bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3589: Adipose stem cell-derived interferon gamma alters breast epithelial stem cell hierarchy
Authors: Anjanappa Manjushree , Burnett Riesa M. , Merfeld-Clauss Stephanie , Wooden William A. , March Keith L. , Tholpady Sunil , Nakshatri Harikrishna 
Published: May 2015

Abstract
Autologous adipose stem cell transplantation is increasingly being used for soft tissue reconstruction, particularly after mastectomy. However, a recent study demonstrated recurrence of invasive ductal carcinoma in the breast within four months of autologous fat grafting. Previous studies have documented how cancer cells commandeer adipose stem cells (ASC) to support their survival by altering extracellular matrix composition and stiffness. This study focused on delineating the effects of ASCs on the self-renewal capacity of breast epithelial cells. The immortalized breast epithelial cell line MCF-10A, MCF-10A overexpressing Slug, and MCF-10A overexpressing SRC were examined using a mammosphere assay and flow cytometry for the effects of ASCs on their self-renewal and stem-luminal progenitor-differentiated cell surface marker profile. MCF-10A-Slug cells provided a unique model system to study breast epithelial cell dedifferentiation as Slug functions downstream of the breast cancer susceptibility gene BRCA1 and is a major suppressor of progenitor cell lineage commitment and differentiation. Interestingly, results with these established cell lines were reproduced in primary breast epithelial cells isolated from a high-risk patient. We show that secreted factors from ASCs promote self-renewal of all cell types examined. ASC co-culture or treatment with ASC conditioned media (CM) altered the number of CD49fhigh/EpCAMlow stem-like and CD49fmedium/EpCAMmedium luminal progenitor cells in 2D culture and mammosphere assays. ASCs secrete Interferon gamma (IFNγ), CD40 ligand, IL-23 and SERPINE1. Among these factors, only IFNγ treatment altered stem cell hierarchy; while MCF-10A-Slug cells displayed only luminal progenitor phenotype, cells treated with IFNγ contained a distinct stem-like cell population. These results suggest that paracrine activity of adipose stem cell-derived factors can either enhance dedifferentiation and promote proliferation of dormant tumor cells or predispose normal cells to transformation by blocking differentiation.
Financial support: Susan G. Komen For the Cure SAC110025 and Zeta Tau Sorority (HN)
Citation Format: Manjushree Anjanappa, Riesa M. Burnett, Stephanie Merfeld-Clauss, William A. Wooden, Keith L. March, Sunil Tholpady, Harikrishna Nakshatri. Adipose stem cell-derived interferon gamma alters breast epithelial stem cell hierarchy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3589. doi:10.1158/1538-7445.AM2014-3589
Abstract 3592: Macrophages confer resistance to cisplatin in MTLn3 and MDA-MB 231 breast cancer cells
Authors: Sabari Joshua K. , Cabrera Ramon , Segall Jeffrey 
Published: May 2015

