bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-326: Zeb1 regulates inflammation-induced invasion and self-renewal of colon cancer cells.
Authors: Wang Lei , Li Yijing , Beckley Amy , Pappan Lorretta , Shi Jishu 
Published: August 2014

Abstract
Up-regulation of inflammatory cytokines such as IL-1β in tumor microenvironment has been associated with progression of human colorectal cancer, although the exact molecular mechanisms are still unclear. To understand how IL-1β influences colon cancer cell behaviors, we used a human colon cancer cell line HCT-116 as well as primary human colon cancer cells derived from a patient, which more closely reflect the properties of the primary tumor than established cell lines.
Here, we demonstrate that IL-1β promotes epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) development in colon cancer. IL-1β treatment resulted in loss of E-cadherin and gain of a mesenchymal phenotype in both HCT-116 cells and primary colon cancer cells. Among E-cadherin suppressors, Zeb1 was up-regulated in IL-1β-induced EMT cells. Consistent with EMT properties, IL-1β-treated HCT-116 cells exhibited higher cell migratory ability. Moreover, IL-1β induced expression of stem-cell marker Bmi-1 in both HCT-116 cells and primary colon cancer cells. IL-1β increased these cells’ self-renewal ability to form spheres in serum-free conditions and chemo-resistance; properties associated with colon CSCs. Taken together, these results indicate that IL-1β can induce EMT and promote generation of CSCs in colon cancer.
More importantly, we found that ZEB1, but not other E-cadherin transcriptional repressors (such as Zeb2, Snail and Twist), was consistently up-regulated in IL-1β-induced EMT cells and sphere cells. This suggests that Zeb1 links IL-1β-induced CSC self-renewal and EMT in colon cancer cells. Moreover, knockdown of Zeb1 in HCT-116 cells using shRNAs reversed the IL-1β effects on these two processes, further indicating that Zeb1 is essential for IL-1β-induced stem cell and EMT phenotypes in colon cancer cells. Our finding indicates that IL-1β promotes colon tumor growth and invasion through activation of CSC self-renewal and EMT, while Zeb1 plays a critical role in activation of these two processes. Thus, targeting tumor microenvironment cytokines or Zeb1 might form the basis of a promising treatment for colon cancer.
Citation Format: Lei Wang, Yijing Li, Amy Beckley, Lorretta Pappan, Jishu Shi. Zeb1 regulates inflammation-induced invasion and self-renewal of colon cancer 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 LB-326. doi:10.1158/1538-7445.AM2013-LB-326
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract LB-327: Inhibition of lymphatic metastasis in neuroblastoma by a novel neutralizing antibody to vascular endothelial growth factor-D.
Authors: Kashima Kenji , Watanabe Miho , Satoh Yasuko , Hata Junichi , Ishii Nobuya , Aoki Yuko 
Published: August 2014

Abstract
Lymphatic spread is an important clinical determinant in the prognosis of many human cancers. The lymphangiogenic factor called vascular endothelial growth factor-D (VEGF-D) is implicated in the promotion of lymphatic metastasis through the development of lymphatic vessels in some human cancers. In this study, we developed an anti-VEGF-D monoclonal antibody, cVE199, and investigated its in vitro properties, in vivo effects against tumors, and possible target indications to evaluate its potential as a therapeutic antibody. The cVE199 molecule was revealed to have a specific binding reactivity against human VEGF-D, as well as a specific inhibitory activity against the binding of human VEGF-D to VEGFR-3. In addition, cVE199 was found to inhibit the biological activity of VEGF-D against lymphatic cells in vitro. Because we determined that a neuroblastoma cell line, SK-N-DZ, abundantly expressed VEGF-D, an in vivo efficacy study was performed using a xenograft model of SK-N-DZ. We found that cVE199 significantly decreased lymphatic metastasis of SK-N-DZ as well as lymphangiogenesis in primary lesions. Finally, we investigated VEGF-D expression in human neuroblastoma, finding that the molecule was expressed in 11 of 29 human neuroblastoma specimens (37.9%). In conclusion, we found that a novel anti-VEGF-D monoclonal antibody, cVE199, with specific reactivity against human VEGF-D prevents lymphatic metastasis of neuroblastoma through the inhibition of lymphangiogenesis in an animal model. In addition, our results show that VEGF-D is expressed in some cases of human neuroblastomas, which suggests that cVE199 is a potential anti-metastasis therapeutic antibody in neuroblastoma treatment.
