Yuji Kamioka, Michiyuki Matsuda. Visualization of ERK and PKA activities in the tumor microenvironment comprising of lung-metastasized 4T1 murine breast tumor cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B58. doi:10.1158/1538-7445.CHTME14-B58
Abstract B64: Alternagin-C, an α2β1 integrin-binding disintegrin-like protein, induces distinct cell responses in fibroblasts, tumor breast and endothelial cells in vitro
Authors: Santosa Lívia Mara , Vieira Tamires de Castro , Selistre-de-Araújo Heloísa Sobreiro 
Published: May 2015

Abstract
Reciprocal interactions between tumor, stromal cells and the extracellular matrix (ECM) are considered crucial steps for tumor development and progression. Both tumor and stromal cells secrete metalloproteases (MMPs) that modify the tumor microenvironment by degrading the ECM and releasing growth factors that may induce tumor cell proliferation, migration and invasion. MMPs activation is stimulated by co-activation of integrins, major cell-surface adhesion receptors. Disintegrins are strong integrin inhibitors found in snake venoms and used as prototypes for angiogenesis inhibitors. Alternagin-C (Alt-C), a disintegrin-like, Cys-rich protein isolated from Bothrops alternatus snake venom, has strong affinity for α2β1 integrin. ALT-C inhibited adhesion to collagen I of a variety of tumor cell lines, and in low concentrations, it induces VEGF expression and angiogenesis in an in vivo matrigel model. However, its mechanism of action was not very clear and it seems to depend on the cell type. Here, we show that ALT-C inhibited MMP-9 activity and mRNA expression in human breast cancer (MDA-MB-231) and MMP-2 activity in human micro vascular endothelial cells (HMEC-1) conditioned media from monocultures. ALT-C also increased the expression of angiogenic genes such as VEGF-A in fibroblasts and tumor cells but not in HMEC-1. However, ALT-C upregulated c-MYC mRNA expression only in tumor cells. ALT-C (10, 40, 100 and 1000 nM) also inhibited transendothelial migration of MDA-MB-231 cells through a monolayer of HMEC-1. In conclusion, these results suggest that α2β1 integrin binding by ALT-C may induce distinct effects in different cell lines by modulating MMP activity and stimulating the expression of angiogenic factors that influence tumor progression. These results may be very useful for medical and biotechnological applications in the development of anti-angiogenic and anti-metastatic therapies.
Support: FAPESP, CNPq, CAPES (Brazil)
Citation Format: Lívia Mara Santosa, Tamires de Castro Vieira, Heloísa Sobreiro Selistre-de-Araújo. Alternagin-C, an α2β1 integrin-binding disintegrin-like protein, induces distinct cell responses in fibroblasts, tumor breast and endothelial cells in vitro. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B64. doi:10.1158/1538-7445.CHTME14-B64
Abstract B78: Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signaling
Authors: Wever Olivier De , Boeck Astrid de 
Published: May 2015

Abstract
Objective: Bone marrow-derived mesenchymal stem cell (BM-MSC) migrate to primary tumors and drive tumor progression. This study aimed to identify the molecular mechanisms associated with these heterotypic cellular interactions and analyse their relevance in colorectal cancer (CRC).
Design: Paracrine interactions of BM-MSC and tumor-derived mesenchymal cells (T-MC) with CRC cells were studied using collagen invasion assays, cell counts, flow cytometric cell-cycle analysis and tumor xenograft models. The role of neuregulin 1 (NRG1) and the human epidermal growth factor receptor (HER) family pathways were investigated using tyrosine kinase assays, mass spectrometry, pharmacological inhibition, antibody-mediated neutralisation and RNA interference. Transmembrane NRG1 (tNRG1), HER2 and HER3 expression was analysed in primary CRCs (n = 54), adjacent normal colorectal tissues (n = 4), liver metastases (n = 3) and adjacent normal liver tissues (n = 3) by immunohistochemistry.
Results: BM-MSC and T-MC stimulate invasion, survival and tumorigenesis of CRCs through release of soluble NRG1, activating the HER2/HER3-dependent PI3K/AKT signaling cascade in CRC cells. Mesenchymal cells in primary CRCs demonstrate high tNRG1 expression. HER2 and HER3 show membrane localization in cancer cells of CRC tissue. High stromal tNRG1 expression is significantly associated with advanced UICC stage (P = .005) and invasion depth (P = .04) and decreased 5-year progression-free-survival (PFS) (P = .01).
Conclusion: Paracrine NRG1/HER3 signals initiated by BM-MSC and T-MC promote CRC cell progression, and high tNRG1 expression is associated with poor prognosis.
Citation Format: Olivier De Wever, Astrid de Boeck. Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signaling. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B78. doi:10.1158/1538-7445.CHTME14-B78
Abstract B79: TIMP-2 mediated growth inhibition of human glioma U87MG is accompanied by elevated IGFBP7 and FSP-1/S100A4 expression at the tumor/stroma interface
Authors: Jensen-Taubman Sandra , Bourboulia Dimitra , Han Huiying , Moss Laurie Shuman , Wei Beiyang , Stetler-Stevenson William G. 
Published: May 2015

