bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1351: Lack of matrix metalloproteinase-10 exacerbates inflammation-associated colon tumor development
Authors: Koller Felicitas L. , Dozier E. Ashley , Fingleton Barbara M. 
Published: February 2011

Abstract
Ulcerative colitis is the most common inflammatory bowel disease, and is associated with increased risk of colon cancer. Understanding the mechanisms by which carcinogenesis occurs in the setting of colitis could lead to both prevention strategies and improved therapies. Matrix metalloproteinase-10 (MMP10), a member of the matrix metalloproteinase family of proteolytic enzymes, is expressed at healing edges of colonic ulcers. Although MMPs are usually considered as destructive players in inflammatory disease, we considered the possibility that MMP10 had a beneficial role in ulcerative colitis. We used dextran sulfate sodium (DSS) treatment in MMP10-null and corresponding control wild-type mice to investigate the consequences of MMP10 deletion on colitis development and recovery. Groups of mice were exposed to DSS for 7-day periods and sacrificed at different timepoints following the cessation of the DSS. Strikingly, MMP10-null mice were more severely affected by the treatment as determined by gross observations such as weight loss and colon length. Histological analysis at the various timepoints indicated that wild-type mice showed almost complete recovery from DSS within 14 days after DSS treatment. In contrast, MMP10-null mice still showed clear signs of damage with persistent inflammatory foci and non-healing ulcers. In situ hybridization indicated MMP10 expression predominantly in inflammatory cells, although some fibroblasts were also positive. Colonic epithelium was negative for MMP10. Bone marrow transplant experiments indicated that wild-type bone marrow partially rescued the MMP10-null phenotype. Measurement of cytokines by ELISA in colonic lavage fluid from MMP10-null and wild-type mice showed that IL-1α was significantly increased in the absence of MMP10. Levels of other cytokines such as TNFα, IL6, IL17 and G-CSF were not different. Multiple exposures to DSS results in conversion of an acute colitis to a chronic inflammatory disease. With only 2 DSS exposures, MMP10-null mice manifested a chronic condition which failed to resolve even after 3 months. Similarly-treated wild-type mice, however, appeared normal at this timepoint. Examination of the colonic tissue from the DSS double exposure showed a significant increase in the number of dysplastic foci present in the MMP10-null mice. Thus, expression of MMP10 appears necessary for resolution of colitis, and in its absence, the development of chronic colitis results in tumor development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1351.
Abstract 1352: Macrophage specific regulation reveals both pro- and anti-tumor effects of NF-kappaB during mammary tumor progression
Authors: Connelly Linda , Barham Whitney , Onishko Hala M. , Zabuawala T , Ostrowski Michael C. , Blackwell Timothy S. , Yull Fiona E. 
Published: February 2011

Abstract
An increased level of macrophages in human tumors is associated with a poorer prognosis. The transcription factor Nuclear Factor-kappaB (NF-kappaB) is an important regulator of gene expression within macrophages. Recent studies point to a pro-tumorigenic role for NF-kappaB activity in macrophages; however NF-kappaB also regulates expression of genes such as inducible nitric oxide synthase which are associated with anti-tumor effects. We believe that NF-kappaB activity in macrophages can have both anti- and pro-tumor effects depending on tumor stage.
We have developed novel murine models to determine the effects of modulation of NF-kappaB activity specifically within macrophages during primary mammary tumor growth and metastasis. We have used the cfms promoter to specifically express the reverse tetracycline transactivator (rtTA) protein in macrophages. The rtTA can drive tet operon regulated gene expression in the presence of doxycyline (dox). We have used this with a dominant negative IkappaBalpha to inhibit NF-kappaB signaling in the Polyoma mouse mammary tumor model, this model is termed DNFP. We have also used the cfms-rtTA in combination with a constitutively active IKK2 transgene to activate NF-kappaB signaling, this model is termed IKFM.
When NF-kappaB is inhibited in macrophages during primary tumor growth in our DNFP model there is a reduction in primary tumor growth accompanied by a reduced level of lung metastasis. This data suggests that NF-kappaB in macrophages is acting in a pro-tumor manner, in agreement with recently published data. In contrast, we have found that activation of NF-kappaB in macrophages by treating IKFM mice with dox for 1 week before and during two weeks following tail vein injection of polyoma mammary tumor cells leads to a significant reduction in surface lung tumor formation. In additional studies, IKFM mice were pretreated with dox for 1 week but treatment was stopped two days after tumor injection. A similar reduction in tumor number was observed, suggesting an inhibition of cell seeding. Real time PCR analysis of lungs from mice with activation of NF-kappaB in macrophages suggests an anti-tumor “M1” macrophage phenotype.
In summary, our data indicates that NF-kappaB activity in macrophages can have both anti- and pro-tumor effects dependent on tumor stage. This data would suggest that cell specificity and timing of treatment are important considerations with regards to the use of NF-kappaB inhibitors in cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1352.
Abstract 1363: Inhibition of Neuropilin-1 by anti-Nrp1 results in reduced angiogenesis and inhibition of tumor growth
Authors: Mak Judy , Pan Qi , Berry Leanne , Ross Sarajane , Koeppen Hartmut , Greg Plowman , Watts Ryan , Bagri Anil 
Published: February 2011

