bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 502: Copy number alterations identify targeted therapies in preclinical models of osteosarcoma
Authors: Sayles Leanne C. , Breese Marcus , Sweet-Cordero Alejandro 
Published: August 2015

Abstract
Osteosarcoma (OS) is an aggressive pediatric bone malignancy that affects 400 children per year in the United States. It has one of the lowest 5 yr. survival rates of any pediatric cancer. OS is characterized by genomic instability and numerous copy number alterations (CNA). We hypothesized that CNA may be drivers of OS and that targeting cancer genes with CNAs may be a novel approach for treatment of OS. We have established a robust approach for generation of patient-derived xenografts (PDX) from patients with OS. To date, 12 PDX have been established from OS patients. Using whole-genome sequencing (WGS), we have identified possible target CNAs for individual patients and are currently testing them in their corresponding PDX. In one patient, an amplification in c-myc suggested possible susceptibility to the bromodomain inhibitor JQ1. In a second patient sample, amplification of Cyclin D1 in the setting of p16 loss and wild-type Rb suggested responsiveness to a CDK4/6 specific inhibitor. This patient sample also has an Aurora kinase B amplification, suggesting susceptibility to inhibition of this kinase as a therapeutic approach. We treated the corresponding PDX with the drug predicted to target the patient sample based on CNA. In one case, JQ1 treatment inhibited tumor growth in the PDX generated from the patient sample with c-myc amplification. In the second case, Aurora kinase B inhibition arrested tumor growth in the PDX harboring the Aurora kinase B amplification. We are currently testing whether CDK4/6 inhibition is sufficient to inhibit tumor growth as predicted by WGS. As a follow up we are currently submitting several more patient samples and paired PDX for WGS as well as RNAseq to determine other potential targeted therapeutics based on CNA. In summary, our work suggests that WGS can be used to identify potential novel therapies for patients with OS. Further work will be needed to determine whether response in PDX models correlates with clinical response in patients.
Citation Format: Leanne C. Sayles, Marcus Breese, Alejandro Sweet-Cordero. Copy number alterations identify targeted therapies in preclinical models of osteosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 502. doi:10.1158/1538-7445.AM2015-502
Abstract 5051: Androgen receptor-mediated regulation of p14ARF transcription in prostate tumor cells
Authors: Mudryj Maria , Siddiqui Salma , Libertini Stephen J. , Lombard Alan P. , Mooso Benjamin , D'Abronzo Leandro , Melgoza Frank , Borowsky Alexander , Drake Christiana , Qi LiHong , Ghosh Paramita M. 
Published: August 2015

Abstract
The p14ARF tumor suppressor is often deleted or silenced in malignancies. Prostate tumors are an exception, where p14 expression is elevated. To understand this phenomenon, we assessed the expression of p53 pathway members, which are most effected by p14ARF. The expression of androgen receptor (AR), a pivotal prostate cancer regulator, which is also affected by p14arf and MDM2 was analyzed as well. The studies used archival prostate tumor tissues obtained from prostatectomies performed at the Veterans Affairs-Northern California Health Care System in Mather California between 1996 and 2002 to better define the relationship between these interrelated networks. A prostate tumor tissue array consisting of 78 tumors of differing stages and grades was constructed to evaluate correlations between multiple parameters. Immunohistochemical studies assessed expression of the proliferation marker Ki67, p53, MDM2, MDM4, p14ARF, and the AR in the nuclear and cytoplasmic compartments of tumor and adjacent cells. p53, MDM4, p14ARF and AR were detected in nuclear and cytoplasmic compartments of tumor and non-tumor cells, but were predominantly nuclear. MDM2 expression was primarily cytoplasmic in tumor cells. Multivariate analysis of the immunohistochemical markers identified a strong correlation between expression of p14ARF and AR. Studies utilizing the prostate CWR22 xenograft and LNCaP cell line models revealed that castration or androgen deprivation resulted in reduced p14arf levels and that this effect correlated with a precipitous decline in E2F1-3a levels. In a reciprocal analysis, RB ablation enhanced p14ARF transcription, arguing that the E2F/RB pathway mediates AR-dependent p14ARF expression. However, we also identified an AR binding site located ∼40 KB upstream of the p14ARF gene. Chromatin immunoprecipitation (ChIP) studies showed that in prostate cells this site was bound by AR. ChIP studies also revealed E2F1 and E2F3 were present at the p14ARF promoter. Together, the studies argue p14ARF is a direct transcriptional target of AR and that AR and E2F collaborate to promote p14ARF expression.
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Citation Format: Maria Mudryj, Salma Siddiqui, Stephen J. Libertini, Alan P. Lombard, Benjamin Mooso, Leandro D'Abronzo, Frank Melgoza, Alexander Borowsky, Christiana Drake, LiHong Qi, Paramita M. Ghosh. Androgen receptor-mediated regulation of p14ARF transcription in prostate tumor cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5051. doi:10.1158/1538-7445.AM2015-5051
Abstract 506: TROY-EGFR signaling complex mediates glioblastoma cells invasion and survival
Authors: Roos Alison , Mayo Zachary , Kloss Jean , Tuncali Serdar , Dhruv Harshil , Berens Michael E. , Loftus Joseph C. , Tran Nhan L. 
Published: August 2015

