bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5093: Fibulin-5 supports pancreatic tumor growth through inhibition of integrin-induced ROS
Authors: Topalovski Mary , Wang Miao , Moore Zachary , Boothman David , Brekken Rolf 
Published: July 2016

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a highly recalcitrant disease. One factor contributing to chemoresistance is thought to be the desmoplastic response seen in these tumors. Fibronectin (FN) is a major constituent of the desmoplastic reaction of PDA. It has been shown that integrin activation by fibronectin can induce reactive oxygen species (ROS) production by stromal cells. Increased ROS has been observed in many cancers, including PDA. Therefore, we propose that oxidation therapy is an attractive approach to increase chemoresponse in PDA as this strategy takes advantage of the sensitivity of these tumors to further ROS insults. We discovered that the matricellular protein Fibulin5 (Fbln5) is upregulated in PDA and reduces FN-mediated integrin-induced ROS production by competing with FN for binding to α5β1 integrin and blocking integrin-induced ROS production. Mutation of the RGD-integrin binding domain in Fbln5 to RGE abolishes the binding of Fbln5 to the integrin and increases integrin-induced ROS production. Fbln5RGE/RGE (RGE) mice, display reduced tumor growth in implant and genetic models of PDA (KIC and KPC) as a direct consequence of elevated ROS levels in the tumor microenvironment. Furthermore, ROS induction correlates with reduced angiogenesis in tumors from RGE animals and had an additive therapeutic effect when combined with standard therapy. We have identified multiple oxidative stress-responsive genes that are elevated in stromal fibroblasts isolated from tumors from RGE animals. One of the most promising targets is NAD(P)H dehydrogenase (quinone 1) (Nqo1). In support of this observation we found that the level of Nqo1 is significantly higher in RGE fibroblasts compared with WT fibroblasts when plated on FN but not collagen or plastic. Furthermore we have demonstrated that FN-mediated induction of ROS and Nqo1 is dependent on β1 integrin and 5-lipooxygenase (5-LOX). Our studies reveal a unique integrin-based mechanism to enhance ROS production to a level that is specifically toxic to the tumor by exploiting the tumor-specific expression of Fbln5. Current studies are focused on understanding the mechanism by which Fbln5 is induced in PDA.
Citation Format: Mary Topalovski, Miao Wang, Zachary Moore, David Boothman, Rolf Brekken. Fibulin-5 supports pancreatic tumor growth through inhibition of integrin-induced ROS. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5093.
Abstract 5105: Exosomes secreted by proinflammatory macrophages modulate breast cancer
Authors: Bednarczyk Robert Bronislaw , Tuli Neha Y. , Ben Rahoma Ghada , Maniyar Rachana , Mittelman Abraham , Tiwari Raj K. 
Published: July 2016

Abstract
Multiple cell types reside within the tumor microenvironment (TME) including cancer stem cells, stromal cells, and inflammatory cells. Cellular crosstalk is initiated between these cells through a variety of secreted biomolecules such as cytokines, growth factors, and exosomes. The role of inflammation and numerous secretory factors within the TME have been implicated in the development and progression of various cancers including breast. In this study, we wanted to evaluate the effect of macrophages (a major constituent of inflammation) on breast cancer development. Our study focused on macrophage secreted exosomes which are membraneous nanovesicles that contain various miRNA, mRNA, and proteins. We hypothesized that macrophage secreted exosomes will modulate breast cancer phenotype. An in vitro cell culture system was used in this study to examine macrophage exosome treatments on breast cancer cell lines MCF-7 (ER+) and MDA-MB 231 (ER-, PR-, HER2/neu-). Human monocytic THP-1 monocytes were activated with a common phorbol ester TPA (12-O-tetradecanoylphorbol-13-acetate) and conditioned media (CM) was collected following 48 h. Exosomes were isolated from THP-1 CM via the use of an exosome isolation reagent and standard centrifugation. Breast cancer cells were then treated with THP-1 exosomes and cell morphology, proliferation, MEK/ERK and PI3K/AKT signaling pathways, and cell cycle were evaluated. MCF-7 and MDA-MB 231 exhibited round and spindle-like morphologies as well as a significant decrease in proliferation at 24 h treatments. Furthermore, MDA-MB 231 displayed increased p-ERK, while MCF-7 showed increased p-MEK following Western blot analysis. Both cell lines exhibited decreased p-AKT and p-S6 kinase expression. Cell cycle analysis showed that MCF-7 and MDA-MB 231 arrested at G2/M at 24 h exosome treatments. THP-1 exosome treatments led to a significant increase in MDA-MB 231 senescence as determined by a senescence assay looking at senescence-associated beta-galactosidase. Increased p21 and decreased Cdc2/Cyclin B1 was also observed which indicates a G2/M arrest. We conclude that specific macrophage secreted exosomes may induce breast cancer cell senescence and affect breast cancer progression.
Citation Format: Robert Bronislaw Bednarczyk, Neha Y. Tuli, Ghada Ben Rahoma, Rachana Maniyar, Abraham Mittelman, Raj K. Tiwari. Exosomes secreted by proinflammatory macrophages modulate breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5105.
Abstract 5106: Unexpected roles for stromal MMP3 during breast cancer
Authors: Hartland Emilia , Jang Charley , Romero Moreno Ricardo , McGarel Megan , Badve Sunil , Littlepage Laurie 
Published: July 2016

