bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4133: Suppressed B7-H3 expression reduces glycolytic capacity and sensitizes tumor cells to anti-cancer agents
Authors: Nunes-Xavier Caroline E. , Flem Karlsen Karine , Øyjord Tove , Tan Ming , Fodstad Øystein 
Published: July 2016

Abstract
B7 family proteins are important immune response regulators, and can mediate oncogenicity-related signals and support cancer development. We have prevously shown that the B7-H3 protein promotes tumor cell invasion, proliferation and mestastasis, and increases resistance to chemotherapy. Now we have used human breast and melanoma cancer cell lines with different expression levels of B7-H3 to further evaluate the role of B7-H3 on the sensitivity to anticancer compounds. B7-H3 knockdown tumor cells showed enhanced chemosensitivity compared to their B7-H3 expressing counterparts, as well as increased inhibition to treatment with compounds that target proteins in the PI3K/AKT/mTOR- and MAPK-pathways (Nunes-Xavier et al. in revision). Treatment of control cells with an anti-B7-H3 monoclonal antibody resulted in similar sensitization, whereas B7-H3 overexpressing cells and xenografts were less sensitive. Of note, knockdown of B7-H3 decreased and B7-H3 overexpression increased the glycolytic capacity of the breast cancer and malignant melanoma cells. In conclusion, we have demonstrated a previously unknown relationship between B7-H3 expression and glycolysis in tumor cells, and found that B7-H3 confers resistance to also to pathway inhibiting agents. The results provide novel insights into the function of B7-H3 in cancer, and suggest that targeting of B7-H3 expression may be a promising alternative to improve current anticancer therapy.
Citation Format: Caroline E. Nunes-Xavier, Karine Flem Karlsen, Tove Øyjord, Ming Tan, Øystein Fodstad. Suppressed B7-H3 expression reduces glycolytic capacity and sensitizes tumor cells to anti-cancer agents. [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 4133.
Abstract 4148: Different immune cell responses are associated with glioblastoma subclassification and typical genetic alterations
Authors: Luoto Suvi , Kesseli Juha , Nykter Matti , Granberg Kirsi J. 
Published: July 2016

Abstract
Interactions between various components in the tumor microenvironment and dysregulated immune responses are thought to play important roles in cancer development. To better understand the role of immune cells in tumor pathogenesis and destruction, we computationally model the microenvironment of an aggressive brain tumor glioblastoma multiforme (GBM).
We downloaded GBM patient RNA-seq data from the Cancer Genome Atlas (TCGA). Using cluster analysis, we identified 16 clusters, each containing 10 to 933 genes that show a statistical enrichment of immune response related gene ontology terms. Utilizing a panel of RNA-seq data from normal cell types, we constructed global and cluster specific regression models to characterize the expression profiles of GBM samples in the clusters of interest as linear combinations of normal cell and reference GBM expression profiles. Simulated data was used to validate that the regression model coefficients accurately reflect the contributions of normal cell types to the expression profiles of tumor samples. Based on the regression analysis, we were able to uncover high variability in the composition of microenvironment across the TCGA cohort, suggesting diverse immune responses in tumors.
The results from global regression analysis were then associated with common genetic alterations in GBM and with GBM subclassification. Especially the estimated macrophage, granulocyte, and CD8+ T lymphocyte proportions show significant differences between different GBM subgroups. Accumulation of immune cells was increased in the mesenchymal and neural subtype compared to other subtypes. Furthermore, estimated immune cell proportions were associated with alterations in EGFR and NF1.
Taken together, our analysis provided a characterization of the immunomicroenvironment in GBM and linked immune cell responses to typical GBM alterations and GBM subtypes. More detailed characterization of diverse immune responses will facilitate patient stratification and might provide tools for personalized immunotherapy in the future.
Citation Format: Suvi Luoto, Juha Kesseli, Matti Nykter, Kirsi J. Granberg. Different immune cell responses are associated with glioblastoma subclassification and typical genetic alterations. [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 4148.
Abstract 4149: Direct immune cell contact to basal-like triple negative breast cancer cells evokes downregulation of EGFR and PD-L1
Authors: Yamaguchi Ayane , Suzuki Eiji , Kawaguchi Kosuke , Nishie Mariko , Tsuda Moe , Toi Masakazu 
Published: July 2016