Abstract
Glioblastoma (GBM) is a highly lethal CNS malignancy in adults with a median survival of about 15 months. Effective therapeutic control of GBM is thwarted by the invasive nature of the tumor, which prevents complete surgical removal and results in tumor recurrence. Thus, there is a dire need to develop innovative approaches to target the invasive tumor cells for improved treatment of this disease. Expression of TROY, a member of the TNFR family, increases with glial tumor grade and inversely correlates with patient survival. Increased expression of TROY stimulates glioblastoma cell invasion and increases resistance to temozolomide (TMZ) and radiation treatment. We have demonstrated that TROY forms a novel complex with EGFR and modulates EGFR survival signaling. IHC analysis of GBM specimens showed that tumors with elevated TROY expression had a statistically positive correlation with increased EGFR expression. TROY expression enhanced EGFR phosphorylation, stabilized EGFR surface expression in the presence of ligand, and significantly increased EGF-stimulated GBM cell invasion. Consistent with invasion, co-expression of TROY with EGFR increased cell survival to TMZ. Moreover, we have shown that in cells treated with EGF, the TROY and ErbB4 receptor are recruited to the EGFR complex. Although the role of ErbB4 in GBM is not well defined, inhibition of ErbB4 expression suppressed tumor growth and invasion in multiple tumor subtypes, decreased EGFR surface retention, and limited EGF-induced cell migration. These data suggest that the TROY-EGFR-ErbB4 complex may represent an unappreciated therapeutic target to inhibit glioma invasion and decrease therapeutic resistance.
Citation Format: Alison Roos, Zachary Mayo, Jean Kloss, Serdar Tuncali, Harshil Dhruv, Michael E. Berens, Joseph C. Loftus, Nhan L. Tran. TROY-EGFR signaling complex mediates glioblastoma cells invasion and survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 506. doi:10.1158/1538-7445.AM2015-506
Abstract 5063: Lysyl oxidase-like 2 (LOXL2) from cancer-associated fibroblasts stimulates the progression of gastric carcinoma
Authors: Kasashima Hiroaki , Yashiro Masakazu , Kitayama Kisyu , Masuda Go , Kinoshita Haruhito , Sakurai Katsunobu , Toyokawa Takahiro , Kubo Naoshi , Tanaka Hiroaki , Muguruma Kazuya , Ohira Masaichi , Hirakawa Kosei 
Published: August 2015

