bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 101: Surgical orthotopic implantation (SOI) lung cancer model with 95% survival and 100% take rate for spectral imaging
Authors: Zhang Yong , Zhang Nan , Zhao Ming A. , Hoffman Robert M. 
Published: May 2015

Abstract
For lung cancer, orthotopic models in mice are difficult to create due to a high death rate due to thoracotomy and anesthetization. In the present study, we achieved anesthesia via mask isoflurane inhalation and then performed a thoracotomy by making an incision between the fourth and fifth intercostal ribs on the left side of the chest. Lung tumor fragments were then implanted at this site. Tumor formation was monitored through spectral imaging using the Maestro (CRi). Breathing rate drop to &lt;60/min was an indicator to interrupt anesthesia. This method exhibited high tumorigenicity (100%) and a low mortality rate (5%) making it ideal for creating orthotopic lung tumor models and useful for sequential follow-up studies using spectral imaging.
Citation Format: Yong Zhang, Nan Zhang, Ming A. Zhao, Robert M. Hoffman. Surgical orthotopic implantation (SOI) lung cancer model with 95% survival and 100% take rate for spectral imaging. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 101. doi:10.1158/1538-7445.AM2014-101
Abstract 1025: Antitumor activity of nintedanib (BIBF 1120), a triple angiokinase inhibitor, in combination with gemcitabine in experimental pancreatic cancer
Authors: Awasthi Niranjan , Hinz Stefan , Brekken Rolf A. , Schwarz Margaret A. , Schwarz Roderich E. 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States with extremely poor prognosis. Gemcitabine (Gem), the standard of care agent over the past 15 years, has limited clinical benefits. There is an urgent requirement for novel therapeutic strategies to improve overall survival of patients with pancreatic cancer. Angiogenesis, an essential process for tumor growth and metastasis, remains a sensible target for PDAC therapy. VEGF, PDGF, FGF and their receptors are all overexpressed and have been correlated with poor prognosis in human PDAC. Nintedanib (BIBF 1120, Nin) is a triple angiokinase inhibitor that targets VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β signaling. Nintedanib is currently under clinical investigation for several solid tumors. The present study investigated the combination treatment benefits of gemcitabine and nintedanib in experimental PDAC. Cell proliferation, migration and protein expression were analyzed by WST-1 assay, wound healing assay and Western blotting. Tumor growth and animal survival experiments were performed in murine xenografts. Percent inhibition of cell proliferation in the Gem, Nin and Gem+Nin groups was 22%, 25% and 53% (AsPC-1 PDAC cells, Gem 50 nM, Nin 100 nM); 55%, 11% and 80% (endothelial cells HUVECs, Gem 100 nM, Nin 100 nM); 91%, 68% and 94% (fibroblast WI-38 cells, Gem 100 nM, Nin 100 nM). Nintedanib increased apoptosis, indicated by the cleavage of caspase-3 protein in all three cell-types tested. In PDAC cells, antitumor activity was accompanied by higher level of cell cycle inhibitor protein p27. Nintedanib (10 μM) inhibited in vitro wound closure by 84% in endothelial cells. In a heterotopic PDAC model, compared to the percent net local tumor growth in controls (100±29), a reduced growth of 60.8±10.5 (p=0.02) was observed in the Gem group, while a net reduction of -2.1±9.9 (p=0.0001) and -12.4±16.2 (p=0.0001) was observed in Nin and Gem+Nin groups, respectively. Compared with controls (16 days) in an AsPC-1 intraperitoneal model, median animal survival in Gem, Nin and Gem+Nin treatment groups was 25 days, 31 days and 38 days. The strong antitumor activity of nintedanib in experimental PDAC supports the potential of nintedanib-controlled mechanisms as targets for improved clinical PDAC therapy.