Abstract
BACKGROUND:
We previously reported that direct co-culture of triple negative breast cancer cell line MDA-MB-231 and immune cells results in reduction of EGFR expression on cell surface of MDA-MB-231 (AACR 2015 #2349). However, a role of reduction of EGFR on MDA-MB-231 via co-culture with immune cells still remains unclear. Therefore, we evaluated a role of reduction of EGFR on MDA-MB-231 at the immunological point of view by testing expression of immune related genes including PD-L1.
METHODS:
In order to verify the importance of direct immune cell contact to breast cancer cell, MDA-MB-231 cells were co-cultured directly or indirectly with THP-1 cells (human monocytic cell line) at 1:50 cellular ratios. In order to study indirect co-culture assay, we used cell culture insert to avoid direct cancer cell-immune cell contact. We analyzed gene expression by quantitative real time PCR and membrane protein expression by flow cytometry of EGFR, also other HER family on MDA-MB-231 which is directly or indirectly co-cultured with THP-1. We also evaluated the expression of immune related genes including PD-L1.
RESULTS:
Both mRNA and protein level of EGFR on MDA-MB-231 cells directly co-cultured with THP-1 were significantly decreased as compared to those with indirectly co-cultured MDA-MB-231 cells. There are no significant differences in EGFR expression between indirectly co-cultured MDA-MB-231 cells and control MDA-MB-231 cells. Importantly, PD-L1 expression on MDA-MB-231 cells directly co-cultured with THP-1 was significantly decreased as compared to that with indirectly co-cultured MDA-MB-231 cells.
CONCLUSION:
It has been reported that PD-L1 expression in cancers is regulated by phosphatidylinositol 3-kinase (PI3K) and Akt signaling. Thus, our findings may give a novel insight on regulation of PD-L1 expression on cancer cells in tumor microenvironment that tumor infiltrated immune cell directly contact with cancer cells and EGFR down-regulation leads to reduction of PD-L1 expression on cancer cells.
Further investigation is needed to elucidate the mechanism of reduction of EGFR by direct immune cell contact to cancer cells and its interaction with modulation of PD-L1 expression. This will provide novel aspects for immune therapy of breast cancer patients.
Citation Format: Ayane Yamaguchi, Eiji Suzuki, Kosuke Kawaguchi, Mariko Nishie, Moe Tsuda, Masakazu Toi. Direct immune cell contact to basal-like triple negative breast cancer cells evokes downregulation of EGFR and PD-L1. [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 4149.
Abstract 415: A new, highly sensitive ALK antibody improves the screening of rearranged-ALK by IHC
Authors: Lu Hsiangmin , Gonzalez Rachel , Shen Yi , Jin Mu-lan , Wu Yipan , Zhang Yungang , Yuan Kehu , Chu Boyang , Qi Lili , Liu Huibo , Wang Chenlin , Wang Guangli , Shu Youmin , McDowell Julie , Ma Donghui , He Wei-wu , Chen Jian , Lin Ray 
Published: July 2016

Abstract
All non-small cell lung cancer (NSCLC) patients are recommended to be screened for anaplastic lymphoma kinase (ALK)-rearrangement despite its low occurrence (&lt; 7%). This is due to recent advances in treatment for patients with ALK-positive NSCLC with receptor tyrosine kinase inhibitors Crizotinib and Ceritini. Current rearranged-ALK testing includes fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), and immunohistochemistry (IHC). Despite the high sensitivities and specificities, the limitations of the first two assays include time-consuming, infeasible, and specialized techniques that make them unsuitable for the routine screening for which IHC has been proposed. However, the biggest obstacle to detecting rearranged-ALK in lung cancer patients by IHC is the lack of highly sensitive ALK antibodies that detect the extremely low abundance of ALK in patients. To overcome this limitation, we have developed an ALK mouse monoclonal antibody (clone OTI1A4) with higher sensitivity in comparison to a rabbit ALK antibody (clone D5F3). Moreover, OTI1A4 identified ALK-positive NSCLC samples (16/16 cases) and showed negative staining for ALK-negative samples (11/11 cases) previously validated by FISH (10/16 ALK-positive cases) or qPCR (10/16 ALK-positive cases). This indicated the potential advantage of using clone OTI1A4 over FISH or qPCR to detect ALK rearrangements. Lastly, there was 100% concordance between OTI1A4 and D5F3 in detecting ALK-rearranged NSCLC samples previously confirmed by FISH (76 ALK-positive and 438 ALK-negative samples). These results support the possibility that ALK clone OTI1A4 could be used for routine screening of patients with ALK-positive NSCLC by IHC.
Citation Format: Hsiangmin Lu, Rachel Gonzalez, Yi Shen, Mu-lan Jin, Yipan Wu, Yungang Zhang, Kehu Yuan, Boyang Chu, Lili Qi, Huibo Liu, Chenlin Wang, Guangli Wang, Youmin Shu, Julie McDowell, Donghui Ma, Wei-wu He, Jian Chen, Ray Lin. A new, highly sensitive ALK antibody improves the screening of rearranged-ALK by IHC. [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 415.
Abstract 4153: Abnormal expression of MUC1 mucin on colon epithelia stimulates production of pro-inflammatory cytokines promoting colitis-associated colon cancer in a murine model
Authors: Cascio Sandra , Faylo Jacque , Xue Jia , Finn Olivera 
Published: July 2016