Abstract
Matrix metalloproteinases (MMPs) are a family of proteases that have been shown to contribute to the degradation of components of the extracellular matrix and other substrates to promote cancer progression and metastasis. Stromelysin / matrix metalloproteinase-3 (MMP3) is one member of the matrix metalloproteinase family that is overexpressed in human breast cancer. During breast cancer, MMP3 is expressed primarily by stromal cells but also by cancer cells. Overexpression of MMP3 induces an epithelial-to-mesenchymal transition (EMT), promotes hyperplastic growth, and expands a mammary gland stem cell population. In addition, MMP3 is required for the mammary gland stem cell population. In this study, we determined if stromal MMP-3 is required for breast cancer progression for primary and metastatic lung tumor growth. To study this, we transplanted mammary epithelial cancer cells (V0PyMT) into the mammary glands of MMP3 knockout and heterozygous syngeneic mice. We quantified the tumor burden of both primary and metastastic tumors over time and discovered that elimination of stromal MMP3 increased the tumor burden. The tumor pathologies, proliferation rate, and apoptosis were similar between cancer and not cancer tissue. In contrast, the vasculature density decreased. These data suggest that stromal MMP3 inhibits, but is not required for, the development of the primary breast tumor. However, in contrast to our primary tumor data, we interestingly discovered that stromal MMP3 was required for visible lung metastases. These experiments begin to distinguish between the contrasting roles of stromal and epithelial MMP3 during breast cancer. Our data reveal that MMP3 contributes to the metastatic tumor formation within the lungs. This study will help to elucidate new mechanisms through which MMP3 functions within particular microenvironmental contexts during breast cancer progression.
Citation Format: Emilia Hartland, Charley Jang, Ricardo Romero Moreno, Megan McGarel, Sunil Badve, Laurie Littlepage. Unexpected roles for stromal MMP3 during breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5106.
Abstract 5113: CXCL12/CXCR4 and integrin signal activation by cancer-associated fibroblasts enhances the chemoresistance in gastric cancer
Authors: Tamaoki Yuka , Ishimoto Takatsugu , Miyake Keisuke , Izumi Daisuke , Kuroda Daisuke , Eto Tsugio , Arima Kota , Shigaki Hironobu , Kurashige Junji , Iwatsuki Masaaki , Baba Yoshifumi , Sakamoto Yasuo , Yoshida Naoya , Baba Hideo 
Published: July 2016