Citation Format: Kenji Kashima, Miho Watanabe, Yasuko Satoh, Junichi Hata, Nobuya Ishii, Yuko Aoki. Inhibition of lymphatic metastasis in neuroblastoma by a novel neutralizing antibody to vascular endothelial growth factor-D. [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 LB-327. doi:10.1158/1538-7445.AM2013-LB-327
Abstract LB-331: Effective chemoimmunotherapy with anti-TGFβ antibody and cyclophosphamide on a mouse model of breast cancer.
Authors: Chen Xin , Yang Yuan , Zhou Qiong , Howard O.M.Zack , McPherson John , Wakefield Lalage , Oppenheim Joost J. 
Published: August 2014

Abstract
Elimination of CD4+FoxP3+ regulatory T cells (Tregs) has become an important strategy of cancer immunotherapy. It was reported that TGFβ is responsible for accumulation of Tregs in tumor. Thus, we treated mouse 4T1 mammary carcinoma model with 1D11 (0.1 mg/mouse), a neutralizing antibody of TGFβ(1,2,3). The treatment delayed growth of primary tumor, however, unexpectedly increased the proportion of FoxP3+ Tregs present in the intratumoral CD4 cells. In order to enhance the anti-tumor effect, 1D11 was administered with a single dose of cyclophosphamide (4 mg/mouse), a chemotherapeutic agent which was previously shown to selectively eliminate intratumoral TNFR2+ Tregs. This combination, but not the therapeutics by themselves, resulted in tumor-free long term survival of up to 80% of mice, and those tumor free mice were more resistant to re-challenge with 4T1 tumor. In order to examine the phenotype of tumor infiltrating immune cells, 4T1 tumor bearing mice were treated with 1D11 and a lower dose of cyclophosphamide (2 mg/mouse). This treatment markedly inhibited tumor growth, accompanied by a massive infiltration by IFNγ-producing T cells. Furthermore, this combination markedly decreased the number of splenic MDSCs, and increased their expression levels of MHC II and CD80. Taken together, our data show that anti-TGFβ Ab and cyclophosphamide represents a novel chemoimmunotherapeutic combination which may prove useful in the treatment of human cancer patients.(Funded by NCI Contract HHSN261200800001E)
Citation Format: Xin Chen, Yuan Yang, Qiong Zhou, O.M.Zack Howard, John McPherson, Lalage Wakefield, Joost J. Oppenheim. Effective chemoimmunotherapy with anti-TGFβ antibody and cyclophosphamide on a mouse model of breast cancer. [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 LB-331. doi:10.1158/1538-7445.AM2013-LB-331
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract LB-40: Guanine nucleotide exchange factors Dock7 and Ect2 mediate HGF/c-MET-induced glioblastoma cell invasion.
Authors: Murray David W. , Didier Sebastien , Paulino Vincent M. , Chan Amanda , Tran Nhan L. , Byrne Annette T. , Symons Marc H. 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor. It is an incurable disease with an average life expectancy of just 14 months following diagnosis. GBM morbidity is primarily due to its rapid growth, neovascularization and invasion throughout the brain. The angiogenesis inhibitor, bevacizumab, now approved for GBM treatment, has been shown to cause enhanced tumor cell invasion in part via c-MET (HGF-receptor) signaling. We have previously shown that several members of the Rho family of small GTPases, including Rac1, Rac3, RhoG and Cdc42, play central roles in GBM tumor cell invasion. Rho GTPases are activated by guanine nucleotide exchange factors (Rho GEFs). Herein we focus on identifying GEFs that act on Rac subfamily members and which are of functional importance in GBM.
