bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1425: FBXO11 suppresses epithelial plasticity and proliferation by ubiquitinating the Snail family of transcription factors
Authors: Lu Jianrong , Jin Yue , Shenoy Anitha K. , Chen Hao , Luo Huacheng , Wu Lizi , Mohammed Kamal A. 
Published: August 2015

Abstract
Epithelial-to-mesenchymal transition (EMT) is central to embryonic development and carcinoma progression. The cell adhesion molecule E-cadherin critically maintains epithelial property and restricts epithelial cell proliferation and motility. The Snail family of transcription factors are core inducers of EMT in part through direct repression of E-cadherin transcription. The Snail factors are normally under tight control to safeguard epithelial identity and homeostasis. However, their physiological regulation remains largely elusive. In the present study, we show that the F-box protein FBXO11 binds to Snail in a phosphorylation-independent manner and targets it for ubiquitin-mediated proteasomal degradation. FBXO11 promotes the degradation of other Snail family members Slug and SCRT1 as well. Overexpression of FBXO11 in mesenchymal cells reduces Snail protein abundance and activates E-cadherin transcription. Conversely, depletion of endogenous FBXO11 in epithelial cancer cells causes Snail protein accumulation, EMT, and tumor invasion. Human cancer-derived FBXO11 missense mutants are impaired to degrade Snail. In human cancer, FBXO11 expression correlates with E-cadherin, and decreased expression of FBXO11 is robustly associated with adverse clinical outcomes. Inactivation of FBXO11 in mice results in neonatal lethality, increased Snail and Slug protein levels, decreased E-cadherin expression, and epidermal hyperplasia, which phenotypically resemble epidermis-specific transgenic overexpression of Snail or deletion of E-cadherin. These findings establish FBXO11 as a physiological ubiquitin ligase of Snails that is indispensable for suppressing epithelial hyperproliferation and plasticity during embryonic development and carcinoma progression.
Note: This abstract was not presented at the meeting.
Citation Format: Jianrong Lu, Yue Jin, Anitha K. Shenoy, Hao Chen, Huacheng Luo,Lizi Wu, Kamal A. Mohammed. FBXO11 suppresses epithelial plasticity and proliferation by ubiquitinating the Snail family of transcription factors. [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 1425. doi:10.1158/1538-7445.AM2015-1425
Abstract 1439: RANK expression by osteosarcoma cells increases lung metastasis in Nude mouse while has no effect in immune-competent mouse
Authors: Navet Benjamin , Ando Kosei , Yagita Hideo , Mueller Christopher G. , Heymann Dominique , Lezot Frederic 
Published: August 2015

Abstract
Abstract
Background: Osteosarcoma, the most frequent malignant primary bone tumor, is characterized by an osteoid tumor tissue formation associated to a tumor-induced osteolysis. Lung metastasis occurs in some osteosarcomas with dramatic consequence for patient lifespan. Expression of RANK has been reported in some osteosarcoma cells and the question of the potential repercussion on tumor growth, tumor-induced osteolysis and lung metastasis was raised.
Methods: Human HOS, human MG63 and mouse MOS-J osteosarcoma cell-lines were transfected to stably over-express RANK and injected in para-tibia muscle of Nude mice and syngeneic C57BL/6 mice for MOS-J cells. Tumor growth was follow and associated osteolysis analyzed by micro-CT and histology comparatively to injections of native cells. Lung metastases were numbered in each group.
Results: In Nude mouse RANK over-expression, whatever the cell-line considered (human or mouse), induces a significant increase of the number of lung metastasis while the tumor growth and the induced osteolysis are not affected. Injections of a RANKL blocking antibody reverse the impact of RANK over-expression on lung metastasis. In the C57BL/6, RANK over-expression has no impact on the lung metastasis and tumor-induced osteolysis. The tumor growth was slightly reduced.
Conclusions: Reported data evidence that RANK expression by osteosarcoma cells has no significant effect on the tumor growth and tumor-induced osteolysis but in immune-deficient Nude mouse induces an important increase of the lung metastases dependently of RANKL stimulation.
Citation Format: Benjamin Navet, Kosei Ando, Hideo Yagita, Christopher G. Mueller, Dominique Heymann, Frederic Lezot. RANK expression by osteosarcoma cells increases lung metastasis in Nude mouse while has no effect in immune-competent mouse. [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 1439. doi:10.1158/1538-7445.AM2015-1439
Abstract 1523: Prostaglandin E2 promotes colorectal cancer stem-like cell expansion and metastasis
Authors: Wang Dingzhi , Fu Lingchen , Sun Haiyan , DuBois Raymond N. 
Published: August 2015

