bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5091: Potent anti-tumor activity of blocking stromal Dll4 in ovarian xenograft models.
Authors: Kuhnert Frank , Chen Guoying , Thurston Gavin 
Published: August 2014

Abstract
Potent anti-tumor activity of blocking stromal Dll4 in ovarian xenograft models
Delta-like ligand 4 (Dll4) is an emerging anticancer target given its predominant tumor vasculature expression and its role in regulating angiogenic sprouting. We have previously demonstrated that pharmacological blockade of the Dll4-Notch axis results in an excessive production of aberrant non-functional tumor vessels, and these changes were associated with reduced tumor growth. Using VelocImmune® mice, we identified a fully human IgG1 monoclonal antibody, termed REGN421/SAR153192, which binds human Dll4 and potently neutralizes Notch signaling. REGN421 treatment caused potent and dose-dependent inhibition of a number of human tumor xenografts grown in immunodeficient mice engineered to express human Dll4. In the current study, we found that REGN421 treatment of ovarian xenograft models produces potent anti-tumor effects that are dependent on targeting Dll4 in the tumor stroma as opposed to tumor cell-expressed Dll4. In particular, REGN421 treatment (2.5 mg/kg, once weekly) of humanized Dll4 mice bearing established subcutaneous TOV-112D or intraperitoneal A2780 human tumor xenografts resulted in growth inhibition of 86% and 83%, respectively. The inhibition of ovarian tumor growth by REGN421 was associated with a marked increase in tumor vascular structures but reduced vascular perfusion, consistent with the function of Dll4 as a regulator of angiogenic sprouting. Similar anti-tumor effects were observed by strictly targeting stromal Dll4 with a mouse Dll4-specific surrogate antibody REGN1035 in SCID mice bearing OVCAR3 tumors. In contrast, the specific blockade of tumor cell-expressed human Dll4 did not exhibit any appreciable anti-tumor activity, indicating the lack of tumor growth-promoting autocrine Dll4-Notch tumor cell signaling in these models. Finally, the combined treatment of Dll4 antibody with the anti-VEGF agent ziv-aflibercept (VEGF Trap) resulted in enhanced anti-tumor effects and virtually the complete suppression of intraperitoneal A2780 tumor growth, suggesting clinical benefit for the combined blockade of VEGF and Dll4 in ovarian cancer. These studies lend further support for the therapeutic targeting of Dll4 as a promising new angiogenesis-based anticancer strategy in ovarian cancer, both as a single agent and in combination with anti-VEGF agents.
Citation Format: Frank Kuhnert, Guoying Chen, Gavin Thurston. Potent anti-tumor activity of blocking stromal Dll4 in ovarian xenograft models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5091. doi:10.1158/1538-7445.AM2013-5091
Abstract 5099: Direct renin inhibitor attenuates rat hepatocarcinogenesis via anti-angiogenic activity.
Authors: Aihara Yosuke , Yoshiji Hitoshi , Noguchi Ryuichi , Kaji Kosuke , Namisaki Tadashi , Moriya Kei , Kitade Mitsuteru , Fukui Hiroshi 
Published: August 2014

Abstract
Direct renin inhibitor (DRI), aliskiren, is widely used as an anti-hypertensive agent in the clinical practice, and several reports have shown that renin plays an important role in several pathological processes. However, the role of renin in the hepatocarcinogenesis is still obscure. The aim of the current study was to examine the effect of DRI on the hepatocarcinogenesis in the rat model. Hepatocarcinogenesis model was induced in male F344 rats by the choline-deficient L-amino acid-defined diet for 12 weeks. The effect of DRI at clinically comparable low dose on the hepatocarcinogenesis was examined especially in conjunction with neovascularization. DRI exerted a marked inhibitory effect on the glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions along with suppression of the neovascularization in a dose-dependent manner. DRI also inhibited the hepatic expressions of angiotensin-II (AT-II), and vascular endothelial growth factor (VEGF). Our in vitro study showed that renin significantly augmented the in-vitro angiogenesis, whereas, interestingly, DRI did not inhibit the renin-induced the endothelial cell proliferation even at high dose. These results indicate that renin plays a pivotal role in hepatocarcinogenesis at least partly mediated by pro-angiogenic activity. Since DRI is already widely used in the clinical practice with safety, this drug may represent a potential new strategy against the hepatocarcinogenesis in the future.
Citation Format: Yosuke Aihara, Hitoshi Yoshiji, Ryuichi Noguchi, Kosuke Kaji, Tadashi Namisaki, Kei Moriya, Mitsuteru Kitade, Hiroshi Fukui. Direct renin inhibitor attenuates rat hepatocarcinogenesis via anti-angiogenic activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5099. doi:10.1158/1538-7445.AM2013-5099
Abstract 5100: MMP-2 suppression inhibits α5β1 integrin and IL-3-mediated Stat5 activation and proliferation of endothelial cells.
Authors: Maddirela Dilip Rajasekhar , Kesanakurti Divya , Chetty Chandramu , Rao Jasti S. 
Published: August 2014