We found that Dock7 and Ect2, two GEFs that can activate Rac proteins, show elevated mRNA and protein expression in human GBM tissue in comparison with non-neoplastic brain. RNAi-mediated depletion of these GEFs in GBM cell lines resulted in decreased HGF- and serum-induced tumor cell invasion in 3-dimensional extracellular matrix in vitro and organotypic ex vivo brain slice invasion assays. GEF activity of Dock7 and Ect2 were shown to be increased by HGF using a pull-down with Rac1G15A, a nucleotide binding-deficient mutant of Rac1. Furthermore, Dock7 and Ect2 were shown to be required for HGF-induced Rac1 activation, lamellipodia formation and cell spreading. Dock7, but not Ect2, was shown to co-immunoprecipitate with c-MET and this interaction was HGF-dependent and required the c-MET adaptor protein GAB1. Dock7 and GAB1 were furthermore shown to co-immunoprecipitate in an HGF-dependent manner. GAB1 was shown to be required for HGF-induced Dock7 and Ect2 Rac1 GEF activities, Rac1 activation and HGF-induced GBM cell invasion.
In summary, we have identified two GEFs that are of functional and clinical relevance in the development of the GBM pathologic phenotype. Dock7 and Ect 2 represent potential new drug targets for the management of GBM, especially in combination with an anti-angiogenic approach.
Citation Format: David W. Murray, Sebastien Didier, Vincent M. Paulino, Amanda Chan, Nhan L. Tran, Annette T. Byrne, Marc H. Symons. Guanine nucleotide exchange factors Dock7 and Ect2 mediate HGF/c-MET-induced glioblastoma cell invasion. [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 LB-40. doi:10.1158/1538-7445.AM2013-LB-40
Abstract LB-43: MiR-147 is a novel tumor suppressor that reverses EMT and native resistance to EGFR inhibitors by inactivating Akt and activating Stat3.
Authors: Lee Chang Gong , Gruidl Michael , Timmee Cindy R. , McCarthy Susan , Yeatman Timothy J. 
Published: August 2014

Abstract
Background: The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer invasion and metastasis, and resistance to chemotherapy. The EGFRi class of reagents are thought to target tumors with the epithelial phenotype.
Hypothesis: We hypothesized that reversing this biological process through a mesenchymal to epithelial transition (MET), using a recently identified miR-147, might also lead to a reversal of resistance to EGFR inhibitors (EGFRi).
Methods/Results: Following a screen of &gt; 400 miRs, we recently identified miR-147 as highly correlated with an “intrinsic” and prognostic EMT gene expression signature derived from an unsupervised analysis of &gt;2000 colorectal cancers. This suggested miR-147 might regulate the EMT program. We have shown that miR-147 is capable of reversing the EMT phenotype in vitro and converting EGFRi-resistant cells to sensitive cells. To further understand the mechanism underpinning this observation, we analyzed the genes affected by miR-147 over-expression in colon cancer cells using a global gene expression survey (Affymetrix). Among significantly altered genes, Akt expression was down-regulated (&gt;2 fold) and Stat3 expression was up-regulated (&gt;2 fold) by miR-147.
Subsequent knock down of Akt with siRNA did induce MET and significantly increased EGFRi sensitivity. Western analysis showed increased Stat3 protein levels and total Stat3 phosphorylation with miR-147 transfection. Interestingly, knockdown of Stat3 inhibited the capacity of miR147 to reverse native EGFRi resistance.
Conclusion: miR-147 induced MET and reversed resistance to EGFRi. This observation appears to be related to both the inhibition of Akt and to the induction of Stat3 activity. Understanding the precise mechanisms by which miRs regulate chemosensitivity and resistance will be important in designing more effective EGFRi therapies.
Citation Format: Chang Gong Lee, Michael Gruidl, Cindy R. Timmee, Susan McCarthy, Timothy J. Yeatman. MiR-147 is a novel tumor suppressor that reverses EMT and native resistance to EGFR inhibitors by inactivating Akt and activating Stat3. [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 LB-43. doi:10.1158/1538-7445.AM2013-LB-43
Abstract LB-50: Identification and functional analysis of p53MRA as a novel p53 target gene.