Citation Format: Niranjan Awasthi, Stefan Hinz, Rolf A. Brekken, Margaret A. Schwarz, Roderich E. Schwarz. Antitumor activity of nintedanib (BIBF 1120), a triple angiokinase inhibitor, in combination with gemcitabine in experimental pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1025. doi:10.1158/1538-7445.AM2014-1025
Abstract 1036: Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition
Authors: Matsubara Daisuke , Ibrahim Reem , Osman Wael , Goto Akteru , Morikawa Teppei , Morita Shigeki , Ishikawa Shumpei , Aburatani Hiroyuki , Fukayama Masashi , Niki Toshiro , Murakami Yoshinori 
Published: May 2015

Abstract
Although protein arginine methyltransferase 5 (PRMT5) has been implicated in various cancers, its expression pattern in lung adenocarcinoma cell lines and tissue samples has not yet been elucidated in detail. In this study, microarray data analysis of 40 non-small cell lung carcinoma cell lines showed that PRMT5 was a candidate histone methyltransferase gene that correlated with epithelial-mesenchymal transition. Immunocytochemical analysis of these cell lines indicated that the expression of PRMT5 was frequently localized to the cytoplasm of E-cadherin-low and vimentin-high cell lines, while it was predominant in the nucleus and faint in the cytoplasm of E-cadherin-high and vimentin-low cell lines. Immunohistochemical analysis of 130 cases of lung adenocarcinoma revealed that the expression of PRMT5 was high in the cytoplasm of 47 cases (36%) and the nuclei of 34 cases (26%). The high cytoplasmic expression of PRMT5 was frequently observed in high grade subtypes such as the solid adenocarcinoma component with low expression of thyroid transcription factor-1 (TTF-1, the master regulator of lung) and low expression of cytokeratin 7 and E-cadherin (two markers for bronchial epithelial differentiation), while the high nuclear expression of PRMT5 was frequently noted in the lepidic growth component, a low-grade subtype. The cytoplasmic expression of PRMT5 was correlated with vessel invasion and poor prognosis. We herein highlighted the importance of PRMT5 expression, especially its cytoplasmic expression, in the process of epithelial-mesenchymal transition and loss of the bronchial epithelial phenotype of lung adenocarcinoma.
Citation Format: Daisuke Matsubara, Reem Ibrahim, Wael Osman, Akteru Goto, Teppei Morikawa, Shigeki Morita, Shumpei Ishikawa, Hiroyuki Aburatani, Masashi Fukayama, Toshiro Niki, Yoshinori Murakami. Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1036. doi:10.1158/1538-7445.AM2014-1036
Abstract 1055: Syntenin positively regulates TGF-β1- and oncogenic Ras-mediated EMT-like phenotypic changes in cancer cells
Authors: Kim Okhwa , Hwangbo Cheol , Tae Nara , Lee Suhyun , Lee Jeong-Hyung 
Published: May 2015

Abstract
Epithelial to mesenchymal transition (EMT) is biological process in polarized epithelial cells, which occurs in various physiological and pathological conditions. In carcinoma progression, EMT has emerged as a critical player in regulating cancer cell invasive phenotype. Syntenin, a tandem PDZ-domain containing scaffold protein, functions as a positive regulator of cancer cell progression in several human cancers. In present study, we investigated a role of syntenin in transforming growth factor (TGF)-β1- and Ras-V12-mediated EMT-like phenotypic changes in cancer cells. Knockdown of syntenin suppressed TGF-β1- and Ras-V12-induced morphological and cell biological alterations in A549, Ep/Ras, and BEAS-2B cells that are consistent with EMT; however, overexpression of syntenin stimulated TGF-β1- and Ras-V12-induced EMT, implying that syntenin is necessary for TGF-β1- and Ras-V12- induced EMT. We found that syntenin is associated with RSK (p90 ribosomal S6 kinase) via PDZ binding motif and syntenin at Ser6 residue may directly be phosphorylated by RSK. Mutation of syntenin Ser6 to Ala suppresses TGF-β1- and oncogenic Ras-mediated EMT in a dominant negative manner by abolishing the interaction of endogenous syntenin with RSK. Strikingly, expression of syntenin-S6E, a phosphomimetic mutant of syntenin at Ser6, into A549, Ep/Ras, or BEAS-2B cells induced EMT-like phenotypic changes, characterized by down-regulation of E-cadherin and up-regulation of vimentin, Snail and Slug, suggesting that Ser6 phosphorylation of syntenin by RSK is necessary and sufficient for the induction of EMT mediated by TGF-β1. In addition, we sought to determine whether Ser6 phosphorylation of syntenin would modulate in vivo metastasis in a mouse model. A549 cells expressing syntenin-S6E dramatically increased lung metastases. Based on these data, we conclude that phosphorylation of syntenin at Ser6 by RSK is necessary and sufficient for the induction of EMT and metastasis in certain cancer cells.