Abstract
Neuropilin-1 (NRP1) guides the development of the nervous and vascular systems and has been implicated in modulating various aspects of tumor cell function. We have previously shown that an antibody directed against NRP1 inhibits tumor growth and reduces tumor angiogenesis, as a single agent and more potently in combination with anti-VEGF. However, as NRP1 was also expressed in the tumor cells tested, the impact from inhibiting tumor cell NRP1 in these experiments was unclear. The objective of this study was to determine if inhibition of tumor cell NRP1 was necessary for the observed anti-tumor effects previously described for anti-NRP1. We tested the effects of anti-NRP1 in tumor lines that do not express NRP1, and where expression of NRP1 is restricted to the vasculature. Inhibition of tumor growth as a single agent, and in combination with anti-VEGF in these xenografted tumor lines, confirm that tumor expression of NRP1 is not necessary for the anti-tumor effects of anti-NRP1. We furthermore demonstrate that anti-NRP1 treatment of endothelial cells in in vitro sprouting assays results in potent inhibition of vascular sprout formation, confirming its anti-angiogenic activity. In vivo, in developmental models of angiogenesis, treatment results in reduced angiogenesis that is augmented by anti-VEGF. Finally, we demonstrate that treatment of primates with anti-NRP1 results in up-regulation of cytokines, such as PlGF, that are commonly increased with anti-angiogenic agent treatment. In total, these data confirm that anti-NRP1 mechanistically acts to inhibit tumor angiogenesis, thus resulting in reduced tumor growth and this tumor inhibition is most effective in combination with VEGF inhibition.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1363.
Abstract 1364: Combination of MEDI3617, a fully human anti-angiopoietin 2 monoclonal antibody, with inhibitors of the VEGF pathway enhances antitumor activity in vivo
Authors: Inigo Ivan V. , Coffman Karen , Fazenbaker Christine , Jallal Bahija , Trail Pamela , LaVallee Theresa , Coats Steve , Chang Yong , Leow Ching Ching 
Published: February 2011

Abstract
Angiopoietin 2 (Ang2) is an important regulator of angiogenesis, blood vessel maturation, and maintenance of the integrity of the vascular endothelium. Ang2-Tie2 interactions for vascular remodeling have been shown to play an important role in tumor vessel plasticity. MEDI3617 is a fully human anti-Ang2 monoclonal antibody that neutralizes the activity of Ang2, thereby inhibiting Ang2 from binding and signaling through the Tie2 receptor. Previously, we have demonstrated that treatment with MEDI3617 resulted in tumor growth inhibition in a wide spectrum of subcutaneous human tumor xenograft models. Given that angiogenesis is a process that requires concerted interplay of mutiple pathways, predominantly the VEGF pathway and the Ang/Tie pathway, we hypothesized that maximal inhibition of tumoral angiogenesis and consequently tumor growth could be achieved by blocking both pathways. We investigated the activity and tolerability of combining MEDI3617 with inhibitors of the VEGF pathway such as sorafenib and bevacizumab. In PLCPRF/5, a hepatocellular carcinoma xenograft model, combination of MEDI3617 and sorafenib resulted in a significant increase tumor growth inhibition. Similarly, in HPAC, a pancreatic cancer xenograft model, combination of MEDI3617 and bevacizumab resulted in greater tumor growth inhibition than either single agent alone. Mice exhibited no adverse effects or wt. loss following combination treatments. Taken together, these data support the clinical evaluation of the combination treatment of MEDI3617 and a VEGF inhibitor in cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1364.
Abstract 1367: The dual selective VEGFR-FGFR kinases inhibitor E-3810 decreases tumor perfusion and inhibits tumor growth: an analysis using dynamic contrast-enhanced magnetic resonance imaging
Authors: Bichat Francis , Tizon Xavier , Provent Peggy , Bari Virginie , Cereda Roberta , Camboni Gabriella , Cavalletti Ennio 
Published: February 2011