Abstract
Drug resistance presents a clinical challenge to the treatment of breast cancer. Stromal cells such as macrophages may play a role in drug resistance. The purpose of this study is to examine the interaction between breast cancer cells and macrophages and its effects on drug therapy resistance. The five-year survival for localized hormone sensitive disease is 98% and as low as 15% for triple negative (ER/PR/Her2) and metastatic disease. Most targeted anticancer therapies, as well as cytotoxic therapies, are burdened by the development of cancer cell resistance. It is hypothesized that the tumor microenvironment may confer innate resistance to drug therapy. It is well established that chemotactic factors found in the tumor microenvironment can promote motility and invasion. We hypothesize that tumor associated macrophages can confer drug resistance to breast cancer cells via overexpression of epidermal growth factor (EGF). EGF is overexpressed in many tumor types and is clinically correlated with a poor overall prognosis. Previous studies have shown that EGF is produced by non-tumor cells in the microenvironment; in particular tumor-associated macrophages (TAM) and endothelial cells. We have previously shown that macrophages and tumor cells, via a paracrine loop, are necessary and sufficient for comigration and invasion. Breast cancer cells produce colony stimulating factor 1 (CSF-1) which positively feeds back to increase macrophage expression of EGF. Increased EGF expression in turn leads to tumor growth and invasion. We selected two triple negative breast cancer cell lines, MDA-MB 231 (human mammary adenocarcinoma) and MTLn3 (rat mammary adenocarcinoma) that were transfected to express GFP. Co-culture cell survival assays were performed with macrophages, fibroblasts, and endothelial cells. All tissue culture was completed in DMEM (HyClone) plus 10% FBS. Cells were grown for 24 hours in co-culture, treated with chemotherapy (doxorubicin or cisplatin at a range of concentrations) for 24 hours, and then analyzed at 72 hours using the DXP-10 Calibur analyzer. Prior to analysis, cells were again replated to measure “replating efficiency” i.e. chemoresistant cell survival. We found that coculture with macrophages increased tumor cell survival upon exposure to cisplatin. We conclude that macrophages are an important component of the tumor microenvironment that may play a role in chemotherapy resistance.
Citation Format: Joshua K. Sabari, Ramon Cabrera, Jeffrey Segall. Macrophages confer resistance to cisplatin in MTLn3 and MDA-MB 231 breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3592. doi:10.1158/1538-7445.AM2014-3592
Abstract 3598: Macrophage-derived reactive oxygen species suppress miR-328 targeting CD44 in gastrointestinal cancer cells and promote redox adaptation
Authors: Ishimoto Takatsugu , Yoshida Naoya , Sugihara Hidetaka , Izumi Daisuke , Miyake Keisuke , Sawayama Hiroshi , Imamura Yu , Iwagami Shiro , Baba Yoshifumi , Baba Hideo 
Published: May 2015

Abstract
Background: CD44 has recently been identified as one of the cell surface markers associated with cancer stem cells (CSCs) in several types of tumor. We have reported the functional role of CD44 variant isoform in the maintenance of low reactive oxygen species (ROS) levels in gastrointestinal cancer cells. While, microRNA (miRNA) is involved in the pathogenesis of many cancers and the networks of miRNA regulate CSCs properties. However, the mechanism underlying the miRNA in the regulation of CSC marker is mostly unrevealed. Objectives: The aim of this study was to investigate the regulation of CD44 expression by miRNAs and to develop newmolecular targets in gastrointestinal cancer. Methods and Results: To investigate the mechanism in the regulation of CD44, We performed miRNA screening in six human gastrointestinal cancer cell lines and identified three candidate miRNAs that could regulate CD44 expression in gastrointestinal cancer. Among these, we focused on miR-328 and examined its functional relevance using growth assays and cytotoxicity assays. CD44 expression was reduced in gastrointestinal cancer cell lines forced to express miR-328, leading to inhibition of cancer cell growth in vitro and in vivo, and impaired resistance to chemotherapeutic drugs and reactive oxygen species (ROS). In contrast, induction of CD44 expression by miR-328 inhibitor led to promotion of cancer cell growth. Furthermore, we revealed that ROS produced by macrophages triggered CD44 expression through suppression of miR-328 in gastric cancer cells. Finally, tumor-infiltrating macrophages (CD68 and CD163) were closely related to both miR-328 down-regulation and CD44 up-regulation in 63 patients with surgically-resected gastric cancer. Conclusions: Macrophages in the tumor microenvironment may cause increased CD44 expression through miR-328 suppression, resulting in tumor progression by enhancing ROS defense. miR-328-CD44 signaling mediated by macrophages may thus represent a potential target for the treatment of gastrointestinal cancer.
Citation Format: Takatsugu Ishimoto, Naoya Yoshida, Hidetaka Sugihara, Daisuke Izumi, Keisuke Miyake, Hiroshi Sawayama, Yu Imamura, Shiro Iwagami, Yoshifumi Baba, Hideo Baba. Macrophage-derived reactive oxygen species suppress miR-328 targeting CD44 in gastrointestinal cancer cells and promote redox adaptation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3598. doi:10.1158/1538-7445.AM2014-3598
Abstract 3601: Stromal fibroblasts mediate extracellular matrix remodeling and invasion of scirrhous gastric carcinoma cells
Authors: Yamaguchi Hideki , Yanagihara Kazuyoshi , Yashiro Masakazu , Sakai Ryuichi 
Published: May 2015

