bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3207: The roles of cancer-associated fibroblasts in stemness maintenance of lung cancer cells
Authors: Lin Chih-An , Ho Chao-Chi , Chen Jeremy J.W. 
Published: August 2015

Abstract
Lung cancer is the leading cause of death worldwide including Taiwan. A lot of therapies have been developed to improve cure rate of lung cancer, however the prognosis remains dismal. Cancer cells can acquire resistance to therapies by several known or unknown mechanisms. Microenvironment is also important for acquiring resistance to corresponding treatments of cancer cells. Cancer-associated fibroblasts (CAFs) are known to support many different aspects of tumor initiation, growth and progression by secretion of growth stimulatory, pro-survival and angiogenic factors. In our studies, we compare the differences between normal fibroblasts (NFs) and CAFs which were cultured from surgical specimens of lung cancer patients. CAFs shows increasing tumorous sphere formation ability and significantly up-regulating stem cell markers such as nanog, klf-4, Sox-2, Oct4 and c-myc of cancer cells. We also found that CAFs regulate cancer stem cells (CSCs) growth through numerous paracrine factors such as IGF-II, HGF and SDF1 and by inducing expression of the corresponding receptors in CSCs, including IGF1R, IGF2R, HGFR and CXCR4. In our studies, CAFs obtain more advanced ability compared to NFs, but the mechanisms of how NFs are educated to become CAFs are still unknown, thus we trying to clarify the mechanisms by genome and epigenome-wide high-throughput analysis, including cDNA array, DNA methylation array and miRNA array.
Citation Format: Chih-An Lin, Chao-Chi Ho, Jeremy J.W. Chen. The roles of cancer-associated fibroblasts in stemness maintenance of lung cancer 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 3207. doi:10.1158/1538-7445.AM2015-3207
Abstract 3210: Level of Osteoprotegerin expression is breast cancer subtype specific
Authors: Tsang Stephanie , Renaud Ashleigh , Roseman Kim , Imaizumi Yuko , Yadav Nalini , Weichhaus Michael , Connelly Linda 
Published: August 2015

Abstract
Osteoprotegerin (OPG) is a regulator of bone metabolism that is also produced by breast tumor cells. There is accumulating evidence that OPG has tumor-promoting effects in breast cancer. We have recently demonstrated that OPG can promote invasion and metastasis of triple negative breast cancer cells. We are now investigating the expression of OPG across major breast cancer subtypes.
We cultured 3 breast cancer cells lines from each of the major subtypes: MCF-7, ZR-75-1 and T47-D (Estrogen Receptor positive; ER+); SKBR-3, HCC1954 and HCC202 (Human Epidermal Growth Factor Receptor 2 positive; HER2+) and MDA-MB-231, MDA-MB-436 and BT-549 (triple negative). We incubated cells for 24 hours and then measured OPG mRNA expression by real time RT-PCR and secreted OPG protein in cell culture supernatant by ELISA.
The triple negative cells that we tested expressed the highest levels of OPG mRNA and protein. A much lower level of OPG expression was observed in the HER2+ cells. Contrasting results were observed with the ER+ cells. While there was no expression from the ZR-75-1 or T47-D cells after 24 hours incubation, the MCF-7 cells produced levels of OPG similar to those observed with the triple negative breast cancer cells.
We also looked at whether OPG expression levels could be altered by incubating breast cancer cells with macrophages, a cell type found in the breast tumor microenvironment. We co-cultured cells from each subtype with THP-1 human macrophages for 8 hours and extracted mRNA from the breast cancer cells or incubated the breast cancer cells for an additional 16 hours alone to measure secreted OPG protein. We found that co-culture with macrophages significantly increased OPG mRNA and protein expression in MCF-7 (ER+) and SKBR-3 (HER2+) cells but there was no increase in the MDA-MB-231 cells (triple negative).
In conclusion, while OPG was expressed at comparatively high levels in triple negative breast cancer cells, there were generally low levels or no expression in the ER+ and HER2+ cells tested. This suggests that the tumor-promoting effects of OPG may contribute to the more aggressive phenotype in triple negative cells. However OPG expression in ER+ and HER2+ cells can be stimulated through co-culture with macrophages. Thus conditions within the breast tumor microenvironment could amplify the effects of OPG in these tumor subtypes.
Citation Format: Stephanie Tsang, Ashleigh Renaud, Kim Roseman, Yuko Imaizumi, Nalini Yadav, Michael Weichhaus, Linda Connelly. Level of Osteoprotegerin expression is breast cancer subtype specific. [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 3210. doi:10.1158/1538-7445.AM2015-3210
Abstract 3218: Transcriptome characterization by RNA sequencing identifies molecular and clinical subgroups in high risk neuroblastoma
Authors: Zhang Shile , Wei Jun S. , Patidar Rajesh , Song Young K. , Sindiri Sivasish , Wen Xinyu , Asgharzadeh Shahab , Seeger Robert C. , Maris John M. , Guidry Auvil Jamie M. , Gerhard Daniela S. , Khan Javed 
Published: August 2015