Authors: Funauchi Yuki , Tanikawa Chizu , Lo Paulisally Hau Yi , Nakamura Yusuke , Matsuda Koichi 
Published: August 2014

Abstract
Identification and characterization of p53-target genes are critical step for the understanding of tumor suppression mechanisms. So far, we have isolated a number of p53 target genes such as p53AIP1, p53R2, p53RDL1, XEDAR and PADI4, and revealed molecular mechanisms by which p53 regulate human carcinogenesis. Here we identified p53MRA (p53-inducible mitochondrial regulator of apoptosis) as a novel p53 target gene that play an important role in an apoptotic pathway through a cDNA microarray analysis using mRNAs isolated from U373MG cells ectopically expressed p53.
p53MRA mRNA and protein expression was remarkably induced by ectopic expression of p53 but not by that of LacZ. We also found that adriamycin treatment remarkably induced p53MRA expression in HCT116 colorectal cancer cells in a p53 dependent manner. Subsequently, we surveyed the genomic sequence of the p53MRA gene and found putative p53-binding region within the first intron. Luciferase assay using reporter vector containing this putative p53-binding region revealed that co-transfection of wild-type p53 expressing plasmid enhanced the luciferase activity more than 10-fold. On the other hand, substitution of nucleotides within putative p53-binding region completely diminished the luciferase activity, indicating that p53 regulates p53MRA expression through this p53-binding region.
To further investigate the role of p53MRA on tumor cell growth, we treated HCT116 cells with adriamycin 36h after transfection with sip53MRA or siEGFP. As a result, treatment with sip53MRA remarkably increased cell viability to the extent similar to that with sip53. Taken together, p53MRA is novel p53 target gene which plays an important role in the p53-mediated apoptotic pathway.
Citation Format: Yuki Funauchi, Chizu Tanikawa, Paulisally Hau Yi Lo, Yusuke Nakamura, Koichi Matsuda. Identification and functional analysis of p53MRA as a novel p53 target gene. [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 LB-50. doi:10.1158/1538-7445.AM2013-LB-50
Abstract LB-51: p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.
Authors: Farkas Carlos , Martins Carla , Escobar David , Castro Ariel , Donner David , Pincheira Roxana 
Published: August 2014

Abstract
SALL2- a member of the Spalt gene family- is a poorly characterized transcription factor found deregulated in various cancers, which suggest it plays a role in the disease. We previously identified SALL2 as a novel interacting protein of neurotrophin receptors and showed that it plays a role in neuronal function, which does not necessarily explain why or how SALL2 is deregulated in cancer. Previous evidences indicate that SALL2 gene is regulated by the WT1 and AP4 transcription factors. Here, we identified SALL2 as a novel downstream target of the P53 tumor suppressor protein. Bioinformatic analysis of the SALL2 gene revealed several putative P53 half sites along the promoter region. Either overexpression of wild-type P53 or induction of the endogenous P53 by the genotoxic agent doxorubicin repressed SALL2 promoter activity in various cell lines. However, Q143A, R175H and R248W P53 mutants, which are frequently found in the tumors of cancer patients, were unable to repress SALL2 promoter activity. Chromatin immunoprecipitation analysis using a specific P53 antibody further supported the binding to, and regulation of the SALL2 promoter by P53. Importantly, by using a p53ERTAM knockin model expressing a variant of P53 that is completely dependent on 4-hydroxy-tamoxifen for its activity, we show that P53 activation diminished SALL2 RNA and protein levels during genotoxic cellular stress in primary mouse embryo fibroblasts (MEFs) and radiosentive tissues in vivo. Thus, our finding indicates that P53 represses SALL2 expression in a context-specific manner, adding knowledge to understanding SALL2 gene regulation, and a potential mechanism for its deregulation in cancer
Citation Format: Carlos Farkas, Carla Martins, David Escobar, Ariel Castro, David Donner, Roxana Pincheira. p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress. [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 LB-51. doi:10.1158/1538-7445.AM2013-LB-51
Abstract LB-52: Increased incidence of cancer in the transgenic mice with 8-Lipoxygenase knocked out.