Abstract
Purpose: Gastric cancer (GC) is an aggressive cancer metastasizing with a high propensity for peritoneal dissemination and liver metastasis. Some studies have been shown that not only cancer cells but also their surrounding stroma, especially cancer-associated fibroblasts (CAFs) play an important role in tumor development. Previously, we reported that CXCL12-CXCR4 and integrin β1 signal activation by CAFs co-operates for promoting FAK phosphorylation and enhances the invasiveness of GC cells in extracellular matrix (ECM).On the other hand, a previous study presented that CXCR4 and integrin signaling co-operates in mediating adhesion and chemoresistance in small cell lung cancer cells. Therefore, we hypothesized that CXCL12-CXCR4 and integrin signal activation by CAFs enhances the chemoresistance in GC as well. The aim of current study is to elucidate the significance of CAFs mediating signal activation for chemoresistance in GCs.
Experimental Design: We first performed chemo-sensitive assays using GC cells cultured with fresh medium or with CAF-conditioned-medium (CM), and these experiments were conducted on non-coated and Matrigel-coated plates. Next, we examined the CXCL12-CXCR4 and integrin related signaling by western blotting analysis. Furthermore, we investigated the critical molecule for chemoresistance using silencing CXCR4 or integrin β1 in GC cells.
Results: Chemo-sensitive assays revealed that GC cells cultured with CAF-CM showed more resistant to cisplatin and reactive oxygen spices (ROS) than those cultured with fresh medium. Moreover, GC cells with CAF-CM on Matrigel-coated plates exhibited remarkable resistance in these assays. On the other hand, western blotting analysis showed that Akt activity in GC cells cultured with CAF-CM was up-regulated in concurrence with FAK phosphorylation. Finally, the chemoresitance induced by CAFs was significantly suppressed by CXCR4 or integrin β1 silencing.
Conclusions: These results suggest that CXCL12/CXCR4 and integrinβ1 signal activation by CAFs promoted the chemoresistance through enhancing their interaction with ECM in GC. This mechanism underlying the chemoresistance may provide a novel therapeutic target in advanced GCs.
Citation Format: Yuka Tamaoki, Takatsugu Ishimoto, Keisuke Miyake, Daisuke Izumi, Daisuke Kuroda, Tsugio Eto, Kota Arima, Hironobu Shigaki, Junji Kurashige, Masaaki Iwatsuki, Yoshifumi Baba, Yasuo Sakamoto, Naoya Yoshida, Hideo Baba. CXCL12/CXCR4 and integrin signal activation by cancer-associated fibroblasts enhances the chemoresistance in gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5113.
Abstract 5134: Evaluation of immune tolerance mechanisms in pulmonary squamous cell and adenocarcinomas - how to interfere beyond PDL1 blockade
Authors: Popper Helmut H. , Brcic Luka , Absenger Gudrun , Prietl Barbara , Lindenmann Joerg , Balic Marija 
Published: July 2016

Abstract
Introduction: Immunotherapy has emerged as a new tool to treat patients with NSCLC. Programmed death ligand 1 (PDL1) expressed on carcinoma cells serve as a marker predicting the response of anti-PDL antibody therapy. However, the results of clinical studies are conflicting as patients might profit from therapy despite not expressing PDL1 on their tumors, and also some tumors expressing PDL1 do not respond to therapy. It is evident that NSCLC cells use other mechanisms of immunotolerance.
Methods: Surgically removed specimen of lung cancer are evaluated for infiltrating innate as well as specific immune cell in tumor centers and invasive front. In addition bronchoalveolar lavage is taken simultaneously and evaluated by flow cytometry for the same immune cells as the tissues. These cell types are evaluated: dendritic cells (classical, plasmocytoid, monocytoid), macrophages (M1 and M2), lymphocytes of Bcell lineage, lymphocytes of Tcell lineage, regulatory Tcells, natural killer cells. In addition tumor cells and lymphocytes are studied for their expression of PD1, PDL1, and PDL2, respectively
Results and discussion: Within lung cancer several different mechanisms of inducing immune tolerance emerged: PD1-PDL1 interaction of tumor cells and CD8 lymphocytes, plasmocytoid as well as monocytoid dendritic cell induced downregulation of cytotoxic Tcell action, influx of myeloid derived cells inducing immune tolerance against tumor cells, M2 macrophage polarization with enhancement of stroma remodeling for tumor cell invasion and reduced Tcell reaction, increase of Treg cells inducing immune tolerance. Some of these mechanisms are seen in combination with PD1-PDL1 induced immune tolerance. This might explain, why some patients do not benefit from anti-PDL1 therapy. BAL emerged as a powerful tool in the evaluation of the immune reaction in NSCLC patients and might be a tool for evaluation of immune responses as well as a diagnostic tool to evaluate resistance mechanisms.
Citation Format: Helmut H. Popper, Luka Brcic, Gudrun Absenger, Barbara Prietl, Joerg Lindenmann, Marija Balic. Evaluation of immune tolerance mechanisms in pulmonary squamous cell and adenocarcinomas - how to interfere beyond PDL1 blockade. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5134.
Abstract 5136: HER2 or EGFR inhibition interacts with tumor microenvironment by downregulation of PD-L1 and chemokines
Authors: Kim Jin Won , Sung Ji Hea , Kang Mi Hyun , Kim Ji-Won , Kim Se-Hyun , Lee Keun-Wook , Lee Hye Seung , Kim Jee Hyun 
Published: July 2016