Abstract
Purpose: Lysyl oxidase families are involved in a variety of pathological processes, including cancer progression. Lysyl oxidase-like 2 (LOXL2) in the tumor stroma was mainly expressed in fibroblasts, which are a major stromal compartment of gastric cancer. Significance of LOXL2 remains unclear in gastric carcinoma. The aim of this study was to clarify the role of fibroblast-derived LOXL2 in the development of gastric cancer.
Methods: Two gastric cancer cell lines, OCUM-12 and NUGC-3, and cancer-associated fibroblasts (CAF) were used in this in vitro study. The effect of fibroblast-derived LOXL2 on the motility of gastric cancer cells was analyzed by wound-healing assay, double-chamber invasion assay, and western blot. The correlation between LOXL2 expression and the clinicopathological features of 548 primary gastric carcinomas was examined by immunohistochemistry.
Results: LOXL2 mRNA expression of CAF, was significantly higher than that of normal fibroblasts. CAF significantly stimulated the migration and invasion of OCUM-12 and NUGC-3 cells. This motility-stimulating ability of CAF was inhibited by LOXL2 siRNA. Western blot analysis indicated that phosphorylation of focal adhesion kinase (FAK) in cancer cells was increased by the conditioned medium from CAF, and was not affected by the conditioned medium from LOXL2 siRNA-treated CAF. Immunohistochemical study indicated that LOXL2 expression in stromal cells was significantly associated with tumor invasion depth, lymph node metastasis, lymphatic invasion, venous invasion, and peritoneal dissemination. The overall survival of all patients with LOXL2-positive stromal cells was significantly poorer than those with LOXL2-negative stromal cells. Multivariable logistic regression analysis revealed that LOXL2 expression in stromal cells was an independent predictive parameter for the overall survival of patients with gastric cancer.
Conclusion: LOXL2 from CAF may stimulate the motility of gastric cancer cells. LOXL2 expression in stromal cells may be a useful prognostic factor for patients with gastric cancer.
Citation Format: Hiroaki Kasashima, Masakazu Yashiro, Kisyu Kitayama, Go Masuda, Haruhito Kinoshita, Katsunobu Sakurai, Takahiro Toyokawa, Naoshi Kubo, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Hirakawa. Lysyl oxidase-like 2 (LOXL2) from cancer-associated fibroblasts stimulates the progression of gastric carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5063. doi:10.1158/1538-7445.AM2015-5063
Abstract 5064: EGFR and HER3 are important in the interaction between lung cancer cells and fibroblasts
Authors: Demuth Christina , Jakobsen Kristine Raaby , Meldgaard Peter , Nielsen Anders Lade , Sorensen Boe Sandahl 
Published: August 2015

Abstract
Introduction: The cancer microenvironment has been recognised as a major factor in the development and treatment of lung cancer. Fibroblasts have gained attention owing to their ability to stimulate the growth of cancer cells and to change the response to chemotherapy. Though, not much is known about the underlying mechanisms.
Methods: Lung cancer cell lines (H1568, Calu-3 and HCC827) and a lung fibroblast cell line (WI-38) were grown in co-culture using a Boyden chamber assay.
Results: The presence of lung fibroblasts markedly increased growth of the lung cancer cells during co-culture. We investigated the activation of 49 different receptor tyrosine kinases and found that H1568 activated only EGFR and HER3. Activation of EGFR and HER3 was confirmed in Calu-3 and HCC827 after co-culture with fibroblasts. To account for this activation, we measured the expression of all EGFR ligands in the cell lines. We found that all lung cancer cell lines had increased levels of amphiregulin mRNA after co-culture with fibroblasts. ELISA confirmed increased protein production. We also found that the amount of available amphiregulin in the media of the co-culture is increased compared to controls.
Conclusion: Lung fibroblasts stimulate the growth of lung cancer cells lines. We suggest that this effect is obtained by activation of EGFR and HER3. Furthermore we show that co-culture induce increased amphiregulin production in the cancer cells. This study identifies EGFR and HER3 as important components in the interaction between lung cancer cells and fibroblasts.
Citation Format: Christina Demuth, Kristine Raaby Jakobsen, Peter Meldgaard, Anders Lade Nielsen, Boe Sandahl Sorensen. EGFR and HER3 are important in the interaction between lung cancer cells and fibroblasts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5064. doi:10.1158/1538-7445.AM2015-5064
Abstract 5070: Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) reduces colon cancer cell migration and metastasis
Authors: Yuge Ryo , Kitadai Yasuhiko , Shinagawa Kei , Onoyama Mieko , Tanaka Shinji , Yasui Wataru , Chayama Kazuaki 
Published: August 2015