Abstract
Endothelial cell (EC) proliferation is a major component of angiogenesis in glioblastoma multiforme (GBM) and is regulated by several growth factors including IL-3. In this study, we have evaluated the effect of conditioned media (CM) obtained from MMP-2 knockdown xenograft 4910 and 5310 cell lines by pMMP-2 siRNA (pM.si) on the growth of ECs. Western blot analysis of CM from pM.si-treated 4910 and 5310 cells showed a significant downregulation of MMP-2 and IL-3 expression compared to mock- and pSV (scrambled vector)-CM. Proliferation decreased in ECs cultured on pM.si-CM from the xenograft cells when compared to ECs cultured on mock- or pSV-CM as determined by Ki-67 staining and MTT assays. Since Stat5 is a known target of IL-3, induces EC proliferation, and promotes neo-angiogenesis, we examined the role of pM.si in regulating IL-3-mediated Jak2/Stat5 signaling in ECs. Jak2/Stat5 suppression in ECs when cultured on pM.si-CM resulted in the decreased expression of integrin β1, Stat5, Bcl2 and Cyclin D2 at the transcription level as compared with ECs cultured on mock- and pSV-CM, as confirmed by RT-PCR analysis. Supplementation of recombinant human IL-3 counteracted and noticeably reversed pM.si-inhibited IL-3Rα, Jak2, p-Stat5 expression and proliferation of ECs, thereby confirming the role of MMP-2 in the regulation of α5β1/IL-3 mediated Jak2/Stat5 signaling. Immunoprecipitation and immunofluorescence studies revealed MMP-2 knockdown resulted in the decreased interaction of MMP-2 and integrin α5β1 in ECs, thereby implicating the downregulation of Jak2/Stat5 expression. Immunohistochemical analysis in tumor sections corroborated our in vitro studies, suggesting that the expression of p-Stat5 and Bcl2 are significantly decreased upon pM.si treatment compared to mock or pSV treatments. Our results suggest that MMP-2 knockdown by pM.si can lead to a significant inhibition of IL-3-induced proliferation of ECs and can be an effective anti-angiogenic therapy when treating patients with GBM in the future.
Citation Format: Dilip Rajasekhar Maddirela, Divya Kesanakurti, Chandramu Chetty, Jasti S. Rao. MMP-2 suppression inhibits α5β1 integrin and IL-3-mediated Stat5 activation and proliferation of endothelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5100. doi:10.1158/1538-7445.AM2013-5100
Abstract 5114: Multi-organ metastatic capability of 4T1 mammary carcinoma cells after surgical resection of primary orthotopic tumor.
Authors: Zhang Yong , Zhang Nan , Hoffman Robert M. , Zhao Ming 
Published: August 2014

Abstract
We report an optically imageable orthotopic metastatic syngeneic model of 4T1 mouse breast cancer expressing red fluorescent protein (RFP). 4T1 cells, expressing RFP, were injected orthotopically into the right second mammary fat pad of BALB/c mice. The primary tumor was removed on day-18 after tumor implantation, when the average tumor volume reached approximate 500-600 mm3. At autopsy, the 4T1-RFP was found to have metastasized to numerous organs, when the mice were sacrificed 6-8 weeks after cell implantation, including the lung in 91% of the animals, the lymph nodes in 100% of the animals including axillary nodes, the liver in 91% of the animals, the bone in 42% of the animals and the brain in 25% of the animal. Detailed fluorescence analysis visualized extensive metastasis in the thoracic cavity and the lymphatic system. Large metastatic nodules in the lung involved most of the pulmonary parenchyma in all lobes. Lymph node metastasis was found mainly in the axillary area. In the liver, fluorescent macroscopic metastatic nodules were found under the capsule. The metastatic pattern in the model thus reflected clinical highly metastatic breast cancer and enables drug discovery for this disease.
Citation Format: Yong Zhang, Nan Zhang, Robert M. Hoffman, Ming Zhao. Multi-organ metastatic capability of 4T1 mammary carcinoma cells after surgical resection of primary orthotopic tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5114. doi:10.1158/1538-7445.AM2013-5114
Abstract 5128: Upregulation of epsin in breast cancer and critical role of epsin in promoting cancer growth and metastasis.
Authors: Cai Xiaofeng , Pasula Satish , Chang Baojun , Hahn Scott , McManus John , Chen Hong 
Published: August 2014