Citation Format: Okhwa Kim, Cheol Hwangbo, Nara Tae, Suhyun Lee, Jeong-Hyung Lee. Syntenin positively regulates TGF-β1- and oncogenic Ras-mediated EMT-like phenotypic changes in cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1055. doi:10.1158/1538-7445.AM2014-1055
Abstract 1059: EGF induces epithelial-mesenchymal transition and cancer stem cell properties in human oral squamous cell carcinoma
Authors: Xu Qilin , Zhang Qunzhou , Le Anh 
Published: May 2015

Abstract
Head and neck cancer is one of the 10 most common cancers worldwide. Despite advances in therapeutic research in the last few decades, morbidity and mortality remain unchanged. Recurrent and metastatic oral squamous cell carcinoma (OSCC) of the head and neck may have correlated with epithelial-mesenchymal transition (EMT), a property acquired by cancer stem cells (CSCs). In our study, SCC-1 cells (a human tongue cancer cell line) treated with epidermal growth factor (EGF) underwent EMT as confirmed by morphological changes and expression of EMT-related markers using Western blot, immunocytostaining, and flow cytometric analyses. Our data showed that, in comparison with non-treated cells, EGF treatment induced SCC-1 cells to undergo EMT, characterized by spindle-shaped mesenchymal-like morphology, an altered suppression of E-cadherin and promotion of vimentin expression, and an enhanced invasive capacity. Our results also indicated that EGF significantly enriched the fraction of CD44+/CD24low/- CSCs in SCC-1 cells, from 7∼8% to 25∼29%, and simultaneously increased the expression of aldehyde dehydrogenase 1 (ALDH1), a common marker for stem cells. Moreover, the purified CD44+/CD24low/- CSC population displayed stem cell properties associated with EMT phenotypes and increased migration and invasion abilities in vitro. Using a murine orthotopic tongue cancer model transplanted with stably GFP-expressing SCC-1 cells (GFP-SCC-1), we confirmed that EGF can promote tumor metastasis to cervical lymph nodes, and simultaneously augmented CD44 and ALDH1 expression in these invasive tumor cells. Taken together, we have demonstrated that EGF-induced EMT process is closely associated with the acquisition of CSC properties in human OSCC, which may contribute to the increased distant metastasis and recurrence of head and neck cancer. Further elucidation of the underlying mechanisms will facilitate development of new generation of effective therapies that aim to specifically target CSCs and eliminate the “root” of cancer recurrence.
This work was supported by National Institute of Health Research Grant, R01DE 019932, Oral and Maxillofacial Surgery Foundation Research Support, 002894, and the Schoenleber funding support.
Citation Format: Qilin Xu, Qunzhou Zhang, Anh Le. EGF induces epithelial-mesenchymal transition and cancer stem cell properties in human oral squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1059. doi:10.1158/1538-7445.AM2014-1059
Abstract 1073: Significant association of neutrophils in regional lymph nodes with lymphangiogenesis and micrometastasis by gastric cancer
Authors: Tokumoto Mao , Tanaka Hiroaki , Ohira Masaichi , Go Yukie , Okita Yoshihiro , Sakurai Katunobu , Toyokawa Takahiro , Kubo Naoshi , Muguruma Kazuya , Maeda Kiyoshi , Sawada Tetsuji , Hirakawa Kosei 
Published: May 2015

Abstract
Recent evidences indicate that inflammation is the seventh hallmark of cancer. Several researches reported that tumor-associated neutrophils (TANs) promote tumor invasion or tumor-induced angiogenesis in the tumor microenvironment. However, the relation between TANs and lymph node metastasis remains unclear. We previously reported that increasing of intranodal lymphatic vessel density (LVD) was significantly correlated to tumor progression, lymph node metastasis and poor prognosis of the patients with gastric cancer. In this study, we aimed to reveal the affect of
TANs in regional lymph nodes in terms of micrometastasis and the prognostic impact. TANs and micrometastasis were immunohistochemically estimated by anti-CD15 and anti-pan cytokeratin antibody in 1596 lymph nodes from 52 patients who were underwent gastrectomy with lymphadenectomy. We investigated the association of the density of TANs in regional lymph nodes with clinicopathological factors. The number of TANs in regional lymph nodes had a positive correlation with accumulation of intranodal LVD and micrometastasis. Furthermore we divided another 96 patients into two groups according to median TAN number of 39 to investigate the prognostic value. Patients in high CD15+TANs group had significantly poorer prognosis compared with low group. Our results suggested that TANs in regional lymph nodes promote the invasion of cancer cells to lymph nodes by augmentation of lymphangiogenesis and contribute to tumor progression. In conclusion, TANs might be an attractive target of novel bioloigical therapies of gastric cancer.