Abstract
Background/objectives: Neuroblastoma (NBL) is characterized with its heterogeneous clinical and biological behavior. Despite improvement of survival rate with multimodal chemo- and immunotherapy, high mortality and morbidity is still substantial for patients with metastatic disease. Previous DNA sequencing studies characterized the genetic basis of the disease and revealed a very low somatic mutation burden and surprisingly few recurrently somatic mutated genes comparing to adult solid tumors. In order to identify the novel molecular therapeutic target and understand the biology of the high-risk neuroblastoma, we investigated gene expression profiles of tumors from a cohort of high-risk neuroblastoma patient using RNA sequencing as an integral part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project.
Methods: We performed RNA sequencing in a cohort of 150 high risk patients (97 survival and 53 death) using polyA selected mRNA. Gene and transcript isoform expression was used to correlate to the clinical parameters for this clinically well-annotated patient cohort. Whole exome sequencing (WES) data was available for 106 of the 150 patients cohort for combined analysis of DNA and RNA sequencing to identify expressed mutation.
Results: On average, we found 12.5% of the human genome, which include 63.7% of exon, 18.0% of intron, and 4.6% of intergenic regions covered by RNA-seq reads in NB samples. Preliminary gene expression analysis showed four molecular subgroups of NB tumors with distinct outcomes (log-ranked p = 0.002). Sixty-two percent of somatic mutations identified by WES was present (&gt;10% VAF) in the RNA transcriptome when the locus was expressed (10X). We found that some of the important pathogenic somatic mutations such as TP53 p.R243W can be only detectable by integrated analysis of the sequencing data of RNA and DNA, possibly due to low tumor purity.
Future directions: We will assess the expressed mutations, fusion genes, mRNA expression, and splicing profiles to provide clinically relevant classification and offer insight into the tumor biology especially for those without detectable oncogenic driver mutation by DNA sequencing.
Citation Format: Shile Zhang, Jun S. Wei, Rajesh Patidar, Young K. Song, Sivasish Sindiri, Xinyu Wen, Shahab Asgharzadeh, Robert C. Seeger, John M. Maris, Jamie M. Guidry Auvil, Daniela S. Gerhard, Javed Khan. Transcriptome characterization by RNA sequencing identifies molecular and clinical subgroups in high risk neuroblastoma. [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 3218. doi:10.1158/1538-7445.AM2015-3218
Abstract 3221: Development of patient-derived xenograft (PDX) models for gastrointestinal stromal tumors (GIST) as a pre-clinical platform for drug development
Authors: Ricono Jill , Mullins Chelsea , Nair Praveen , Mirsaidi Cyrus , Broudy Thomas 
Published: August 2015

Abstract
Patients with gastrointestinal stromal tumors (GIST) continue to face a poor prognosis. GISTs are a type of soft tissue sarcoma primarily affecting adults over the age of 50. They are the most common mesenchymal tumor within the GI tract. Survival rates vary greatly depending on the location when it is first diagnosed and there has been minimal progress in improving the survival rates of metastatic GISTs. It has been difficult to accurately evaluate the effectiveness of targeted drugs to develop treatment strategies due to the rarity and complexity of GISTs. In an effort to overcome this challenge, we have established PDX models to recapitulate the original patient tumor. In this work, we selected four primary GIST samples based on mutational and clinical profile. PDX models were developed in immunocompromised mice and were further characterized by immunohistochemistry, sequencing and pharmacological efficacy. We then evaluated the efficacy of chemotherapeutic agents in these models. Our data demonstrates that these preclinical PDX models could be used in evaluation and development of novel drug candidates for GIST.
Citation Format: Jill Ricono, Chelsea Mullins, Praveen Nair, Cyrus Mirsaidi, Thomas Broudy. Development of patient-derived xenograft (PDX) models for gastrointestinal stromal tumors (GIST) as a pre-clinical platform for drug development. [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 3221. doi:10.1158/1538-7445.AM2015-3221
Abstract 3222: Biomarker discovery through bioinformatic analysis of genomic profiles of PDX models with different responses to cancer therapies
Authors: Jiang Jingjing , Yu Tengfei , Yan Ying , Du Wei , Tan Tingting , Yang Xuqin , Gu Jiali , Hua Liang , Ye Katherine Xin , Gu Zhenyu 
Published: August 2015