Abstract
We have previously demonstrated that deficiency of epsins, a family of endocytic clathrin adaptor proteins, decreases tumor growth by enhancing VEGF signaling in endothelial cells and causing dysfunctional tumor angiogenesis. However, the role of epsin in cancer cells is unclear. Our preliminary data indicate that epsins are upregulated in various human cancers, including breast cancer, prostate cancer, ovary cancer, cervix cancer, bladder cancer, and esophagus cancer. Here, we determined the role of epsin in cancer cells in regulating breast cancer growth and metastasis. Increased epsin level was found in ER(+/-) and/or PR(+/-) human breast cancer cell lines including MDA-MB-231, BT-20, ZR751, MCF7 and T47D, and in mouse breast cancer cell lines, such as
168FARN and 4T1. The level of epsins was also considerably augmented in tumors derived from MMTV-PyMT spontaneous breast cancer mouse model at different progressive stages. We observed a correlative increase in epsin expression with cancer progression in MMTV-PyMT mice. We also generated stable epsin-deficient MDA-MB-231 and 4T1 cells. Epsin deficiency markedly inhibited cell proliferation and migration in vitro. Xenograft mouse models of epsin-deficient breast cancer cells revealed striking reduction in tumorigenesis and lung metastasis. Lung metastasis by tail-vein injection of epsin-deficient MDA-MB-231 cells was also decreased compared to controls. Mechanistically, we showed that epsin-deficiency induced morphological change from mesenchamal-like to epitheial-like in MDA-MB-231 cells, indicating a reversal of Epithelial-Mesenchymal Transition (EMT) to Mesenchymal-Epithelial-Transition (MET). Moreover, epsin-deficiency increased E-cadherin expression but decreased vimentin, and EMT inducing genes snail/slug expression in MDA-MB-231 cells. Epsin-deficiency also dramatically reduced cyclin D1 expression and Rb activation. Accordingly, elevated E-cadherin but attenuated vimentin, slug and cyclin D1 were observed in tumor tissues or lung tissues isolated from epsin-deficient MDA-MB-231 and 4T1 tumor models. Conversely, overexpression of epsin in MDA-MB-231 cells enhanced cyclin D1 and vimentin expression. Collectively, epsin promotes breast tumor growth and metastasis through coordinated regulation of cell cycle and EMT. Our study provides a basis for novel therapeutic targets for anti-cancer treatments.
Citation Format: Xiaofeng Cai, Satish Pasula, Baojun Chang, Scott Hahn, John McManus, Hong Chen. Upregulation of epsin in breast cancer and critical role of epsin in promoting cancer growth and metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5128. doi:10.1158/1538-7445.AM2013-5128
Abstract 5135: Analysis of formalin-fixed paraffin-embedded (FFPE) samples.
Authors: Stojanov Petar , Carter Scott L. , Rosshandler Ivan Imaz , Sivachenko Andrey , Salido Guadarrama Alberto , Vazquez Karla , Cordoba Sandra Romero , Cibulskis Kristian , Sougnez Carrie , Voet Douglas , Saksena Gordon , Lichtenstein Lee , Zou Lihua , Frazer Scott , Stewart Chip , Beroukhim Rameen , Meyerson Matthew , Lawrence Michael S. , Getz Gad 
Published: August 2014