Citation Format: Mao Tokumoto, Hiroaki Tanaka, Masaichi Ohira, Yukie Go, Yoshihiro Okita, Katunobu Sakurai, Takahiro Toyokawa, Naoshi Kubo, Kazuya Muguruma, Kiyoshi Maeda, Tetsuji Sawada, Kosei Hirakawa. Significant association of neutrophils in regional lymph nodes with lymphangiogenesis and micrometastasis by gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1073. doi:10.1158/1538-7445.AM2014-1073
Abstract 1084: Triple-negative breast cancer displays a unique subset of macrophages dependent on CCL5 signaling
Authors: Rabe Daniel C. , Frankenberger Casey , Bainer Russell , Gilad Yoav , Rosner Marsha Rich 
Published: May 2015

Abstract
Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer. While five-year survival rates have reached 98% in patients treated with anti-ER or anti-HER2 therapies, patients with TNBC have a five-year survival rate of only 24%. Currently, the only form of therapy for these patients is surgery and platinum based chemotherapy. However, patient outcome is generally poor. Additionally, this disease disproportionately affects African-American women and lower income women, with rates seen approximately three times higher in African-American women compared to the rest of the population.
An alternative strategy for treating TNBC patients involves targeting the tumor stroma. Here we have used an RNA sequencing approach that utilizes species information to precisely resolve tumor- and stroma-specific gene expression in a xenograft system. We employed a triple-negative breast cancer (TNBC) model in which primary tumor invasiveness is controlled by the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP). RKIP expression, which converts invasive tumors to noninvasive tumors, dramatically inhibits macrophage infiltration. The mechanism, which is dependent on Let-7 suppression of HMGA2, involves decreased expression of the chemokine CCL5. Furthermore, overexpression of CCL5 partially rescued the infiltration of macrophages into the tumor and intravasation of tumor cells into the blood stream. MALDI-TOF mass spectrometry was used to characterize the TNBC-infiltrating macrophages. Together, these studies identify targetable pathways involving tumor-macrophage crosstalk that potentiate TNBC cell invasion and metastasis.
Citation Format: Daniel C. Rabe, Casey Frankenberger, Russell Bainer, Yoav Gilad, Marsha Rich Rosner. Triple-negative breast cancer displays a unique subset of macrophages dependent on CCL5 signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1084. doi:10.1158/1538-7445.AM2014-1084
Abstract 1100: Macrophage infiltration is associated with release from dormancy in a novel model of dormant prostate cancer
Authors: Long Thomas , Sprenger Cynthia C. , Coleman Ilsa , Nelson Peter , Ratner Buddy , Plymate Stephen 
Published: May 2015

Abstract
Background: Circulating tumor cells are found in approximately 70% of men with prostate cancer at the time of primary treatment. Less than a third of these men will develop recurrent cancer within 20 years of primary treatment, suggesting that only a subset of dormant tumor cells are able to escape dormancy and develop into clinical metastases. Escape from dormancy, though, is clinically significant since these men are at greatest risk of dying from prostate cancer. Mechanisms by which cancer cells escape dormancy are poorly understood and very few models exist to study dormancy, especially in prostate cancer. We previously found that when a dormant prostate cancer cell line was seeded into a bioscaffold and placed in vivo, tumor formation was detected after 6-8 weeks, whereas no growth was seen up to six months after the dormant cells were injected s.c. with Matrigel. Analysis of the tumors revealed significantly greater macrophage infiltration into the scaffold tumors. Gene expression and cytokine antibody arrays demonstrated increased expression of macrophage associated cytokines in scaffold tumors. While macrophages have been implicated in metastatic spread of various cancers, their role in escape from dormancy has not been elucidated.