Abstract
Patient derived xenograft (PDX) tumor models have been proved to recapitulate the complexity and heterogeneity of their corresponding human tumors by phenotypic and genomic characterization, and thus become to be widely used in recent years in preclinical setting to facilitate drug discovery, translational studies and clinical trials support. Results from increasing number of preclinical studies, especially mouse trials, with PDX models in the past several years, have also demonstrated close correlation between drug response profiles with PDX models and clinical outcomes.
GenenDesign has established over 800 PDX tumor models and derived around 100 resistance models to drugs of interest. Genomic profiling data of PDX models are acquired at hot-spot mutation, gene expression, gene copy number and RNA/Exome sequence levels. Through our in-house efforts, PDX models of different tumor types were tested with related SOCs and clinical candidates in biomarker-driven multi-drug multi-arm clinical trial settings. So far, more than 1200 data sets have been generated, including responses to targeted inhibitors against HER2, EGFR, FGFRs, c-Met/ALK, cell cycle regulators, Ras/Raf pathway, PI3K/Akt pathway, epigenetic targets, as well as chemotherapy drugs.
In this study, we use bioinformatic tools to compare the genomic profiles of NSCLC PDX models based on their response profiles to multiple chemotherapy drugs. Biomarker signatures associated with SOC treatment sensitivity or resistance are revealed from bioinformatic analysis and being tested with both new NSCLC PDX models and clinical cohorts.
The combination of genomic profiles and drug response information to multiple chemo/targeted therapies of over 800 PDX models at GenenDesign would help biomarker discovery for companion diagnosis to meet the increasing needs for precision medicine.
Citation Format: Jingjing Jiang, Tengfei Yu, Ying Yan, Wei Du, Tingting Tan, Xuqin Yang, Jiali Gu, Liang Hua, Katherine Xin Ye, Zhenyu Gu. Biomarker discovery through bioinformatic analysis of genomic profiles of PDX models with different responses to cancer therapies. [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 3222. doi:10.1158/1538-7445.AM2015-3222
Abstract 3228: Establishment and characterization of orthotopic mouse models for human uveal melanoma hepatic metastases
Authors: Ozaki Shinji , Terai Mizue , Kageyama Ken , Cheng Hanyin , Ohara Masahiro , Aplin Andrew E. , Mastranjelo Michael J. , Sato Takami 
Published: August 2015

Abstract
Uveal melanoma (UM) is a rare type of melanoma although it is the most common primary ocular malignant tumor in adults. Nearly half of patients with primary UM subsequently develop systemic metastasis, preferentially to the liver. Currently, there is no effective treatment for UM hepatic metastasis and the prognosis is universally poor. The major challenge in designing a treatment strategy for UM hepatic metastasis is the lack of suitable animal models. We have developed two orthotopic mouse models for human UM hepatic metastases: (1) Direct hepatic implantation model (intra-hepatic dissemination model), and (2) Splenic-implantation model (hematogenous dissemination model) and investigated the tumor genesis in the liver. A human UM cell line, established from a hepatic metastasis and NSG mice were used for development of in vivo tumor models.
In direct hepatic implantation model, a localized tumor developed in the liver in all cases and intrahepatic dissemination was subsequently seen in about half of cases. On the other hand, in splenic implantation model, multiple hepatic metastases were observed after splenic implantation. Hepatic tumors subsequently developed intra-abdominal metastasis; however, lung metastases were not seen. These findings are consistent with those observed in human UM hepatic metastases. In addition, there are broad extracellular matrix connecting the blood vessels lined with endothelium in the hepatic tumors. These structures are assumed to be so called “vasculogenic mimicry (VM)” formed by the the tumor cells themselves. Notably, we found tumor cells in the liver begin to form VM, despite a small number of them and eventually develop a broad network of VM in the tumor. Thus, VM might contribute to the microcirculation in the tumor preceding development of vessels lined with endothelium. Moreover, we have generated orange-red fluorescence protein (td-Tomato fluorescent protein) expressing cell line using the same UM cell line and developed the same mouse models. This allowed us to monitor the growth of hepatic metastasis over time by in vivo live-imaging system.
These orthotopic mouse models offer useful tools to investigate the biological behavior of human UM cells in the liver.
Citation Format: Shinji Ozaki, Mizue Terai, Ken Kageyama, Hanyin Cheng, Masahiro Ohara, Andrew E. Aplin, Michael J. Mastranjelo, Takami Sato. Establishment and characterization of orthotopic mouse models for human uveal melanoma hepatic metastases. [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 3228. doi:10.1158/1538-7445.AM2015-3228
Abstract 3229: Distinct types of cetuximab resistant KRAS mutant of colorectal cancer revealed by an integrated sensitivity assay
Authors: Tashiro Takahiro , Okuyama Hiroaki , Endo Hiroko , Kawada Kenji , Ohue Masayuki , Sakai Yoshiharu , Inoue Masahiro 
Published: August 2015