Abstract
Scirrhous gastric carcinoma (SGC; also called diffusely infiltrative carcinoma, Borrmann's type-IV carcinoma, or the linitis plastica-type carcinoma) has the worst prognosis of all gastric cancers, owing to its rapid expansion by invasion and frequent peritoneal dissemination. Due to the increased proliferation of stromal fibroblasts (SFs) that occurs within SGC lesions and the peritoneal metastatic sites, SFs have been proposed to support the progression of this disease. However, the biological and molecular basis and the pathological role of the intercellular interaction between SGC cells and SFs remain largely unknown. In this study, we investigated the role of SFs in the invasion of the extracellular matrix (ECM) by SGC cells. When SGC cells were cocultured with SFs derived from SGC tissue on three-dimensional (3D) Matrigel, they were attracted together to form large cellular aggregates that invaded within the Matrigel. Time-lapse imaging revealed that this process was associated with extensive contraction and remodeling of the ECM. Immunofluorescence and biochemical analysis showed that SGC cells stimulate phosphorylation of myosin light chain and actomyosin-mediated mechanical remodeling of the ECM by SFs. By utilizing this assay system for inhibitor library screening, we have identified several inhibitors that potently suppress the cooperation between SGC cells and SFs to form the invasive structures. Among them, a Src inhibitor dasatinib impaired the interaction between SGC cells and SFs both in vitro and in vivo and effectively blocked peritoneal dissemination of SGC cells. These results indicate that SFs mediate mechanical remodeling of the ECM by SGC cells, thereby promoting invasion and peritoneal dissemination of SGC.
Citation Format: Hideki Yamaguchi, Kazuyoshi Yanagihara, Masakazu Yashiro, Ryuichi Sakai. Stromal fibroblasts mediate extracellular matrix remodeling and invasion of scirrhous gastric carcinoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3601. doi:10.1158/1538-7445.AM2014-3601
Abstract 3602: PTEN dependent angiogenesis is mainly regulated by (tumor secreted-) uPAR
Authors: Unseld Matthias , Chilla Anastasia , Pausz Clemens , Breuss Johannes , Schabbauer Gernot , Prager Gerald 
Published: May 2015

Abstract
Tumor stroma crucially influences the growth of most epithelial tumors and is in focus of many therapeutic approaches. Several oncogenes and tumor suppressors coordinate complex signaling cascades in the tumor and its microenvironment. In this context, downregulation of the tumor suppressor PTEN was shown to be indispensable for (tumor-)angiogenesis and cancer outgrowth. However, the essential process leading to PTEN downregulation, favouring a pro-angiogenic phenotype, in tumor vasculature is unknown so far. Here we show that PTEN-dependent angiogenesis is centrally affected by tumor- secreted soluble uPAR. In detail, the presence of uPAR significantly influenced the levels of PTEN in vitro and in vivo. Endothelial cell stimulation with tumor- derived soluble uPAR remarkable decreased PTEN levels, which led to increased cell migration, enhanced wound healing as well as capillary-sprouting in vitro and enhanced endothelial cell invasion and functional vessel formation in a directed-in vivo angiogenesis assay. uPAR- derived PTEN regulation was not mediated via mRNA stability or decrease in PTEN degradation, but via regulation of PTEN transcription as revealed by actinomycin D experiments. uPAR thereby interacted with αv integrins, which enhanced FAK activation and - as a consequence - led to NFkB-dependent PTEN repression. Finally, the biological relevance of uPAR- dependent PTEN regulation was evaluated and confirmed via uPAR -/- crossbreds with either PTEN +/- or PTEN +/+ mice. Our results provide first evidence of the role of tumor-derived uPAR in regulation of the central phosphatase PTEN in angiogenic cell behaviour. Our findings give novel insights into the complex mechanism of the tumor- microenvironmental interaction and might lead to new therapeutic strategies in cancer.
Citation Format: Matthias Unseld, Anastasia Chilla, Clemens Pausz, Johannes Breuss, Gernot Schabbauer, Gerald Prager. PTEN dependent angiogenesis is mainly regulated by (tumor secreted-) uPAR. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3602. doi:10.1158/1538-7445.AM2014-3602
Abstract 3605: The inhibitor of NF-ĸB kinase, IKKβ, regulates the stability of GLI1 transcription factor
Authors: Agarwal Nitin K. , Kunkalla Kranthi , Vega Francisco 
Published: May 2015