Abstract
The availability of large numbers of formalin-fixed, paraffin-embedded (FFPE) tumor DNA samples, together with accurate and specific clinical annotations, can be a great resource for in-depth analysis of correlations of somatic and germline DNA alterations with clinical outcome. However, the effects of this tissue preservation technique on next-generation DNA sequencing technologies and downstream analyses are still being investigated. Furthermore, usually the archives of such FFPE samples do not include matched normal tissue, which complicates the process of identifying somatic alterations. We are in the process of analyzing lung adenocarcinoma, colorectal and prostate patient datasets, which contain both an FFPE and a fresh-frozen tumor together with a matched blood normal sample. The availability of both a frozen and an FFPE tumor sample enables us to compare the detected somatic point mutations and indels, taking into account the fact that these pairs are produced from different aliquots of DNA. This analysis includes calculating the power to detect variants in the FFPE sample given that they have been observed in the fresh frozen tumor, as well as the validation rate of clonal SNVs between the two samples. We are also developing a method for classification of SNVs as germline or somatic without a paired normal sample by taking advantage of the fact that most tumor samples contain a substantial fraction of normal cells. Because stromal contamination has a different effect on the allelic fraction of somatic vs. germline SNVs, we can apply algorithms to estimate tumor purity and absolute somatic copy numbers in order to distinguish the two types of events. We present preliminary results from these analyses.
Citation Format: Petar Stojanov, Scott L. Carter, Ivan Imaz Rosshandler, Andrey Sivachenko, Alberto Salido Guadarrama, Karla Vazquez, Sandra Romero Cordoba, Kristian Cibulskis, Carrie Sougnez, Douglas Voet, Gordon Saksena, Lee Lichtenstein, Lihua Zou, Scott Frazer, Chip Stewart, Rameen Beroukhim, Matthew Meyerson, Michael S. Lawrence, Gad Getz. Analysis of formalin-fixed paraffin-embedded (FFPE) samples. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5135. doi:10.1158/1538-7445.AM2013-5135
Abstract 5151: Integrative genomic analysis identifies cancer-testis antigen LEMD1 as a prognostic biomarker.
Authors: Park Jenny , Chiu Beatrice , Delaney Joe , Paschal Cate , Roche Daniel , Shima James , Umesh Anita , Wisotzkey Robert , Shekar Mamatha , Kupershmidt Ilya 
Published: August 2014

Abstract
The ability to molecularly distinguish disease states can improve prognostic resolution and therapeutic options. Cancer-testis antigens (CTA), expressed in germ cells of the testis and in a variety of cancers, are of particular interest for their potential use as targets for anti-cancer vaccines. We highlight the application of the NextBio platform, which integrates multiple datatypes such as RNA/miRNA expression, copy number variation, epigenetic changes, and next-generation sequencing with clinical attributes to identify and characterize novel disease associations in multiple myeloma.
Genomic and clinical data of 2,546 multiple myeloma patients obtained from public data sources were investigated in the NextBio platform. We initially analyzed the gene expression of various clinical subgroups to the median expression of all groups to identify genes significantly correlated to patient survival. We filtered for patients with advanced disease, defined as those with beta-2 microglobulin blood levels greater than 5.5mg/L, and identified LEMD1, a CTA, as positively correlated with survival (p=2.3E-6). We then analyzed the gene expression of LEMD1 in patients of all disease stages, and found those with increased expression of LEMD1 had improved survival compared to those who did not (p=9.4E-3). Patients with increased expression of LEMD1, however, had concomitant decreased expression in 14/20 CTAs of the MAGE family (p &lt; 0.05), members of which were previously described as expressed in multiple myeloma patients with reduced survival.
A preliminary exploration of LEMD1 expression in other cancers found increased expression of LEMD1 to be significantly associated with improved survival in ovarian cancer (p=5.4E-3) but reduced survival in renal cancer (p=0.01). Further analysis of LEMD1 expression in normal tissues showed high expression of LEMD1 in spermatozoa and limited expression in 315 other tissue and cell types. As tissue specific antigens behind the blood-testis barrier, the expression of CTAs in cancer can potentially serve as immunogenic targets, and further investigation is warranted to explore their use in tumor immunotherapy.
Citation Format: Jenny Park, Beatrice Chiu, Joe Delaney, Cate Paschal, Daniel Roche, James Shima, Anita Umesh, Robert Wisotzkey, Mamatha Shekar, Ilya Kupershmidt. Integrative genomic analysis identifies cancer-testis antigen LEMD1 as a prognostic biomarker. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5151. doi:10.1158/1538-7445.AM2013-5151
Abstract 5161: Identification of epithelial stromal interaction 1 as a novel mediator of breast cancer cell invasion and metastasis downstream of Krüppel-like factor 8.
Authors: Li Tianshu , Lu Heng , Shen Chao , Lahiri Satadru , Watson Melissa , Mukherjee Debarati , Yu Lin , Zhao Jihe 
Published: August 2014