Abstract
Emerging evidence suggests that chronic inflammation and inflammatory mediators contribute to cancer stem-like cell (CSLC) formation, maintenance, and expansion. However, the mechanisms underlying their contribution to CSLC regulation are poorly understood. Here we demonstrate that an inflammatory mediator, prostaglandin E2 (PGE2), induces colorectal CSLC expansion in vivo and in vitro. PGE2 also accelerates liver metastatic tumor incidence and numbers in an orthotopic model. Furthermore, we show that NF-κB is required for PGE2 induction of CSLCs and colorectal tumor metastatic spread. PI3K and MAPK pathways mediate PGE2 activation of NF-κB in induction of CSLCs. These results demonstrate that PGE2 induces colorectal CSLC expansion by activating NF-κB via PI3K-Akt and MAPK pathways. Our findings not only uncover a previously unrecognized role of PGE2 in induction of CSLCs and metastasis, but also may delineate a novel therapeutic approach for CRC patients by targeting CSLCs via inhibition of the PGE2 signaling pathway.
Citation Format: Dingzhi Wang, Lingchen Fu, Haiyan Sun, Raymond N. DuBois. Prostaglandin E2 promotes colorectal cancer stem-like cell expansion 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 1523. doi:10.1158/1538-7445.AM2015-1523
Abstract 1524: Establishing long-term circulating tumor cells (CTCs) in a 3D culture system in vitro
Authors: Cabrera Marina C. , Hurte Elaine 
Published: August 2015

Abstract
Circulating tumor cells (CTCs) are cells that have detached from the primary tumor and entered the bloodstream with the potential to seed metastatic tumors in distal sites. High CTC numbers correlate with aggressive disease, increased metastasis, and decreased time to relapse. It has also been shown that cancer stem cells (CSCs) represent a proportion of the CTCs present in patients. Given that CSCs are resistant to chemotherapy and are responsible for tumor initiation, it is posited that the CSCs are the seeds of metastasis. However, direct evidence for this hypothesis is limited due to the fact that there are few methods for culturing and studying these rare cells. We used a 3D culture chamber system (RealBio D4 ™) to establish long-term cultures of human-derived pancreatic tumors and to assess the effect of gemcitabine treatment on the CSC population of these cultures. We observed that the system's 3D matrix supported culture development and incorporation of tissue organization and microenvironment. The chamber design allowed CTCs generated within the cultures to migrate out of the cell mass into the circulating nutrient medium where they were collected for characterization. Further, tumor tissue grown on the matrix showed an enrichment of CSCs after gemcitabine treatment analogous to the enrichment observed in vivo. Future studies will focus on characterizing isolated CTCs and circulating CSCs from pancreas and breast cancer models, determine their response to therapy, and elucidate the relationship of different CTC populations on tumor spread. Ultimately, these studies may support the use of CTCs and circulating CSCs as biomarkers in clinical trials.
Citation Format: Marina C. Cabrera, Elaine Hurte. Establishing long-term circulating tumor cells (CTCs) in a 3D culture system in vitro. [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 1524. doi:10.1158/1538-7445.AM2015-1524
Abstract 1546: Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma
Authors: Takahashi Hideyuki , Sakakura Koichi , Chikamatsu Kazuaki 
Published: August 2015