Abstract
MUC1 is a transmembrane glycoprotein aberrantly expressed in human adenocarcinoma as well as chronic inflammatory conditions. We have previously demonstrated that the tumor form of MUC1, in association with p65, upregulates the expression of pro-inflammatory cytokines in the tumor microenvironment, including IL-6 and TNF-alpha, by modulating their transcriptional activity in epithelial cancer cells. Here, we explored the mechanism underlying MUC1/p65-induced transcription of IL-6 and TNF-alpha in colon cancer cells and its significance for the microenviroment of colitis that is known to be the precursor to cancer. We used a mouse model of colitis-associated colon cancer where wild type (WT) and human MUC1 transgenic (MUC1.Tg) mice are given carcinogen azoxymethane (AOM), followed by three cycles of 1.2% dextran sodium sulfate (DSS) in drinking water to induce colitis. MUC1.Tg showed higher tumor incidence, decreased survival, increased body weight loss and shorter colon length. These features accelerated the severity of inflammation-induced colon cancer. Consistent with our previous in vitro data, expression of NF-kB family members was higher in MUC1.Tg mice compared to WT. We previously showed that in tumors, MUC1/p65 complex modulated the expression of histone methyltransferase Enhancer of Zeste protein-2 (EZH2) and interaction with pro-inflammatory cytokine promoters. In order to understand the significance of MUC1/p65-modulated cytokines in progressive colitis that gives rise to colon cancer, we analyzed infiltration of inflammatory cells into the inflamed colon tissues. The number of infiltrating macrophages was much higher in AOM/DSS-treated MUC1.Tg mice compared to WT. ELISA assay and gene expression analyses demonstrated that the treatment with AOM/DSS in the presence of human MUC1 on the colonic epithelia resulted in a significant increase in M1 type macrophage-associated genes, including IL-6, TNF-alpha and iNOS, whereas M2 type macrophage markers such as Arginase 1, Ym1, and IL-10 were drastically reduced when compared to colon tissues of treated WT mice. Taken together, our findings reveal a pro-inflammatory role for MUC1 in colitis-related carcinogenesis. Our study also provides a mechanism by which MUC1 accelerates tumor initiation and progression.
Citation Format: Sandra Cascio, Jacque Faylo, Jia Xue, Olivera Finn. Abnormal expression of MUC1 mucin on colon epithelia stimulates production of pro-inflammatory cytokines promoting colitis-associated colon cancer in a murine model. [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 4153.
Abstract 416: Tumor cell isolation using antibody/aptamer-based multivalent binding
Authors: Fan Z. Hugh , Zhang Jinling , Sheng Weian 
Published: July 2016