Abstract
Lymphoma microenvironment has a crucial role in lymphoma initiation, progression and drug resistance. Fibroblastic reticular cells (FRCs) participate dynamically in the cytokine microenvironment of the lymph node paracortex as well as the regulation of cell trafficking and access of T-cells into the paracortex. The FRC niche also participates in the cytokine microenvironment of lymphomas providing homing and survival signals including CCL19, CCL21, IL-7, CXCL12 and hedgehog (Hh) ligands. Hh signaling is evolutionary conserved signaling pathway that serves several physiological and development processes mediated by externally secreted Hh ligands. We previously demonstrated that the canonical Hh ligand-PTCH1-SMO-GLI axis is functional and contributes to cell survival, proliferation and enhances chemo tolerance in DLBCL. We further showed that GLI1, Hh signaling transcription factor is aberrantly activated in ∼87% of DLBCL and this activation is in part mediated by sonic Hh ligands secreted by stromal cells. Although the importance of GLI1 in tumor development is well recognized, the molecular mechanisms controlling the transcriptional activity of GLI1 is limited. To identify regulatory components that participate in the transcriptional activity of GLI1, we explored GLI1 putative interacting proteins by liquid chromatography tandem mass spectrometry following immunoprecipitation of endogenous GLI1. We identified the inhibitor of NF-ĸB kinase, IKKβ as a novel GLI1-binding protein. In addition, we found that the kinase activity of IKKβ is critical to recruit and phosphorylate GLI1 in the C-terminal fragment. We further showed that in DLBCL cells stimulated with TNFα, IKKβ phosphorylates GLI1 and restricts the binding between GLI1 with HECT-type E3 ubiquitin ligase (ITCH) resulting in GLI1 stability and increased oncogenic potential. Inhibition of IKKβ-mediated GLI1 phosphorylation restored the binding between GLI1 and ITCH and promoted ubiquitination and degradation of GLI1. Collectively, these results indicate that IKKβ regulates the transcriptional activity of GLI1 by phosphorylating GLI1 and modulating the binding between GLI1 and ITCH. In DLBCL, canonical NF-κB and GLI1 mediated Hh signaling pathways are strongly responsive with tumor microenvironment; our study will help to understand the cross talk between these two pathways which could represents a novel therapeutic approach for DLBCL.
Citation Format: Nitin K. Agarwal, Kranthi Kunkalla, Francisco Vega. The inhibitor of NF-ĸB kinase, IKKβ, regulates the stability of GLI1 transcription factor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3605. doi:10.1158/1538-7445.AM2014-3605
Abstract 3607: Modulation of neuroblastoma metabolism by an extracellular chaperone SPARC
Authors: Chlenski Alexandre , Dobratic Marija , Salwen Helen R. , Applebaum Mark , Cohn Susan L. 
Published: May 2015

Abstract
Secreted Protein Acidic and Rich in Cysteine (SPARC) is an extracellular matrix protein with diverse biologic functions. We have shown that SPARC is a scavenger chaperone that regulates matrix degradation, remodeling, and repair. We have also demonstrated that SPARC blocks angiogenesis and inhibits the growth of several cancers, including neuroblastoma. In this study we examined how extracellular chaperone SPARC affects neuroblastoma tumor progression.
The chaperone properties of SPARC were characterized with cell biology methods and Surface Plasmon Resonance. Neuroblastoma cell lines derived from the high-risk tumors were treated with SPARC. The effect of SPARC on cancer cell metabolism was characterized using the Seahorse analyzer with and without inhibitors of glycolysis and mitochondrial oxidation. Standard cell culture techniques were used to assess the effect of SPARC-induced metabolic changes on neuroblastoma cell proliferation and survival.
We demonstrate that SPARC functions as a chaperone, shuttling extracellular ligands between cellular and extracellular tissue compartments. We characterize physical and biological properties of SPARC-mediated ligand transport, and further demonstrate that as a chaperone, SPARC can significantly affect tissue physiology, to the degree of altering cell metabolism. We show that in addition to inhibition of neuroblastoma progression in vivo, SPARC-induced changes in cellular metabolism severely impair neuroblastoma growth and survival in vitro.
This novel mechanism of metabolism regulation by an extracellular chaperone SPARC may lead to additional insights into the therapy of neuroblastoma.
Citation Format: Alexandre Chlenski, Marija Dobratic, Helen R. Salwen, Mark Applebaum, Susan L. Cohn. Modulation of neuroblastoma metabolism by an extracellular chaperone SPARC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3607. doi:10.1158/1538-7445.AM2014-3607
Abstract 3610: High stromal S100A9 expression serves an early oral cancer recurrence marker possibly through enhancing cancer cell invasivenes, angiogenesis, and differentially recruiting infiltrating immune cells
Authors: Wu Li-Wha 
Published: May 2015