Abstract
The tissue inhibitor of matrix metalloproteinase–2 (TIMP-2) belongs to a small family of multifunctional secreted proteins that inhibit matrix metalloproteases (MMPs), proteases principally associated with promoting tumor invasion and metastasis. We have previously shown that forced TIMP-2 expression inhibits human lung tumor growth through MMP-independent mechanisms including tumor cell apoptosis and upregulation of insulin growth factor binding protein-7 (IGFPB7), a protein reported to function as a potential tumor suppressor in a variety of tumor types including human glioma. In the current study, we used immunohistochemistry, TUNEL assay, and dual immunofluorescence to assess the growth inhibitory effects of TIMP-2 in human glioma xenografts generated using U87MG cells lentivirally transfected to overexpress the human TIMP-2 cDNA sequence (U87MG-T2) or vector alone (U87MG-EV). Compared to EV controls, U87MG-T2 xenografts demonstrated a significant inhibition of tumor growth, accompanied by increased tumor cell apoptosis at the tumor edge. Moreover, a dramatic increase in IGFBP7 and fibroblast specific protein-1 (FSP1)/S100A4 was detected in distinct subpopulations of non-tumor cells at the tumor/stroma interface, whereas both markers were sparsely observed in U87MG-EV controls. In an effort to determine the origin of IGFBP7 positive cells, we performed dual immunofluorescence using antibodies to the blood vessel marker CD34, FSP-1/S100A4, and human mitochondria (clone 113-1). IGFBP7 positive cells did not co-express any of the three markers analyzed, indicating that IGFBP7 positive cells are host derived and consist of cells other than blood vessels or stromal fibroblasts. We conclude that endogenous TIMP-2 significantly inhibits human glioma tumor growth in vivo through tumor cell apoptosis and tumor-host interactions involving discrete subsets of non-tumor cells in the adjacent tumor microenvironment.
Citation Format: Sandra Jensen-Taubman, Dimitra Bourboulia, Huiying Han, Laurie Shuman Moss, Beiyang Wei, William G. Stetler-Stevenson. TIMP-2 mediated growth inhibition of human glioma U87MG is accompanied by elevated IGFBP7 and FSP-1/S100A4 expression at the tumor/stroma interface. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B79. doi:10.1158/1538-7445.CHTME14-B79
Abstract IA03: Combinatorial targeting of endothelial growth factor pathways
Authors: Alitalo Kari K. 
Published: May 2015

Abstract
Solid tumors require blood vessels for growth and dissemination, and use lymphatic vessels as additional conduits for metastatic spread. The identification of growth factor receptor pathways regulating angiogenesis has led to clinical approval of the first anti-angiogenic molecules targeted against the vascular endothelial growth factor (VEGF)-VEGFR-2 pathway. However, in many cases resistance to anti-VEGF-VEGFR therapy occurs, and thus far the clinical benefit has been limited to only modest improvements in overall survival. Therefore, novel treatment modalities are required. I will discuss the other members of the VEGF-VEGFR family, as well as the angiopoietin growth factors and their Tie2 receptor as targets for the inhibition of tumor angiogenesis, lymphangiogenesis and metastasis. Our recent studies reveal that also the orphan receptor Tie1 is crucial for tumor angiogenesis and growth, but not for steady-state function of the vasculature. Combinatorial targeting of multiple vascular growth factor pathways shows promise for improving the efficacy of anti-angiogenic tumor therapy.
Citation Format: Kari K. Alitalo. Combinatorial targeting of endothelial growth factor pathways. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA03. doi:10.1158/1538-7445.CHTME14-IA03