Abstract
Background: E-3810 is a potent VEGFR1, 2 and 3 and FGFR 1 kinases inhibitor showing potent anti-angiogenic and antitumor activity in several in vitro and in vivo mouse models (Proceedings AACR-EORTC-NCI Meeting, Boston, November 2009; Abstracts No. 252 and 257). The aim of this study was to investigate, in a rat model, the antitumor activity of E-3810 and its anti-angiogenic effects by using DCE-MRI and to correlate the response with a panel of biological markers.
Methods: Nude rats were subcutaneously xenografted with human Calu-6 lung cancer cells and treated orally once daily for 14 consecutive days, either with E-3810 − 10 mpk (dose chosen on the basis of a preliminary study in the same model) or Sorafenib − 100 mpk. Tumor growth and parameters reflecting tumor vascular permeability/perfusion (Ktrans) were evaluated by T2-weighted MRI and by T1-weighted DCE-MRI using Gd-DTPA (Magnevist®) as contrast agent at D-1, D1, D3, D7 and D14. The number, maturity and functionality of tumor vessels were assessed using CD31/α-SMA colocalisation by IHC and injection of Hoechst fluorescent dye on D1, D3, D7 and D14. On the same days, the level of circulating endothelial cells (CEC) and collagen IV were measured by FACS and ELISA assays.
Results: In comparison to vehicle-treated animals, a marked tumor growth inhibition was observed in E-3810-treated rats (max T/C 21%) with no remarkable signs of toxicity. In the same animals, Ktrans value in the tumor rim was significantly decreased (up to 49% on D14). This DCE-MRI finding was supported by the significant decrease in the Hoechst stained area observed at D1 (−97%), D7 (−96%) and D14 (−75%). In addition, the number of tumor vessels (both CD31 and colocalized CD31/α-SMA) was significantly decreased at D3 (−72%), D7 (−68%) and D14 (−86%) in E-3810-treated rats. Always in comparison to vehicle group, no significant changes in CEC were observed after treatment with E-3810, whereas collagen IV levels significantly increased at D14 (+38). Similar effects on all the above mentioned parameters were observed in Sorafenib treated animals. Conclusions: E-3810 displayed a marked antitumor activity in the model of Calu-6 tumor bearing nude rats. The antitumor effect is coupled with a strong antiangiogenic activity, as indicated by decrease in vascular permeability/perfusion and decrease of microvessels density that occur early on and are maintained throughout the treatment period.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1367.
Abstract 1368: L-5F, an ApoA-I mimetic peptide, inhibits tumor angiogenesis by suppressing VEGF/bFGF signaling pathways
Authors: Gao Feng , Su Feng , Roberts Svetlana , Grijalva Victor , Reddy Srinivasa T. , Farias-Eisner Robin 
Published: February 2011