Authors: Al-Fardan Rana , Karki Rabindra , Guo Changxiong , Nie Daotai 
Published: August 2014

Abstract
15-Lipoxygenase-2 (ALOX15B), an oxidoreductase in the metabolism of arachidonic acid, is a functional tumor suppressor whose expression is reduced in a variety of human cancers. To determine the roles of ALOX15B in carcinogenesis, we generated transgenic mice with ALOX8, the murine homolog of ALOX15B, knocked out. ALOX8 expression at mRNA level was abolished in homozygous knockout mice and reduced to half of wild type in heterozygous knockout mice. It's observed that homozygous female ALOX8 knockout mice are infertile but male ALOX8 knockout mice are fertile. Increased incidence of tumor as uni or multimass was found in the lung, prostate and in the mesentery region of homozygous and heterozygous ALOX8 knockout mice, when compared with little mate wild type mice. Histological evaluations showed an increase in secondary tumors and inflammation in different tissues like lung and large intestine in mice with ALOX8 knocked out. The transgenic mice could be a good model to study the role of 8-lipoxygenase in carcinogenesis and may provide insights into the tumor suppressing activities of human ALOX15B.
Citation Format: Rana Al-Fardan, Rabindra Karki, Changxiong Guo, Daotai Nie. Increased incidence of cancer in the transgenic mice with 8-Lipoxygenase knocked out. [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 LB-52. doi:10.1158/1538-7445.AM2013-LB-52
Abstract LB-59: ERG induces taxane resistance in castration-resistant prostate cancer.
Authors: Galletti Giuseppe , Beltran Himisha , Matov Alexandre , Fontugne Jacqueline , Mosquera Juan Miguel , Fazli Ladan , Tagawa Scott , Nanus David , Gleave Martin , Rubin Mark , Giannakakou Paraskevi , Rickman David S. 
Published: August 2014

Abstract
Taxanes are the only chemotherapies to prolong survival for patients with metastatic castration-resistant prostate cancer (CRPC), and both docetaxel (doc) and cabazitaxel (cab) are FDA approved for this indication. Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. In this study we show that ERG over-expression, which occurs in roughly 50% of prostate cancers, is associated with both doc and cab resistance using in vitro and in vivo models of CRPC. Using either tetracycline-inducible or constitutively active expression systems in multiple prostate cancer cell lines, we found that ERG over-expression leads to at least a 10 fold increase in IC50 doses of doc or cab based on cell viability assays and inhibition of taxane-induced apoptosis. Similarly, ERG over-expressing prostate cancer xenografts were reproducibly more resistant to cab compared to the cab-sensitive control xenografts. Based on a biochemical and cell biological characterization, we observed that ERG binds directly to tubulin in the cytoplasm of prostate cancer cells, as well as in circulating tumor cells from patients treated with doc, and prevents taxane-induced microtubule stabilization. ERG over-expression affects several parameters of microtubule dynamics and inhibits effective drug-target engagement of doc or cab with tubulin, either directly via its tubulin interaction or indirectly by affecting transcription of genes that modulate microtubule homeostasis. In addition, ERG induces and binds to clusterin, a molecular chaperone also associated with taxane resistance. Clusterin knock-down with siRNA abrogates ERG-induced taxane resistance. Altogether, this data suggests that ERG, an oncogenic transcription factor, plays a novel role beyond regulating gene expression and functions outside the nucleus to cooperate with clusterin and tubulin in promoting taxane resistance. Determining ERG status in patient tumors may aid in patient selection for doc or cab therapy and/or influence co-targeting approaches using the clusterin antisense inhibitor OGX-011.
Citation Format: Giuseppe Galletti, Himisha Beltran, Alexandre Matov, Jacqueline Fontugne, Juan Miguel Mosquera, Ladan Fazli, Scott Tagawa, David Nanus, Martin Gleave, Mark Rubin, Paraskevi Giannakakou, David S. Rickman. ERG induces taxane resistance in castration-resistant prostate cancer. [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 LB-59. doi:10.1158/1538-7445.AM2013-LB-59