Abstract
S100A9 belongs to S100 family with Ca+2-binding EF-hands in both N- and C-termini and is frequently deregulated in several cancer types. Consistent with this notion, we identified the increase of S100A9 mRNA expression by 2.6 fold (p&lt;0.01) in oral cancer cells when compared to normal oral keratinocytes using DNA microarray analysis. The increase of S100A9 protein validated in clinical tissue specimens was also detected in the adjacent tumor stroma, especially in CD15+ or CD68+ immune infiltrates. High S100A9 expression in the stroma was positively associated not only with the poor differentiation of tumor but also tumor recurrence. Moreover, high stromal S100A9 expression in early-stage patients had shorter recurrence-free survival, suggesting a role of S100A9 in oral cancer recurrence. Although altering the expression of S100A9 affected cell proliferation depending on the cell lines, S100A9 functioned as a promoting molecule for cell migration and invasion. Moreover, S100A9 secreted from oral cancer cells inhibited anti-inflammatory IL-10 production and acted as positive regulator in angiogenesis. Ectopic S100A9 expression promoted subcutaneous tumorigenesis in vivo with the enhanced recruitment of a CD11c+ myeloid cells and production of several inflammatory cytokines. The serum concentration of S100A9, a secretable protein, was significantly increased in early-stage but not late stage oral cancer patients. Together, stromal S100A9 plays a tumor-promoting role in oral carcinogenesis and serum S100A9 may serve as an early marker for cancer recurrence. Understanding the potential role of S100A9 in oral cancer and stromal cells should facilitate the development of new therapeutic approaches for oral cancer treatment.
Citation Format: Li-Wha Wu. High stromal S100A9 expression serves an early oral cancer recurrence marker possibly through enhancing cancer cell invasivenes, angiogenesis, and differentially recruiting infiltrating immune cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3610. doi:10.1158/1538-7445.AM2014-3610
Abstract 3611: Stromal transforming growth factor-beta 1 is crucial for reinforcing the invasive potential of low invasive cancer
Authors: Hwang Young Sun , Park Kwang-Kyun , Chung Won-Yoon 
Published: May 2015

Abstract
Comparative analyses of gene expression profiles between metastatic and non-metastatic cells have revealed that various genes are differentially expressed in association with the metastatic potential of cancer cells. Interactions between tumor cells and their adjacent microenvironment are intimately associated with tumor growth and the development of metastasis. Cancer-associated fibroblasts (CAFs) are a source of various paracrine and autocrine growth factors that regulate growth of surrounding cells as well as themselves. Thus, there is an increasing interest to study CAFs as drug targets for anticancer therapies.
In the present study, we investigated the existence of molecular crosstalk between cancer cells and surrounding stromal cells to reinforce the invasive potential of low invasive cancer. Molecular crosstalk between cancer cells and tumor microenvironment components suggests potential targets for new therapeutic approaches.
Material and methods: Isolated normal fibroblasts (NFs) or CAF was co-cultured with low invasive HSC-2 cells to evaluate whether stromal TGF-β1 induced PDPN expression by Transwell invasion and influenced tumor growth in orthotopic xenografts.
Results: Stimulation by TGF-β1 promoted PDPN expression and Transwell invasion through SMAD signaling as well as activation of Src, P38 mitogen activated protein kinase, and extracellular regulated kinase 1/2. PDPN induction was TβRII-dependent. Tumor growth of HSC-2 OSCC in a mouse orthotopic xenograft was intensified in the tumor CAF microenvironment.
Conclusions: Stromal TGF-β1 signaling promoted PDPN expression in cancer cells, thereby enhancing tumor growth and leading to a more invasive phenotype.
Citation Format: Young Sun Hwang, Kwang-Kyun Park, Won-Yoon Chung. Stromal transforming growth factor-beta 1 is crucial for reinforcing the invasive potential of low invasive cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3611. doi:10.1158/1538-7445.AM2014-3611