Abstract
Introduction:
Evidence has accumulated indicating that cancer-associated fibroblasts (CAFs) play an important role in angiogenesis, invasion, and metastasis. Simultaneously, CAFs might actively participate in inducing immunosuppressive ability and promoting evasion from immunosurveillance. In the present study, we investigated whether CAFs within the tumor microenvironment contribute as one of key components of tumor immune evasion in head and neck squamous cell carcinoma (HNSCC).
Materials and methods:
CAFs and normal fibroblasts (NFs) were prepared from surgical tissue of HNSCC patients. Flow cytometric analysis was performed for the expression of A-smooth muscle actin (A-SMA) and co-stimulatory molecules. Inhibition of T-cell proliferation, T-cell apoptosis and induction of regulatory T cells (Treg) were also examined using flow cytometry. The mRNA expression of various cytokines was investigated by real-time qRT-PCR.
Results:
Generated CAFs and NFs were negative for CD11b, CD34, and CD45, and were positive for CD90 and FAP. The A-SMA expression of CAFs was higher than that of NFs. CAFs efficiently suppressed T cell proliferation as compared with NFs. Of note, this suppressive activity was found under co-cultivation with not only CAFs, but also supernatant from CAFs. CAFs, but not NFs expressed co-regulatory molecules, B7H1 and B7DC and CAFs showed increased expression levels of cytokine genes including IL-6, IL-8, TNF-A, TGF-β, and VEGF. Moreover, PBMCs co-cultured with supernatant from CAFs preferentially induced T-cell apoptosis and Treg as compared with those from NFs.
Conclusion:
Our findings suggest that, in the tumor microenvironment, CAFs might play a pivotal role in establishing an immunosuppressive network along with tumor cells, and subsequent facilitation to activate the immunosuppressive pathway.
Citation Format: Hideyuki Takahashi, Koichi Sakakura, Kazuaki Chikamatsu. Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell 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 1546. doi:10.1158/1538-7445.AM2015-1546
Abstract 1565: Magnetic bead-based serum peptidome profiling for identifying potential biomarkers in esophageal squamous cell carcinoma
Authors: Jia Kun , Li Wei , Wang Feng , Liu Fang , Liu Xiaofei , Qiao Yuanyuan , Xu Yang , Zhou Lanping , Sun Yulin , Ma Qingwei , Zhao Xiaohang 
Published: August 2015

Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant neoplasms worldwide, especially in China. Patients are often diagnosed at advanced stages with poor prognosis due to the absence of obvious early symptoms. Therefore, there is an urgent need to develop novel serological biomarkers for ESCC. Here, we performed a two-stage serum peptide profiling in 477 unique samples using weak cationic exchange magnetic beads coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The three significantly differentially expressed peaks were used to establish a genetic algorithm model for ESCC. The sensitivity and specificity were 97% and 95.92% in the training set, and 97.03% and 100% in the validation set, respectively. It was significantly better than the other well studied serum proteins such as squamous cell carcinoma antigen (SCC-Ag) and cytokeratin 19 fragment 21-1 (Cyfra 21-1). Notably, the diagnostic capability of this model was superior for early stage ESCC with a sensitivity of 96.94% and a specificity of 100%. Furthermore, the three diagnostic peptides were identified as fragments of alpha-2-HS-glycoprotein, thrombospondin-1, and fibrinogen alpha, respectively. The immunohistochemical staining assay showed that TSP1 was significantly overexpressed in tumor tissues and associated with lymph node metastasis and poor prognosis. Overall, we constructed a novel diagnostic model which will benefit the screening, early detection and diagnosis of ESCC. And the identified proteins and their derivative peptides will deepen our understanding of tumorigenesis and serve as potential serological biomarkers for ESCC.
Note: This abstract was not presented at the meeting.
Citation Format: Kun Jia, Wei Li, Feng Wang, Fang Liu, Xiaofei Liu, Yuanyuan Qiao, Yang Xu, Lanping Zhou, Yulin Sun, Qingwei Ma, Xiaohang Zhao. Magnetic bead-based serum peptidome profiling for identifying potential biomarkers in esophageal squamous cell 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 1565. doi:10.1158/1538-7445.AM2015-1565
Abstract 1568: Detection of HBV-host junction DNA sequences in urine of patients with HBV-infected HCC
Authors: Lin Selena , Song Benjamin , Trauger Evan , Hoffman Malcolm , Thompson Emilie , Zhou Rebecca , Jain Surbhi , Song Wei , Su Ying-Hsiu 
Published: August 2015