Abstract
Purpose: Cetuximab, an anti-EGFR antibody, is clinically used in colorectal cancer (CRC) patients. Several clinical trials revealed that KRAS mutant is resistant to cetuximab. As KRAS is one of the downstream molecules in EGFR pathway, KRAS mutants are thought to be resistant to cetuximab due to the constitutive activation of downstream signaling, although mechanism of resistance in KRAS-mutant CRC remains to be elusive. We developed a primary culture system, CTOS method, by which cancer cells are prepared and cultured from patient tumors, maintaining histological and molecular characteristics of original tumors (Kondo 2011 PNAS). CTOS method can be applied to patient tumors as well as mouse xenografts. In this study, we performed integrated sensitivity assays by in vivo/in vitro CTOS sensitivity assay, and CTOS signaling assay in order to investigate characteristics of KRAS mutant CRC cells.
Methods: Nine CTOS lines (3 KRAS-wild type, and 6 KRAS-mutant) were analyzed. For in vivo sensitivity assay, growth suppression by cetuximab was evaluated in mouse xenografts derived from CTOSs. CTOSs were classified into three groups according to the response (Regression: tumors became smaller than initial size; Intermediate; tumors became smaller than untreated control but bigger than initial size; Progression: no effect). For in vitro sensitivity assay, growth suppression by cetuximab was evaluated in CTOSs. For signaling analysis, CTOSs were treated with EGF and/or cetuximab, and phosphorylation of EGFR, AKT, and ERK were evaluated.
Results: Regression in vivo was found in the tumors originated only from KRAS-wt (2/3). KRAS-mutant CTOSs were able to be clearly divided into two groups. Type I (2 CTOSs) showed Progression in vivo, no response in vitro, and no response in signaling assay. Even the phosphorylation of EGFR was not inhibited by cetuximab treatment. On the other hand, Type II (4 COTSs) showed Intermediate in vivo, moderate response in vitro, and variable responses in signaling assay. ERK phosphorylation was inhibited by cetuximab treatment in all 4 CTOSs.
Conclusions: Using integrated in vivo and in vitro assays, KRAS mutant was able to be divided into two distinct groups according to the response to cetuximab. Resistant mechanism of KRAS mutant rather than MAPK pathway activation can be studied in this integrated assay system.
Citation Format: Takahiro Tashiro, Hiroaki Okuyama, Hiroko Endo, Kenji Kawada, Masayuki Ohue, Yoshiharu Sakai, Masahiro Inoue. Distinct types of cetuximab resistant KRAS mutant of colorectal cancer revealed by an integrated sensitivity assay. [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 3229. doi:10.1158/1538-7445.AM2015-3229
Abstract 3231: An orthotopic xenograft model of sarcoma metastasis demonstrates essential role of tumor microenvironment for metastasis
Authors: Goldstein Seth D. , Hayashi Masanori , Albert Catherine M. , Jackson Kyle W. , Loeb David M. 
Published: August 2015

Abstract
Sarcoma metastasis is a multi-step process that includes migration, intravasation into the circulation, extravasation and invasion to distant tissue, and distant tumor growth, and because commonly used xenograft models do not account for every step in the process, we sought to develop a novel metastasis model system. Our technique involves implanting small fragments of patient-derived xenografts into either the tibia or gastrocnemius muscle of NOD/SCID/IL-2Rγ knock-out mice and amputating the affected limb when the tumor reaches at least 1 cm in diameter. Mice are then followed for the development of distant metastases. We found that Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma xenografts all undergo distant metastasis when implanted in an orthotopic location, but do not metastasize after subcutaneous implantation, even when the subcutaneous tumor is excised and mice are observed long-term post-excision. We also investigated whether the difference in metastatic potential is related to cell intrinsic or cell extrinsic factors. Analysis by immunofluorescence revealed that tumors are infiltrated by macrophages regardless of site of implantation, but that the polarization of these macrophages differs. We also found differences in expression of arginase and NOS2 based on site of xenograft implantation. Thus, we have demonstrated that sarcoma patient-derived xenografts undergo spontaneous distant metastasis when implanted in an orthotopic location, but not when implanted in a heterotopic location, highlighting the essential role of the tumor microenvironment in determining metastatic potential. This model has significant benefits compared with the more commonly used tail vein injection model of metastasis, which bypasses the requirements for local invasion and vascular intravasation, processes that are amenable to study using our model. We have begun to use this model to investigate the mechanisms by which tumor microenvironment influences metastasis, and also are using this model for preclinical drug evaluation to determine a therapy's effect not only on growth of the primary tumor, but also on development of metastasis.
Citation Format: Seth D. Goldstein, Masanori Hayashi, Catherine M. Albert, Kyle W. Jackson, David M. Loeb. An orthotopic xenograft model of sarcoma metastasis demonstrates essential role of tumor microenvironment for 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 3231. doi:10.1158/1538-7445.AM2015-3231