Abstract
Background:
Agents targeting HER2 or EGFR have been applied in several cancer types. Tumor microenvironment including tumor-infiltrating lymphocytes could be a predictive marker in HER2- or EGFR- targeted therapy, although there are some controversies. However, the effects of HER2 and EGFR inhibition on tumor microenvironment are unclear.
Method:
We screened HER2, EGFR, and PD-L1 expression in gastric cancer cell lines by western blot (SNU216, SNU668, SNU719, AGS, N87, YCC3, and YCC10). HER2 and EGFR was inhibited by using dual inhibitor (afatinib, lapatinib). After HER2 and EGFR inhibition, the change of PD-L1 expression was evaluated in HER2 overexpressed cell lines (SNU216, N87, SKBR3) at western blot, FACS, PCR, and qPCR. Selective blockade for down-steam molecules of HER2 and EGFR was conducted by using pictilisib (PI3K inhibitor) and trametinib (MEK inhibitor). The change of chemokines such as CXCL1, CCL2, and CCL21 was evaluated after HER2 and EGFR inhibition by PCR. In clinical data, PD-L1 expression and HER2 expression in resected gastric cancer were also evaluated by immunohistochemistry analysis.
Results:
EGFR-overexpressed or HER2-overexpressed gastric cancer cell lines (SNU216, SNU668, N87) showed higher protein expression of PD-L1. PD-L1 expression decreased with dose-dependent manner in afatinib- or lapatinib- treated cell lines (SNU216, N87, SKBR3). In pictilisib-treated cell lines, PD-L1 was also down-regulated. However, trametinib-treated cell lines did not show down-regulation of PD-L1. After lapatinib treatment in HER2 overexpressed cell lines, CXCL1, CCL21, and CCL2 decreased with dose-dependent manner. In 289 patients with resected gastric cancer, there was a significant association between HER2 and PD-L1 expression (p = 0.03).
Conclusions:
PD-L1 is associated with HER2 and EGFR expression. PD-L1 is regulated by inhibition of PI3K pathway. Therefore, HER2 or EGFR inhibition could interact with tumor microenvironment by down-regulation of expression of PD-L1 and chemokines.
Citation Format: Jin Won Kim, Ji Hea Sung, Mi Hyun Kang, Ji-Won Kim, Se-Hyun Kim, Keun-Wook Lee, Hye Seung Lee, Jee Hyun Kim. HER2 or EGFR inhibition interacts with tumor microenvironment by downregulation of PD-L1 and chemokines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5136.
Abstract 514: Effect of radiation therapy on breast epithelial cells in BRCA1/2 mutation carriers
Authors: Chiang Huai-Chin , Elledge Richard , Larson Paula , Jatoi Ismail , Li Rong , Hu Yanfen 
Published: July 2016

Abstract
Women carrying BRCA1 and BRCA2 mutations have significantly elevated risk of developing breast and ovarian cancers. BRCA1-associated breast cancer likely originates from progenitors of the luminal epithelial lineage. Recent studies indicate that radiation therapy (RT) for BRCA1 cancer patients is associated with lower incidence of developing subsequent ipsilateral breast cancer. In the current study, we analyzed tumor-free breast tissue procured via prophylactic bilateral mastectomy from three BRCA1 and one BRCA2 mutation carriers, who had been previously treated with RT for unilateral breast cancers. Freshly isolated breast cells from the irradiated and non-irradiated breasts of the same individuals were subjected to flow cytometry, using established cell-surface markers. Two out of the three BRCA1 carriers and the BRCA2 carrier exhibited significantly diminished luminal cell population in the irradiated breast versus the non-irradiated side. The remaining BRCA1 carrier showed similar cell abundance between the two sides. Our finding suggests that prior RT could result in preferential depletion of the luminal epithelial compartment and thus reduced incidence of BRCA1-associated breast cancer. Further investigation may inform development of RT-based preventive approaches aimed at specifically decimating the source of BRCA1-associated tumors.
Citation Format: Huai-Chin Chiang, Richard Elledge, Paula Larson, Ismail Jatoi, Rong Li, Yanfen Hu. Effect of radiation therapy on breast epithelial cells in BRCA1/2 mutation carriers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 514.
Abstract 5142: Correlation of peripheral blood S100A9+ myeloid-derived suppressor cells and tumor-associated macrophages in lung adenocarcinoma patient
Authors: Lee Kang-Yun , Feng Po-Hao 
Published: July 2016