Abstract
Hepatitis B virus (HBV) related liver diseases often progresses from hepatitis to cirrhosis and eventually to hepatocellular carcinoma (HCC), which has a poor prognosis, mostly due to late detection. Chronic HBV infections are associated with &gt;50% of HCC cases worldwide, and up to 90% of HBV-related HCCs (HBV-HCC) were found to contain integrated HBV DNA. During infection, HBV DNA integrates in the host chromosome at variables sites, generating a unique HBV-host junction sequence (HBV-JS) that can serve as a DNA finger print of an infected hepatocyte. During hepatocarcinogenesis, tumorigenic hepatocyte(s) undergo uncontrolled clonal expansion resulting in one to few particular HBV-JS's becoming dominant. Thus, we hypothesize that the appearance of expanded HBV-JS species is a marker of clonal expansion and can be a potential marker for early detection of HBV-HCC.
A PCR-based enrichment assay and next generation sequencing (NGS) approach were developed for the HBV DR1-2 integration hotspot region to explore the feasibility of detecting HBV-JS's in the circulation (i.e. urine) of patients with HBV-HCC. HBV-HCC tissue DNA samples underwent library construction and were enriched for DNA containing the HBV DR1-2 sequences. Enriched DNA fragments were then cloned and sequenced, from which 5 HBV-JS's were discovered at Chr5 (hTERT promoter), Chr7 (AOAH intronic transcript 1), Chr12 (KCN2), Chr19 (miRNA 512-1,-2), and Chr22 (LARGE) in four patient samples. These sites were further confirmed in matched urine DNA samples by designing primers to amplify the HBV-JS. The NGS approach, which includes HBV-HCC (n = 18), HBV-hepatitis (n = 5), and HBV-cirrhosis (n = 8) urine samples to identify HBV-JS’s, is in progress. Overall, this would be the first study both to demonstrate unambiguous detection of HBV-JS's in the urine of HBV-HCC patients and to suggest the potential of detecting expanded HBV-JS species in urine as a marker for HBV-HCC screening. Furthermore, if successful, the high-throughput detection of HBV-JS's in urine by NGS offers a promising noninvasive HBV-HCC screening platform, as well as provides insight into the carcinogenic mechanisms of HBV DNA integration.
Citation Format: Selena Lin, Benjamin Song, Evan Trauger, Malcolm Hoffman, Emilie Thompson, Rebecca Zhou, Surbhi Jain, Wei Song, Ying-Hsiu Su. Detection of HBV-host junction DNA sequences in urine of patients with HBV-infected HCC. [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 1568. doi:10.1158/1538-7445.AM2015-1568
Abstract 1600: A multiplexed marker-based algorithm for diagnosis of carcinoma of unknown primary using circulating tumor cells
Authors: Matthew Elizabeth M. , Zhou Lanlan , Vijayvergia Namrata , Dicker David T. , Gustafson Karen S. , Cooper Harry S. , Ross Eric A. , Lim Bora , Harouaka Ramdane , Zheng Si-Yang , Lamparella Nicholas E. , Drabick Joseph J. , Truica Cristina I. , Yang Zhaohai , El-Deiry Wafik S. 
Published: August 2015

Abstract
Abstract: Real-time, single-cell multiplex immunophenotyping of circulating tumor cells (CTCs) is hypothesized to inform diagnosis of tissue of origin in patients with carcinoma of unknown primary (CUP). In 20 to 50% of CUP patients, the primary site remains unidentified, presenting a challenge for clinicians in diagnosis and treatment. Invasive tissue biopsy is the gold standard for diagnosis but improved methodology is needed. We developed a post-CellSearch CTC assay using multiplexed Q-dot or DyLight conjugated antibodies with the goal of detecting multiple markers in single cells within a CTC population. We adapted our approach to size-based CTC enrichment protocols for capturing CTCs and subsequent immunofluorescence (IF) using a minimal set of markers to predict the primary sites for common metastatic tumors. The carcinomas are diagnosed with cytokeratin 7 (CK7), cytokeratin 20 (CK20), thyroid transcription factor 1 (TTF-1), estrogen receptor (ER) or prostate-specific antigen (PSA) as the minimal set of informative markers. IF has been optimized in cultured tumor cells with individual antibodies, then with conjugated antibodies to form a multiplex antibody set. With IF, we evaluated antibodies specific to these 5 markers in lung, breast, colorectal, and prostate cancer cell lines and blood samples from metastatic prostate and breast cancer patients. Our technological advance provides a noninvasive, inexpensive, diagnostic blood test as an adjunct to routine tissue biopsy. Its further implementation requires prospective clinical testing.
Citation Format: Elizabeth M. Matthew, Lanlan Zhou, Namrata Vijayvergia, David T. Dicker, Karen S. Gustafson, Harry S. Cooper, Eric A. Ross, Bora Lim, Ramdane Harouaka, Si-Yang Zheng, Nicholas E. Lamparella, Joseph J. Drabick, Cristina I. Truica, Zhaohai Yang, Wafik S. El-Deiry. A multiplexed marker-based algorithm for diagnosis of carcinoma of unknown primary using circulating 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 1600. doi:10.1158/1538-7445.AM2015-1600
Abstract 1665: Design, synthesis, biological evaluation of cyclopenta[d]pyrimidines as antitubulin agents and discovery of N-(4-methylthiophenyl) and N-(4-dimethylaminophenyl) substituted N,2-dimethyl-cyclopenta[d]pyrimidines as long acting and poten
Authors: Gangjee Aleem , Xiang Weiguo , Mooberry Susan L. , Hamel Ernest 
Published: August 2015