Abstract
Epithelial stromal interaction 1 (EPSTI1) is a recently identified novel gene that is highly upregulated in breast cancer cells when co-cultured with the stromal fibroblasts and in invasive breast carcinomas as compared with normal breast biopsies. The regulation and function of EPSTI1 are largely unknown. Our studies showed that EPSTI1 expression is upregulated by Kruppel-like factor 8 (KLF8), a transcriptional factor that is highly over-expressed in breast cancer and critical for cell cycle progression, oncogenic transformation, epithelial to mesenchymal transition (EMT) and metastatic progression of breast cancer, by directly activating EPSTI1 promoter. Also, we demonstrated that EPSTI1 was necessary and sufficient to promote breast cancer cell invasiveness by genetically modifying EPSTI1 expression and Matrigel invasion assays. We also found that EPSTI1 could interact with valosin containing protein (VCP) and subsequently activate NF-kB nuclear function. Finally, our mouse mammary fat pad injection and tail vein injection experiments indicated that ectopic overexpression of EPSTI1 in MCF7 cells could enhance the tumor invasion and metastasis in vivo. These findings suggest that EPSTI1 is a novel target of KLF8 and plays a critical role in the regulation of breast cancer invasion and metastasis.
Citation Format: Tianshu Li, Heng Lu, Chao Shen, Satadru Lahiri, Melissa Watson, Debarati Mukherjee, Lin Yu, Jihe Zhao. Identification of epithelial stromal interaction 1 as a novel mediator of breast cancer cell invasion and metastasis downstream of Krüppel-like factor 8. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5161. doi:10.1158/1538-7445.AM2013-5161
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5174: Involvement of COX-2 in p53 induction and Jnk activation following DNA damage.
Authors: Kim Joohwee , Lee Hyunju , Park Kawngil , Eling Thomas E. , Shim Minsub 
Published: August 2014

Abstract
Cyclooxygenase (COX) is a rate-limiting enzyme in arachidonic acid cascade and exists as two related but unique isoforms, COX-1 and COX-2. While COX-1 is constitutively expressed in many tissues and is believed to play a role in tissue homeostasis, COX-2 is highly inducible by various stimuli including inflammatory cytokines, growth factors, and DNA damage. In addition, aberrant COX-2 expression is frequently observed in many types of cancer, suggesting the role of COX-2 in tumor development and progression. p53 is a well-known tumor suppressor and plays a key role in the control of normal cell's response to environmental or cellular stresses. Although p53 has been shown to regulate COX-2 expression, the modulation of p53 levels by COX-2 has not been determined. In the present study, we have examined the role of COX-2 as an upstream regulator of p53 levels using COX-2 knockout (KO) mouse embryonic fibroblasts (MEFs). DNA damage-induced increase in p53 protein levels were greatly reduced in COX-2 KO MEFs compared to wild type (WT) or COX-1 KO MEFs. Furthermore, a COX-2 specific inhibitor suppressed doxorubicin-induced p53 accumulation and cell death. However, initial induction of p53 accumulation in response to doxorubicin was not altered by deficiency or inhibition of COX-2, suggesting that COX-2 may be involved in maintenance of p53 stability. Doxorubicin-induced accumulation of p53 appeared to be mediated through the activation of Jun-N-terminal Kinase (Jnk). Activation of Jnk by doxorubicin was decreased in COX-2 KO MEFs or by COX-2 inhibition, suggesting that DNA damage induces activation of Jnk by a mechanism that involves COX-2. Our results suggest the existence of novel cross-talk between COX-2 and p53 and identify COX-2 as a potential target for reducing the side effects from chemotherapy.
Citation Format: Joohwee Kim, Hyunju Lee, Kawngil Park, Thomas E. Eling, Minsub Shim. Involvement of COX-2 in p53 induction and Jnk activation following DNA damage. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5174. doi:10.1158/1538-7445.AM2013-5174