Objective: To determine if macrophages play a role in escape from tumor dormancy in prostate cancer.
Methods: In vitro we cultured a dormant prostate cancer cell line, M12mac25, with macrophage conditioned media and then examined proliferation and gene expression. In vivo, mice were implanted with sphere-templated polyHEMA bioscaffolds pre-seeded with M12mac25 cells. To inhibit macrophage activity, mice received s.c. injections of clondronate liposomes or PBS liposomes as a control for 6 weeks.
Results: In vitro culture of M12mac25 cells with macrophage-derived conditioned medium led to increased proliferation of the M12mac25 cells and similarly upregulated genes as those seen the in vivo bioscaffold-derived tumors. In vitro treatment of primary bone-marrow derived macrophages with clondronate liposomes resulted in apoptosis while exposure to PBS liposomes did not affect the macrophages. In contrast, M12mac25 cells were not affected by either PBS or clondronate liposomes. In vivo, clondronate liposomes effectively eliminated macrophages from the M12mac25 seeded scaffolds and prevented tumor growth in these scaffolds.
Interpretation: Macrophages contribute to M12mac25 escape from dormancy.
Citation Format: Thomas Long, Cynthia C. Sprenger, Ilsa Coleman, Peter Nelson, Buddy Ratner, Stephen Plymate. Macrophage infiltration is associated with release from dormancy in a novel model of dormant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1100. doi:10.1158/1538-7445.AM2014-1100
Abstract 1104: The role of DLL4 in cancer immune-surveillance and its pathogenicity in p53-dysregulated environment
Authors: Yao Zhixing , Sherif Zaki A. 
Published: May 2015

Abstract
Recent advances in cancer studies reveal that tumorigenesis results from an accumulation of mutational and epigenetic changes that alter normal cell growth and survival pathways. Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome characterized by mutation of the TP53 tumor suppressor gene (locus 17p13.1). The p53 transcription factor responds to diverse cellular stresses by regulating target genes that induce apoptosis, cell cycle arrest, DNA repair, and senescence. LFS can provide powerful insights into our understanding of somatic mutations present in sporadic cancers as well as the de-regulation of cell signaling pathways. We will be using LFS cells and mice as models to build on our previous discovery that showed a balanced reciprocal translocation between chromosomes 11q23 and 15q15 in LFS patients' skin fibroblast cells. In our present study, analysis of the breakpoint region reveals that in LFS, breast cancer (MCF7) and neuroblastoma (IMR32) cell lines, there is a dramatically increased activation in the expression of cancer susceptibility candidate 5 gene (CASC5), a part of kinetochore-microtubule attachments associated with cell proliferation. Furthermore, there was an abrogation in the expression of a critical protein, Delta-like ligand-4 (DLL4), in LFS normal skin fibroblasts of TP53 mutation carriers and non-carriers. There was also a down-regulation of DLL4 in unrelated breast cancer and neuroblastoma cell lines by DNA hypermethylation. DLL4 is a ligand for Notch family of receptors with crucial functions in normal development, immune surveillance and tissue homeostasis. TP53 and CTCF (a transcription factor involved in chromatin architecture) have a direct activator effect at the DLL4 promoter. Notch/DLL4 plays a key role in the generation of hematopoietic stem cells during embryonic development and regulates the T cell lineage and subsequent stages of thymopoiesis. WNT2 is also down-regulated in LFS cell lines and abolished in MCF7. Whereas Notch signaling controls cell fate specification in a variety of cell contexts during embryonic and postnatal development, Wnt signaling plays a critical role in cell differentiation and proliferation. Both Notch and Wnt pathways are activated by oncogenic mutations and dysregulated in cancer. The long-term objective of this research is to develop a critical understanding of the mechanisms by which p53 regulates cancer immune-surveillance through cross-talk with the tumor microenvironment so that therapeutic agents can be developed to curtail cancer progression.
Citation Format: Zhixing Yao, Zaki A. Sherif. The role of DLL4 in cancer immune-surveillance and its pathogenicity in p53-dysregulated environment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1104. doi:10.1158/1538-7445.AM2014-1104