bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1019: Salmonella break tumor immune tolerance by downregulation tumor indoleamine 2, 3-dioxygenase 1 expression
Authors: KUAN YU-DIAO , Lee Che-Hsin 
Published: May 2015

Abstract
Over past decades, bacteria have been proven the capability of inhibiting tumor growth. It can specifically target tumor and due to its facultative anaerobe property, can be more penetrative than other drug therapies. However, the molecular mechanism that bacteria inhibit tumor growth is still incompletely known. Here we used Salmonella choleraesuis to investigate the mechanism. The antitumor therapeutic effect mediated by Salmonella is associated with an inflammatory immune response at tumor site and T helper 1-type immune response. Many tumors have been proven high expression of indoleamine 2, 3-dioxygenase 1 (IDO), which is a rate-limiting enzyme that catalyzes tryptophan to kynurenine thus causing immunotolerance within tumor microenvironment. Our previous studies elucidated that Salmonella can also upregulate connexin 43 (CX43) to inhibit tumor progression and even enhance tumor chemosensitivity. Herein, we demonstrated that Salmonella can inhibit IDO expression through upregulation of CX43 in melanoma cells. Furthermore, we can also find the same phenomena in CX43 knock-down 4T1 and B16F10 cells. In brief, we point out that Salmonella-induced CX43 expression is a modulator of IDO expression and may play a crucial role in anti-tumor therapy, which combined with immunotherapy and Salmonella may be a prospective anti-tumor strategy.
Citation Format: YU-DIAO KUAN, Che-Hsin Lee. Salmonella break tumor immune tolerance by downregulation tumor indoleamine 2, 3-dioxygenase 1 expression. [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 1019. doi:10.1158/1538-7445.AM2014-1019
Abstract 1020: Trefoil factor 3 promotes angiogenesis in mammary carcinoma
Authors: Lau Wai-Hoe , Pandey Vijay , Kong Xiangjun , Banerjee Arindam , Zhu Tao , Lobie Peter E. 
Published: May 2015

Abstract
Mammary carcinoma cells produce various growth factors that stimulate endothelial cells to promote angiogenesis in mammary carcinoma. Trefoil Factor 3 (TFF3) is a small secreted protein which is involved in protection of the gastrointestinal tract against mucosal damage. Our laboratory has also previously identified TFF3 as an orthotopically expressed oncogene in mammary carcinoma and observed that TFF3 stimulated oncogenicity and invasiveness of mammary carcinoma cells. Several studies have reported a significant positive association between TFF3 protein expression and microvessel density. However, the potential functional role of TFF3 in mammary carcinoma angiogenesis has not been determined. Herein, we defined the functional effect of TFF3 secreted by mammary carcinoma cells on the behavior of endothelial cells in de novo tumor angiogenesis. We utilized MCF-7 and T47D cells as our in vitro models by stable forced expression of TFF3 or siRNA mediated depletion of TFF3 in these cell lines. The effect of TFF3 secreted from mammary carcinoma cells on human umbilical vein endothelial cells (HUVEC) was determined by using a co-culture transwell system, whereby HUVEC cells were co-cultured with mammary carcinoma cells. We demonstrated that TFF3 secreted from mammary carcinoma cells promoted HUVEC cells monolayer cell cycle progression and proliferation, survival, migration, invasion, and in vitro tubule formation. In a xenograft model, mammary carcinoma cells with forced expression of TFF3 produced tumors with increased microvessel density (CD31 and CD34) compared to tumors formed by control cells. Depletion of TFF3 in mammary carcinoma cells by siRNA or inhibition with anti-TFF3 polyclonal antibody significantly decreased HUVEC cells monolayer cell cycle progression and proliferation, migration, invasion, and in vitro tubule formation. Mechanistically, we observed that TFF3 increased IL-8 expression in mammary carcinoma cells with forced expression of TFF3. Depletion of IL-8 in mammary carcinoma cells by siRNA or inhibition with anti-IL8 monoclonal antibody significantly decreased migration, invasion, and in vitro tubule formation of HUVEC cells promoted by TFF3. Hence, TFF3 is a promoter of tumor angiogenesis, which may co-coordinate with the growth promoting and metastatic actions of TFF3 in mammary carcinoma to enhance tumor progression.