Abstract
Background: Peripheral blood S100A9+ monocytic myeloid derived suppressor cells (MDSCs) is a predictive factor for treatment response of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) of lung adenocarcinoma patients. Tumor associated macrophages (TAMs), which might derived from peripheral blood monocyte, is also a predictive factor to treatment response of EGFR-TKI. However, the correlation of S100A9+ monocytic MDSCs and TAMs is not well understood in lung adenocarcinoma patients.
Methods: Stage IV lung adenocarcinoma patients with paired formalin fixed paraffin embedded (FFPE) tumor tissue and peripheral blood mononuclear cell (PBMCs) were enrolled. CD68+ cells were calculated in 3 different 200X microscopic field of FFPE as TAMs, and S100A9+ cells also calculated with same method as MDSCs in tumor microenvironment. S100A9+ MDSCs percentage was calculated by flow cytometry from CD14+S100A9+ in PBMC.
Results: Twenty-four lung adenocarcinoma patients with paired FFPE tissue and PBMC data were enrolled. PBMC S100A9+ MDSCs percentage is 17.9± 13.6; average number of S100A9+ cells and CD68+ TAMs in tumor tissue is 96.8±45.7 and 79.3±13.3, respectively. The correlation between S100A9+ MDSCs percentage and tissue S100A9+ cells and CD68+ TAMs is significant (Spearman r = 0.54, p = 0.003 for S100A9+; Spearman r = 0.03, p = 0.03 for CD68; n = 24) CD68+ and S100A9+ cells were also correlated (Spearman r = 0.41, p = 0.04, n = 24). Clinically, high or low (cutoff value as median number) tissue S100A9+ cells and CD68+ TAMs were both predictive factors for treatment PFS for EGFR-TKI. (For CD68, median: 56, high vs low TAM PFS = 7.4 vs 15.4 months, p = 0.04; For S100A9+ cells, median: 76, high vs low S100A9+ cells PFS = 7.2 vs 13.6 months, p = 0.05)
Conclusion: Peripheral blood S100A9+ MDSCs is well correlated to tumor tissue S100A9+ cells and CD68+ TAMs. Both tissue S100A9+ cells and CD68+ TAMs were predictive factors for EGFR-TKI PFS. Our study suggests that peripheral blood S100A9+ monocytic MDSC might be one of the origin of tumor tissue CD68+ TAMs.
Citation Format: Kang-Yun Lee, Po-Hao Feng. Correlation of peripheral blood S100A9+ myeloid-derived suppressor cells and tumor-associated macrophages in lung adenocarcinoma patient. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5142.
Abstract 5145: To explore the tumorigenic regulation mechanism of SPZ1 in hepatocellular carcinoma
Authors: WANG LI-TING , HSU SHIH-HSIEN 
Published: July 2016

Abstract
Cancer directly affects at least one-third of the human population. Despite this extensively, the genetic determinants of cancer risk remain unknown. Spermatogenic leucine zipper 1 (SPZ1), a basic helix loop helix leucine zipper (bHLH-Zip) transcription factor, acted as a proto-oncogene in mouse and human. It has been demonstrated that SPZ1 was involved in early embryonic development, cell growth and differentiation. In this study, we compared the expression of SPZ1 in 168 paired specimens of HCCs and adjacent normal tissues and also in paired specimens from 140 patients with non-HCCs. In pathologic analysis, SPZ1 exhibited a tumor-specific expression pattern and a high correlation to patient survival time, tumor size, tumor number, and progression stage. Enforced expression of SPZ1 accelerated cell proliferation and tumorigenic activity in hepatoma cells. In contrast, short hairpin RNA-mediated attenuation of SPZ1 in hepatoma cells decreased cell proliferation and malignant transformation in vitro and in vivo. Together, we speculated that SPZ1 as a potential therapeutic target of HCCs
Citation Format: LI-TING WANG, SHIH-HSIEN HSU. To explore the tumorigenic regulation mechanism of SPZ1 in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5145.