Abstract
Compounds that bind to the colchicine site of microtubules have promising antitumor potential. Some of these agents also possess the ability to overcome multiple drug resistance mechanisms, including those mediated by the expression of P-glycoprotein (Pgp) or expression of the tubulin β-III isotype. We have reported that compounds 1 and 2 were potent antiproliferative agents that bind to the colchicine site of tubulin. The previous structure-activity relationship studies of cyclopenta[d]pyrimidine based antitubulin agents demonstrated the importance of the para-methoxyphenyl moiety for antiproliferative activity. However, the literature suggests that the major metabolism of the methoxyphenyl moiety was likely O-demethylation. In order to increase the potency and in vivo stability of 1, we focused our attention on the variation of the para-methoxy aniline moiety. Compound 3 with a 4′-methylthiophenyl substitution was designed to decrease potential metabolic demethylation. This S-methyl analog was a potent inhibitor of proliferation with an IC50 of 4.6 ± 0.5 nM in MDA-MB-435 cells. The possible sulfoxide metabolite, 4 was synthesized and had an IC50 = 7.9 ± 0.5 nM. Each of these depolymerized microtubules. In addition, the 4′-dimethylamino moiety compound 5 also demonstrated potent antitubulin and antiproliferative activity (MDA-MB-435: IC50 = 8.2 ± 0.6 nM). The possible N-demethylated metabolite of 5, para-methylamino 6 was also a highly potent antiproliferative agent (MDA-MB-435: IC50 = 20 ± 1.9 nM). The parent compounds 3 and 5, as well as their probable metabolites 4 and 6, inhibited the binding of [3H]colchicine to tubulin, which showed that these compounds bind to the colchicine site. The potent antiproliferative activities of the parent compounds and the potential metabolites of compounds 3 and 5 suggest the utility of 3 and 5 as long acting, potent antimitotic agents. Finally, the in vivo efficacy of the S-methyl analog 2 was demonstrated against MDA-MB-435 triple negative breast cancer murine xenograft model, indicating the potential utility of these analogs as antitumor agents.
Citation Format: Aleem Gangjee, Weiguo Xiang, Susan L. Mooberry, Ernest Hamel. Design, synthesis, biological evaluation of cyclopenta[d]pyrimidines as antitubulin agents and discovery of N-(4-methylthiophenyl) and N-(4-dimethylaminophenyl) substituted N,2-dimethyl-cyclopenta[d]pyrimidines as long acting and poten [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 1665. doi:10.1158/1538-7445.AM2015-1665
Abstract 1672: Structural basis for inhibition of ligand-dependent and -independent ErbB3 activation by KTN3379
Authors: Alvarado Diego , Lee Sangwon , Greenlee Etienne , Ligon Gwenda F. , Lillquist Jay S. , Natoli Edward J. , LaVallee Theresa M. , Schlessinger Joseph 
Published: August 2015

Abstract
ErbB3 signaling plays an important role in the progression of a number of solid tumor types, and is the target of several therapeutic monoclonal antibodies. In cancer, ErbB3 activation can be driven by its ligand Neuregulin, or in its absence, through high overexpression of its co-receptor ErbB2. Here, we report that the ErbB3 monoclonal antibody KTN3379, currently in phase 1 clinical development, robustly inhibits both mechanisms of ErbB3 activation in different tumor model settings. The crystal structure of a KTN3379 Fab in complex with the full ErbB3 extracellular domain reveals that the antibody binds with very high affinity to a novel and unique epitope in the boundary of domains 2 and 3, and locks the receptor in an inactive conformation. Thus, KTN3379 interferes with the first step of ErbB3 activation, which is required for both ligand-dependent and ligand-independent signaling. The mechanism of inhibition described here should be also applicable to EGFR and ErbB4.
Citation Format: Diego Alvarado, Sangwon Lee, Etienne Greenlee, Gwenda F. Ligon, Jay S. Lillquist, Edward J. Natoli, Theresa M. LaVallee, Joseph Schlessinger. Structural basis for inhibition of ligand-dependent and -independent ErbB3 activation by KTN3379. [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 1672. doi:10.1158/1538-7445.AM2015-1672