Citation Format: Wai-Hoe Lau, Vijay Pandey, Xiangjun Kong, Arindam Banerjee, Tao Zhu, Peter E. Lobie. Trefoil factor 3 promotes angiogenesis in mammary 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 1020. doi:10.1158/1538-7445.AM2014-1020
Abstract 1023: NOV C-ter: A novel preclinical anti-angiogenic agent
Authors: Luo Junfeng , Teng Yong , Li Minghui , Johnson Theodore S. , Cuttitta Franck , Chu Zhengtao , Qi Xiaoyang , Cowell John K. , Rixe Olivier 
Published: May 2015

Abstract
NOV (Nephroblastoma OVerexpressed) C-ter (NOV C-ter) is the carboxy-terminal sequence (170aa) of NOV/CCN3 protein. NOV/CCN3 (357aa), a member of CCN family, is secreted by quiescent endothelial cells and is involved in the regulation of various cellular functions including angiogenesis, proliferation, differentiation, survival, adhesion and migration. Although NOV C-ter does not have a direct cytotoxic effect when tested on a large panel of human cell lines including the NCI 60 cell lines (NCI Drug Screening Program), our data demonstrates significant anti-angiogenic and anti-tumor effects in a variety of experimental models. NOV C-ter inhibits in vitro endothelial cell tube formation in a dose-dependent fashion, using endothelial cells derived from porcine aorta, human microvasculature, or human umbilical vein (HUVECs). In addition, NOV C-ter impairs HUVEC proliferation, migration, invasion and adhesion. Interestingly, inhibition of HUVEC proliferation occurs via interference with growth-promoting signals involving Apelin-13 and adenomedullin. Furthermore, NOV C-ter specifically reduced phosphorylation of PI3K/Akt in endothelial cells, with no significant effect on the p44/42 (ERK1/2) pathway. In vivo, NOV C-ter had significant anti-tumor effect as a single agent in a murine glioblastoma xenograft model using human X-12 culture-adapted cells and in a nude mouse xenograft model using human non-small-cell lung cancer cells (A549). In these two systems, NOV C-ter provided superior survival benefit compared to treatment with bevacizumab or vehicle (PBS). Similarly, NOV C-ter significantly increased overall survival versus vehicle (PBS), an effect which was comparable to temozolomide treatment, in a murine syngeneic orthotopic glioblastoma model using the GL-261 cell line. To directly study the effect of NOV C-ter on angiogenesis, we treated zebrafish embryos prior to the onset of angiogenesis, and found a considerable reduction in vessel formation compared to bevacizumab-treated or untreated zebrafish. NOV C-ter also reduced tumor neovascularization in human breast cancer (T47D cell line) implanted in zebrafish. In summary, NOV C-ter demonstrates anti-angiogenic and tumoricidal effects via a novel mechanism of action. Mechanistic studies of NOV C-ter are underway to evaluate its precise effects on key signaling pathways in endothelial cells. Preclinical pharmacology and toxicology studies are also underway with a plan to advance to early-phase clinical trials.