Abstract
Accumulating evidence suggests that a unique set of receptor tyrosine kinases, known as discoidin domain receptors (DDRs), plays a role in cancer progression by regulating the interactions of tumor cells with their surrounding collagen matrix. We investigated the role of DDR1 in the tumor progression of colorectal cancer.
We examined the DDR1 mRNA and protein expression levels in a series of human colorectal cancer cell lines by RT-PCR and Western blotting. We also analyzed the DDR1 protein expression in 27 surgical specimens of colorectal cancer by immunohistochemistry. Migration, invasion, and proliferation assays were conducted with a high-content time-lapse assay system in a series of colon cancer cell lines. Nilotinib, a well-known DDR1 inhibitor, and DDR1-silenced colon cancer cells were used for inhibition of DDR1 tyrosine kinase activity. In an in vivo study, we orthotopically implanted KM12SM human colon cancer cells into the cecum of nude mice and administered nilotinib (100 mg/kg/day) by daily oral gavage. After 4 weeks of treatment, primary tumors and metastatic lesions were resected, and specimens were analyzed histologically.
DDR1 mRNA and protein expression was observed in the human colon cancer cell lines and in cancer cells of most of the surgical specimens. Colon cancer cell lines KM12SM, KM12c, LoVo, and HT29 exposed to nilotinib (20 μM) showed reduced migration. When incubated with type I collagen, however, these cells showed increased migratory activity. Nilotinib treatment significantly inhibited this effect. The migratory activity of DDR1-silenced cells was not affected by nilotinib treatment. The orthotopic xenografts grew invasively as aggressive tumors with a stromal reaction, but under nilotinib treatment, the stromal reaction was reduced, and tumors grew expansively. In addition, the numbers of lymph node metastases were significantly reduced.
Disruption of DDR1 attenuated colon cancer cell migration and led to altered primary tumor morphology and to impaired lymph node metastasis. DDR1 may be a promising therapeutic target in patients with colon cancer.
Citation Format: Ryo Yuge, Yasuhiko Kitadai, Kei Shinagawa, Mieko Onoyama, Shinji Tanaka, Wataru Yasui, Kazuaki Chayama. Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) reduces colon cancer cell migration and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5070. doi:10.1158/1538-7445.AM2015-5070
Abstract 508: Identification of FRA-1 as a potential driver of pro-invasive properties in pancreatic cancer in conjunction with MUC1
Authors: Hanson Ryan L. , Hollingsworth Michael A. 
Published: August 2015

Abstract
The transmembrane mucin, MUC1, contributes to the progression of pancreatic cancer, in part by conducting signals from the cell surface that regulate expression of molecules associated with aggressive tumor behavior. We investigated transcriptional co-regulatory effects mediated by interactions of the MUC1 cytoplasmic tail with activator protein 1 (AP-1). Previous results suggest that MUC1 regulates the capacity of AP-1 to bind specific promoter elements and regulate genes that contribute to tumor progression. The DNA binding activity of AP-1 is controlled in several ways including composition of the protein dimer. The precise mechanism by which MUC1 alters transcriptional complexes remains unknown. We sought to determine how MUC1 influences the formation of AP-1 complexes and potential downstream effects.
We found MUC1 increased c-Jun protein levels, the major component of AP-1, in a manner largely independent of transcriptional upregulation (mRNA upregulation was observed in only one cell line of several analyzed). Formation of the AP-1 dimer was assessed by quantitative and semi-quantitative assays. MUC1 promoted the association of c-Jun with the Fos protein, FRA-1. This association was promoted by enhanced ERK2 signaling in MUC1 expressing cell lines. In breast cancer, FRA-1 drives an invasive and metastatic phenotype. Overexpression of FRA-1 in pancreatic cancer cell lines promoted migratory and invasive behaviors in vitro. Blocking FRA-1 activity by shRNA knockdown or ERK inhibition decreased migration and invasion. Analysis of gene expression in pancreatic tumor samples and normal, uninvolved tissue [mined from the Gene Expression Omnibus (GEO)] revealed that tumor samples had significantly increased levels of FRA-1 mRNA. A subset of these samples exhibited gene expression patterns consistent with a FRA-1:EMT phenotype previously observed in colorectal cancer cells. We evaluated expression of FRA-1 protein in primary pancreatic tumors, liver metastases, and uninvolved non-malignant pancreas. Robust nuclear localization of FRA-1 was observed in primary and metastatic tumor cells whereas uninvolved pancreas showed lower levels of diffuse cytoplasmic staining.
Based on these results, we hypothesize that FRA-1 plays an important role in a subset of pancreatic cancers by altering the binding profile of AP-1. Due to a dependence on ERK activity for FRA-1 function, we propose that cancers with activating mutations in the RAS-RAF-MEK-ERK cascade are the most likely candidates for utilization of FRA-1.
Citation Format: Ryan L. Hanson, Michael A. Hollingsworth. Identification of FRA-1 as a potential driver of pro-invasive properties in pancreatic cancer in conjunction with MUC1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 508. doi:10.1158/1538-7445.AM2015-508
Abstract 5092: Midkine as a potential target for combating drug resistance and invasion in melanoma
Authors: Kaur Amanpreet , O'Connell Michael , Webster Marie , Behera Reeti , Dang Vanessa , Ndoye Abibatou , Weeraratna Ashani 
Published: August 2015