Abstract
Isolation and enumeration of circulating tumor cells (CTCs) in peripheral blood have been used for cancer diagnosis, prognosis, and theragnosis. The majority of the CTC isolation methods, including the FDA-approved CellSearch®, employ one antibody to capture tumor cells. Using such a monovalent-binding capture agent likely results in lower cell capture efficiency than multivalent-binding methods, which tend to have stronger binding force (or lower dissociation constant).
We have investigated in a multivalent-binding-based tumor cell isolation method by immobilizing a mixture of aptamers and antibodies on the surfaces of microfluidic devices. Since aptamers are much smaller in the size (8-15 kDa) than antibodies (150 kDa), aptamers and antibodies could interact with different receptors on cell surfaces, resulting in a configuration that one cell simultaneously interacts with multiple different types of capture agents. The microfluidic devices we used are in the size of a microscope slide and each of them consists of an inlet, eight parallel channels connected via consecutive bifurcation, and an outlet. There are micromixers inside the channels for enhanced interactions. Biotinylated aptamers and biotinylated antibodies were coated onto microchannel surfaces using avidin-biotin chemistry.
We tested the devices by isolating human leukemia cells (CCRF-CEM) in devices immobilized with a mixture of sgc8 aptamers and protein tyrosine kinase-7 (PTK7) antibodies. Both sgc8 aptamers and anti-PTK7 exhibited strong binding with CCRF-CEM cells according to flow cytometry. An antibody-to-aptamer ratio of 1:300 showed the highest capture efficiency among the range we studied (from 1:30 to 1:3000). We found that the antibody-aptamer surfaces had higher capture efficiency than antibody-alone or aptamer-alone surfaces; the degree of enhancement increased with the flow rate. Control experiments using non-specific aptamer (TD05) and non-specific antibody (anti-EpCAM) were carried out to verify the benefits of multivalent binding. We also found that the multivalent-binding surfaces have higher specificity than monovalent-binding surface, especially at a high flow rate. A calibration curve was obtained by spiking leukemia cells into human whole blood.
In summary, antibody/aptamer-coated multivalent-binding surfaces in microfluidic devices showed higher capture efficiency and specificity than monovalent-binding surfaces, suggesting their potential for the isolation and enumeration of CTCs for clinical applications.
Citation Format: Z. Hugh Fan, Jinling Zhang, Weian Sheng. Tumor cell isolation using antibody/aptamer-based multivalent binding. [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 416.
Abstract 4165: Myc vs. Akt therapy in RapidCap, a GEM model for metastatic prostate cancer
Authors: Stahlhut Carlos E. , Ambrico Alexandra J. , Watrud Kaitlin E. , Cho Hyejin , Wang Lily , Qi Jun , Cantley Lewis C. , Bradner James , Trotman Lloyd 
Published: July 2016

Abstract
We describe our efforts to determine the effect of MYC and PI3K inhibition in a genetically engineered mouse model of naïve and castration-resistant metastatic prostate cancer. Metastasis is a major driver of mortality and morbidity in prostate cancer, the most common cancer type in men and the second leading cause of cancer-related deaths in the western world. To recapitulate the metastatic process in genetically engineered mice, we have developed the RapidCaP system, which uses prostate-directed viral infection to trigger focal loss of Pten and Trp53. Using luminescence and fluorescence, the RapidCaP system allows us to track disease progression in real-time and isolate metastases in distant tissues. This system provides a powerful platform for the identification and validation of candidate driver genes and for the efficient testing of novel therapeutics. Using this system, we have recently identified Myc as a critical, spontaneously activated driver in Pten-negative metastatic prostate cancer. Preliminary trials indicate that the Myc-suppressing Brd4 inhibitor JQ1 is ineffective towards primary disease, but induces metastatic regression. This specificity correlates with a switch from AKT-driven primary disease to MYC-driven metastatic disease. Our current efforts seek to determine how, when and why targeting of Myc using JQ1 and the PI 3-Kinase pathway using NVP-BKM120 can be best used to treat naïve and castration-resistant metastatic prostate cancer. In addition, we are examining changes to the transcriptome and epigenetic alterations that characterize Pten-negative metastatic prostate cancer, with the goal of understanding the mechanisms of progression toward a metastatic state and establishing new therapeutic targets.
Citation Format: Carlos E. Stahlhut, Alexandra J. Ambrico, Kaitlin E. Watrud, Hyejin Cho, Lily Wang, Jun Qi, Lewis C. Cantley, James Bradner, Lloyd Trotman. Myc vs. Akt therapy in RapidCap, a GEM model for metastatic prostate 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 4165.
Abstract 4169: Systematic in vivo analysis of PI3K pathway aberrations in a mouse model of invasive lobular carcinoma
Authors: Van Miltenburg Martine 
Published: July 2016