Citation Format: Junfeng Luo, Yong Teng, Minghui Li, Theodore S. Johnson, Franck Cuttitta, Zhengtao Chu, Xiaoyang Qi, John K. Cowell, Olivier Rixe. NOV C-ter: A novel preclinical anti-angiogenic agent. [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 1023. doi:10.1158/1538-7445.AM2014-1023
Abstract 1031: Blockade of radiation-induced neuropilin-1 in glioblastoma cells impairs migration of endothelial cells
Authors: Maddirela Dilip Rajasekhar , Kesanakurti Divya , Gogineni Venkateswara R. , Chetty Chandramu 
Published: May 2015

Abstract
Neuropilin-1 (NRP-1) is an isoform specific receptor for vascular endothelial growth factor (VEGF), that regulates the development of the nervous system and also promotes angiogenesis in endothelial cells. Glioblastoma multiforme (GBM) is a malignant tumor characterized by robust neoangiogenesis with an aberrant elevation of VEGF. Recent evidence suggests that the majority of GBMs after radiation therapy (IR) exhibit an angiogenic regeneration process, which contributes phenotypic plasticity and therapeutic resistance. A high expression of NRP-1 in GBM correlates with disease progression. In this study, we show that the IR-induced NRP-1 role in the VEGFR-2 mediated signaling cascade promotes migration of endothelial cells. We observed that IR (8Gy) significantly elevated levels of VEGF and NRP-1 expression in 4910 and 5310 human GBM xenograft cells. Endothelial cells cultured on tumor- conditioned media from IR induced xenograft cells showed a significant increase in migration of endothelial cells; whereas, conditioned medium (CM) from NRP-1 knockdown xenograft cells inhibited IR-induced migration effects in endothelial cells. Further, CM from NRP-1 inhibited cells downregulated IR-induced expression of VEGFR-2 and its downstream molecules Sema3A, Plexin-A1 and E-cadherin in endothelial cells. Immunoflourescence co-localization studies revealed that the interaction of NRP-1 and VEGFR-2 were significantly decreased in endothelial cells cultured on CM from NRP-1-siRNA-transfected xenograft cells compared to mock- and SV-transfected cells. Collectively, our data indicate that NRP-1 plays a significant role in the regulation of VEGF/VEGFR-2 signaling and migration in endothelial cells, and thereby suggests NRP-1 as an important therapeutic target for glioma patients receiving radiation therapy.
Citation Format: Dilip Rajasekhar Maddirela, Divya Kesanakurti, Venkateswara R. Gogineni, Chandramu Chetty. Blockade of radiation-induced neuropilin-1 in glioblastoma cells impairs migration of endothelial 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 1031. doi:10.1158/1538-7445.AM2014-1031
Abstract 1033: Inhibiting bladder cancer metastasis with a dietary supplement
Authors: Hoye Kelly T. , Yates Travis , Alonzo David , Lokeshwar Vinata B. 
Published: May 2015

Abstract
INTRODUCTION AND OBJECTIVE: Hyaluronic acid (HA) and HYAL-1 hyaluronidase (HAase) family molecules are potential markers for BCa diagnosis and prognosis and promote tumor growth and metastasis. 4-Methylumbelliferone (4-MU) is an orally bioavailable dietary supplement that inhibits HA synthesis. Epithelial-to-mesenchymal transition (EMT) is the hallmark of invasion and metastasis. Since HA promotes tumor metastasis and EMT, we evaluated the expression of EMT markers in bladder tissues and antitumor effects of 4-MU in BCa models.
METHODS: Quantitative PCR was used to measure mRNA expression of EMT genes (β-catenin, Twist, and Snail) in 66 bladder tissue specimens (27 normal; 39 tumor); follow-up: 26±4.3 months; median 20 months. The effect of 4-MU (40 - 120 µg/ml) on cell proliferation, apoptosis, intracellular signaling, and the expression of HA receptors and EMT genes were examined in BCa cell lines, 253J-Lung and HT1376. Effect of 4-MU on tumor growth was analyzed in subcutaneous xenografts.
RESULTS: Among the EMT genes, Snail and Twist were differentially expressed in BCa tissues when compared to normal bladder (P&lt;0.001). Furthermore, elevated Twist expression significantly correlated with metastasis (2-fold increase; P=0.028). β-catenin expression negatively correlated with survival (chi square=4.3, p=0.038). At IC50 for HA synthesis, 4-MU inhibited proliferation (∼ 2.5-fold) and induced apoptosis (3-fold) in BCa cells. 4-MU induced caspase-8, -9 and -3 activation and up-regulation of Fas and FADD. 4-MU caused 4-10-fold downregulation of HA-receptors (CD44, RHAMM), and EMT promoters - β-catenin, Snail and Twist, but increased E-cadherin expression by 2-fold. In xenograft studies, 4-MU significantly decreased tumor growth (&gt; 3-fold) when treatment was started either on the day of tumor cell injection or after tumors became palpable. No weight loss or serum or organ toxicity was observed in treated mice. Tumors showed reduced microvessel density (∼3-fold) and HA expression but increased TURNEL positive cells.
CONCLUSION: This study shows that expression of EMT determinants correlates with clinical outcome. Furthermore, the non-toxic dietary supplement 4-MU has potent antitumor activity and reverses EMT.
Support: R01 CA 123063-04 (VBL); R01 CA 72821-11 (VBL).