Abstract
Melanoma is an aggressive disease. Although about 13% of melanoma cases are diagnosed at metastatic stage, the 5-year survival rate for these patients is 16%. We have previously shown that metastatic melanoma cells express high levels of Wnt5a. Wnt5a is a member of the Wnt family of proteins, which play an important role during development and tumorigenesis. In melanoma, Wnt5a signaling is mediated by an autocrine loop that also modulates the activity of midkine. Midkine is a 16kDa protein that is elevated in many different cancers. Overexpression of midkine promotes the growth, migration, survival and angiogenic capability of the tumors. However, the molecular mechanisms that regulate the activity of midkine are unknown, especially in metastatic melanoma. We asked whether Wnt5a can positively regulate the functions of midkine to promote the progression of metastatic melanoma. To address this, we analyzed melanoma cells for midkine expression and observed that Wnt5a high melanoma cells also express high levels of midkine. Further, an increase in Wnt5a signaling by treatment with recombinant Wnt5a led to an increased midkine signaling. By performing 3D spheroid assays, we observed that higher expression of midkine is correlated with an increased metastatic ability of the cells. The expression of midkine also correlated with an increased resistance to BRAF inhibitors in BRAF V600E mutated melanoma. This indicates that midkine may signal through MAPK pathway to affect invasion and drug resistance in metastatic melanoma. Developing adjuvant therapies targeting midkine can prolong the overall survival of patients with metastatic melanoma.
Citation Format: Amanpreet Kaur, Michael O'Connell, Marie Webster, Reeti Behera, Vanessa Dang, Abibatou Ndoye, Ashani Weeraratna. Midkine as a potential target for combating drug resistance and invasion in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5092. doi:10.1158/1538-7445.AM2015-5092
Abstract 5098: Participation of Crk-associated substrate (CAS) in human pancreatic cancer cell migration, invasion and metastatic processes
Authors: Okamoto Hirotaka , Fujii Hideki 
Published: August 2015

Abstract
Introduction; Crk-associated substrate (CAS, p130Cas) is a major tyrosine phosphorylated protein in cells transformed by v-crk and v-src oncogenes. In non-transformed cells, CAS localizes to focal adhesions and undergoes tyrosine phosphorylation in response to integrin-mediated signaling. In the current study, we evaluate the role of CAS in cell migration, invasion and metastatic processes in human pancreatic cancer cells. Materials and Methods; We investigated that CAS tyrosine kinase activity and tumor cell migration, invasion to endothelial cell monolayer in human pancreatic cancer cell lines, in vitro. CAS tyrosine phosphorylation were measured by immunoblotting and immunoprecipitation using anti-CAS monoclonal antibody and anti-phosphotyrosine antibody. Tumor cell migration was measured with Matrigel-coated modified-Boyden's chamber assay. Tumor cell invasion to endothelial cell monolayer was assayed with a co-culture invasion bioassay. Results; Tyrosine phosphorylation of CAS in human pancreatic cancer cells were induced during tumor cell migration and invasion. Phosphorylated tyrosine level of CAS was coincident with invasion capability in human pancreatic cancer cell lines, PSN-1, MiaPacaII, Panc1, despite of similar protein expression level. Protein tyrosine kinase inhibitor, Herbimycin A, had an inhibitory effect on migration and invasion as well as CAS tyrosine phosphorylation in tumor cells. Conclusion; These results indicated that CAS tyrosine phosphorylation in pancreatic tumor cells was correlated with invasive capability, suggesting a pivotal role of CAS in migration, invasion and metastatic processes.
Citation Format: Hirotaka Okamoto, Hideki Fujii. Participation of Crk-associated substrate (CAS) in human pancreatic cancer cell migration, invasion and metastatic processes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5098. doi:10.1158/1538-7445.AM2015-5098