Abstract
Invasive lobular carcinoma (ILC) is the second most prevalent breast cancer subtype, which develops in the milk-producing glands (lobules) and metastasizes to distant organs. A key feature of ILC is loss of the CDH1 gene, encoding the E-cadherin cell-cell adhesion receptor. Though E-cadherin is thought to be a tumour suppressor, it is interesting to note that mammary-gland specific deletion of E-cadherin does not lead to tumour development indicating that other factors are necessary for the induction of ILC. Recent data from the cancer genome atlas reveals that besides E-cadherin loss, mutations in PIK3CA, and to a lesser extent PTEN, TBX3, and FOXA1 were found as ILC enriched features. These data implicate PI3K signaling as a driving force in ILC development. Using our in-house established GEMM-ESC strategy, we have developed innovative mouse models for ILC to study novel aspects of the functional interplay between E-cadherin and PI3K in ILC development. We have discovered an intriguing new interplay between these components in which E-cadherin loss suppresses growth of normal mammary epithelium, which appears to involve senescence, whereas it effectively accelerates tumor growth in a PIK3CAmutant background. Therapeutically, PIK3CAE545K and AKTE17K ILCs were sensitive to AZD8055, an mTOR inhibitor, and BKM120, a PI3K 110α inhibitor in vivo, indicating that PI3K signaling is required for their tumor maintenance. Currently, we are dissecting the sensitivity of ILCs displaying PIK3CAE545K or AKTE17K mutations, and PTEN loss, to a large panel of inhibitors, which will likely provide new clinical options.
Citation Format: Martine Van Miltenburg. Systematic in vivo analysis of PI3K pathway aberrations in a mouse model of invasive lobular 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 4169.
Abstract 4182: Statins induce apoptosis in osteosarcoma cells by activation of Ampk and p38-MAPK via suppression of mevalonate pathway
Authors: Kamel Walied Abd-Elghani , Sugihara Eiji , Yamaguchi Sayaka Iwai , Nobusue Hiroyuki , Maki Kenta , Muto Akihiro , Saya Hideyuki , Shimizu Takatsune 
Published: July 2016

Abstract
Osteosarcoma (OS) is the most common, non-hematopoietic, primary malignant bone tumor. OS is characterized by its aggressive local growth and systemic dissemination. Although combination of surgical operation and adjuvant chemotherapy greatly improved the prognosis, more than 20% of patients still cannot get long-term survival. Therefore, novel therapeutic approaches should be expected to be developed. Previously, we developed an OS mouse model by overexpressing c-MYC in bone marrow stromal cells derived from Ink4a/Arf knockout mice. We isolated highly tumorigenic cells (designated AXT cells) from tumors after serial transplantation. Inoculation of AXT cells into syngeneic C57BL/6 mice results in the development of lethal OS with metastatic lesions including lung, which pathologically and clinically mimics human osteoblastic osteosarcoma. To obtain the novel therapeutic agents for OS, we performed drug screening using existing drug collections and found that statins strongly suppressed AXT cell growth and migration in vitro. Simvastatin induces caspase dependent apoptosis, which can be completely rescued by the supplement of mevalonate and geranylgeranyl pyrophosphate but not by farnesyl pyrophosphate, suggesting that OS cells are susceptible to the inhibition of the mevalonate pathway. As the responsible effectors, we found treatment of simvastatin drives RhoA-GTP translocation from cell membrane to cytosol as well as the disruption of interaction between RhoA and Rho-GDI, indicating that, in spite of the accumulation of RhoA-GTP in OS cells, RhoA cannot work properly, which appears to affect cell motility and anchorage dependent survival. As downstream signaling of RhoA, p38-MAPK and AMPK are strongly activated by simvastatin treatment. Activation of p38-MAPK is not accompanied by the ROS production. The specific inhibitor for p38-MAPK or AMPK can rescue this activation as well as the simvastatin-induced cell death, respectively, suggesting that activation of both kinases is responsible for the anti-tumor effect of simvastatin. A single treatment of statins attenuated OS tumor growth in vivo. These findings suggest that the activation of p38-MAPK and AMPK by statins become a potential therapeutic option for OS.
Citation Format: Walied Abd-Elghani Kamel, Eiji Sugihara, Sayaka Iwai Yamaguchi, Hiroyuki Nobusue, Kenta Maki, Akihiro Muto, Hideyuki Saya, Takatsune Shimizu. Statins induce apoptosis in osteosarcoma cells by activation of Ampk and p38-MAPK via suppression of mevalonate pathway. [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 4182.