Citation Format: Kelly T. Hoye, Travis Yates, David Alonzo, Vinata B. Lokeshwar. Inhibiting bladder cancer metastasis with a dietary supplement. [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 1033. doi:10.1158/1538-7445.AM2014-1033
Abstract 1037: WISP3/CCN6 regulates epithelial-mesenchymal transition and tumor initiating cell properties in triple negative breast cancer cells through Slug
Authors: Huang Wei , Toy Kathy A. , Kleer Celina G. 
Published: May 2015

Abstract
Background: Although triple-negative breast cancers (TNBCs) constitute 10%-20% of all breast cancers, they are aggressive tumors with higher recurrence and poorer prognosis than other breast cancer subtypes. TNBCs frequently exhibit features of epithelial to mesenchymal transition (EMT) and are enriched in breast tumor initiating cells (BTICs). Recent studies have demonstrated that aberrant activation of the EMT program induces stem cell features in breast cells, suggesting that blocking the cross-talk between EMT and stemness may be an effective treatment for TNBCs. WISP3/CCN6, a secreted matrix associated protein, is expressed in normal breast tissues and is decreased in aggressive breast cancer samples. We have shown that CCN6 knockdown in nontumorigenic breast cells triggers EMT and invasion. We hypothesize that CCN6 regulates the cross-talk between EMT and BTICs pathways in TNBCs.
Methods: We overexpressed CCN6 in the TNBC cell lines, MDA-MB-231, SUM-159 and MDA-MB-436, which are aggressive and exhibit a mesenchymal-like phenotype and low endogenous CCN6 expression. We tested the effect of CCN6 overexpression in these cell lines using motility and invasion assays in vitro. Stem cell features were investigated by mammosphere assays, and the ALDEFLUOR assay by flow cytometry. We developed mammary xenografts in nude mice using serial dilutions to investigate the role of CCN6 in tumor initiation and metastasis.
Results: Overexpression of CCN6 inhibits cell motility and invasion, and leads to phenotypic changes of mesenchymal-epithelial transition (MET), with downregulation of the mesenchymal cell marker vimentin, increased epithelial marker cytokeratin, and decreased protein levels of the EMT transcription factor Slug. CCN6 overexpression significantly decreased the ALDEFLUOR-positive population and mammosphere formation of TNBC cell lines. In vivo, CCN6 overexpression delayed tumor initiation and reduced metastasis in human breast cancer xenografts. Slug reconstitution was sufficient to rescue the effects of CCN6 on MET and stem cell properties of TNBCs.
Conclusions: These data demonstrate that CCN6 regulates EMT and tumor initiating cell features in TNBC at least in part through Slug. Further, our study suggests that CCN6 may be a novel regulator of the EMT-stem cell cross talk in TNBC, with possible clinical application.
Citation Format: Wei Huang, Kathy A. Toy, Celina G. Kleer. WISP3/CCN6 regulates epithelial-mesenchymal transition and tumor initiating cell properties in triple negative breast cancer cells through Slug. [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 1037. doi:10.1158/1538-7445.AM2014-1037
Abstract 1038: ZEB1 plays a pivotal role in hypoxia-mediated increase of in vitro invasion of glioblastoma-derived cell cultures and represents a novel neural stem cell marker in early development
Authors: Kahlert Ulf D. , Raabe Eric E. , Siebzehnrubl Florian A. , Bar Eli E. , Maciaczyk Jaroslaw , Eberhart Charles G. 
Published: May 2015

Abstract
Objective
Hypoxia is thought to induce migration in many neoplasms, often by promoting epithelial-to-mesenchymal transition (EMT), but the mechanisms by which it affects brain tumor invasion is less well understood. In particular, little is known about the possible role of EMT-associated factors in hypoxia-mediated induction of migratory phenotype in gliomas.
Methods
Migration and invasion of GBM-derived cell lines (n=3) cultivated as spheres in serum-free media under atmospheric oxygen (21% O2) and hypoxia (1% O2) were assessed in Boyden Chamber-based in vitro assays. Digoxin was used to inhibit the HIF-1-mediated hypoxic response. The importance of the EMT-factor ZEB1 in our model was investigated by inhibiting its expression using sh-RNA delivered by lentivirus.
Results
Hypoxia led to a significant increase of in vitro invasion in all three neurosphere lines tested (GBM1 up to 6fold, 622 up to 3fold and over 10fold for 821; p=0.001). This was accompanied by induction of EMT effectors including ZEB1, SNAI1 and TWIST1 as compared to normoxic cultures. Digoxin-mediated inhibition of HIF1a transcription resulted in abolition of this phenomenon. Additionally, histological analysis of patient-derived GBM samples revealed an abundance of ZEB1 positive cells in hypoxic, peri-necrotic tumor areas. Strikingly, ZEB1-knockdown significantly reduced the invasive behavior of the cells. Interestingly, we also identified numerous ZEB1-postive cells in fetal neurogenic regions and migrating neuroblasts in both human and rodent brains. Furthermore, analyses of human fetal neural progenitors showed that ZEB1 expression is correlated with stem cell phenotype and established neural stem- and progenitor markers including SOX2 and NESTIN. Finally, analysis of TCGA and Rembrandt datasets identified up-regulation of EMT factors such as TWIST1, SNAI1 and SNAI2 was found in the aggressive, mesenchymal subgroup of GBM.
Conclusion
While malignant gliomas are not epithelial tumors, hypoxia increases the invasion capacity of GBM cells at least in part by inducing expression of EMT markers such as ZEB1. ZEB1 is also most highly expressed in the developing fetal brain in migrating stem and progenitor cells, suggesting it may play a similar role in normal development.
Citation Format: Ulf D. Kahlert, Eric E. Raabe, Florian A. Siebzehnrubl, Eli E. Bar, Jaroslaw Maciaczyk, Charles G. Eberhart. ZEB1 plays a pivotal role in hypoxia-mediated increase of in vitro invasion of glioblastoma-derived cell cultures and represents a novel neural stem cell marker in early development. [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 1038. doi:10.1158/1538-7445.AM2014-1038
Abstract 1044: Pyruvate kinase M2 stimulates the epithelial-mesenchymal transition by genetically controlling E-cadherin expression in colon cancer
Authors: Konno Masamitsu , Hamabe Atsushi , Doki Yuichiro , Mori Masaki , Ishii Hideshi 
Published: May 2015

Abstract
Pyruvate kinase M2 (PKM2) maintains aerobic glycolysis in cancer cells and stimulates cell proliferation by controlling cancer metabolism (Warburg effect)(Nature, 2008). In addition, PKM2 translocates to nucleus in response to EGFR signaling and up-regulates Cyclin D1 expression by controlling its transcription (Nature, 2011). PKM2 confers malignant potential by controlling both metabolism and nuclear function. In this study, we investigated the correlation between PKM2 and invasion and metastasis of colorectal cancer in terms of nuclear function, which has yet to be investigated. Tumor invasion is initiated with the change of epithelial-mesenchymal transition (EMT) in cancer cell, and we induced EMT by adding TGF-β1 and EGF to SW 480. After EGF induction, in parallel with E-cadherin down-regulation and Vimentin up-regulation, the expression of PKM2 was increased both in transcriptional and translational level and PKM2 translocated into nucleus. PKM2 knock-down by siRNA suppressed E-cadherin decrease and invasion capacity in invasion assay. We created sh pyruvate kinase SW 480 with mouse PKM1 or PKM2 was overexpressed both of which have DNA sequence resistant to sh pyruvate kinase. PKM2 overexpression stimulated EMT induction by enhancing E-cadherin decrease. The protein X was identified which interacted with PKM2 in nucleus in response to EMT induction, which was considered to have a key role in controlling EMT induction. We performed immunohistochemical staining with specific antibody to PKM2 using clinical samples of colorectal cancers. Clinicopathological analysis showed that PKM2 positivity significantly correlated with lymph node metastasis and distant organ metastasis. In conclusion, our data suggested that PKM2 nuclear function had a crucial role in controlling invasion and metastasis.
Citation Format: Masamitsu Konno, Atsushi Hamabe, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Pyruvate kinase M2 stimulates the epithelial-mesenchymal transition by genetically controlling E-cadherin expression in colon 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 1044. doi:10.1158/1538-7445.AM2014-1044