Abstract
Objective
We recently demonstrated that overexpression of ApoA-I inhibits tumor growth and improves survival in mice. In the present study we examined whether apoA-I mimetic peptide, L-5F reduces tumor development in mice by inhibiting angiogenesis.
Methods
Flank tumors were generated in immunocompetent C57BL6/J mice as described previously (Zhang L, et al. 2002) by injecting ID8 cells, a mouse ovarian cancer cell line. L-5F was injected s.c. once a day for 5 weeks (10 mg/kg). 3D vessel images of tumor tissues were created using a micro-CT scanner from Numira Biosciences. The effects of L-5F in vitro were studied in human umbilical vascular endothelial cells (HUVEC) following VEGF and bFGF treatment. MTS assay, BrdU cell proliferation assay, wound-healing assay, and trans-well assay were used to determine cell viability, proliferation, migration, and invasion of HUVEC, respectively. Activation of Erk and Akt pathways were analyzed using western blots.
Results
Daily s.c. injection of L-5F significantly reduced tumor size and quantity and size of vessels of flank tumors in C57BL6/J mice, compared to mice that did not receive L-5F peptide. L-5F (10 µg/ml) significantly inhibited both VEGF- and bFGF-induced cell viability (∼46% for VEGF and ∼56% for bFGF), proliferation (∼50% for VEGF and ∼70% for bFGF), migration (∼80% for VEGF and ∼77% for bFGF), and invasion (∼65% for VEGF and ∼44% for bFGF) in HUVECs. L-5F mediated effects were dose-dependent between 1 and 10 µg/ml including the inhibition VEGF and bFGF-induced phosphorylation of Erk and Akt. L-5F did not affect the viability and proliferation of HUVECs in the basal state (i.e. absence of VEGF and bFGF treatments).
Conclusion
Our data suggest that apoA-I mimetic peptide, L-5F inhibits tumor development in mice, in part, by inhibiting angiogenesis. ApoA-I mimetic peptides may serve as novel anti-angiogenesis and anticancer therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1368.
Abstract 1375: Amlexanox inhibits FGF-mediated paracrine and autocrine activity of tumor-derived melanoma cell lines and cell strains
Authors: Huang Ruea-Yea , Bowers Dawn , Wong Michael K. 
Published: February 2011

Abstract
Melanoma is a highly invasive disease characterized by widespread lymphatic and systemic metastases. Although angiogenesis is critical for this to occur, the responsible mechanisms within melanoma cells remain unclear. The purpose of this study is to identify factors secreted by tumor-derived melanoma cells which can mediate these processes. Serum-free conditioned medium (CM) isolated from two melanoma cell lines and four newly derived melanoma cell strains promote both the growth in culture and angiogenic outgrowth activity of HUVEC and HMEC1 in 3-dimensional (3-D) collagen gel culture. Substantial amounts of both FGF1 (acidic) and FGF2 (basic) are found in the conditioned medium (CM). The addition of neutralizing antibodies to FGF1 (5 μg/ml) and FGF2 (3 μg/ml) to the melanoma CM significantly decreased the proliferation of HUVEC and HMEC1 by (20%) and (40%), respectively, and the angiogenic activity of HMEC1 by (20%). Amlexanox (AMX) is an anti-inflammatory agent that binds intracellular S100A13, one component of the putative FGF1-secretion complexes. AMX suppresses constitutive release of FGF1, but not FGF2, from these melanoma cells. AMX-treated melanoma-CM results in significant reduction of: HUVEC mitogenic activity, endothelial migration into 3-D collagen gel as well as melanoma cell proliferation. These AMX-mediated effects correlate with a concomitant decrease of FGFR1 phosphorylation in melanoma cells. The sum of these results point to the importance of the FGF-1 pathway and nominate AMX as a significant anti-melanoma agent by virtue of its impact on both paracrine and autocrine activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1375.
Abstract 1377: Vascular shutdown effects of tetra-arsenic oxide in solid murine tumors
Authors: Wen Lan Ying , Bae Su Mi , Kim Young Jae , Kim Kyung Tae , Ahn Woong Shick 
Published: February 2011

Abstract
Tetra-arsenic oxide [As4O6, 2,4,6,8,9,10-Hexaoxa-1,3,5,7-tetraarsatricyclo(3.3.1.13,7) decane]- one kind of arsenic compound, has shown more potent antitumor effect on cervix cancer cells. As4O6 also showed an inhibitory effect on tube formation of endothelial cells in vitro. The aim of this study was investigate the vascular shutdown effects of As4O6 on TC-1 cell implanted mice.
TC-1 cell, which is HPV 16 E6/E7 transfected cell, was used both in vitro and in vivo study. In vitro experiments: to assess cell viability MTT assay was employed, and morphology was determined by microscopy. In vivo experiments, 6 weeks old C57BL/6, female mice were used. 5′106 TC-1 cells were inoculated subcutaneously to abdomen and when tumor size reach to 350∼400 mm3 (12 to 14 days after inoculation when reaching a surface diameter of 8 to 10 mm), tumor bearing mice were randomly divided into two groups of PBS injected (n=14) and As4O6 (10 mg/kg b.w., i.p.) injected groups (n=14). Tumor volume was measured by caliper every two or three days for 3 weeks and recorded as volume diameter [longest surface length (a), width (b) and height (c), (a x b x c)]. Hoechst 33342 uptake method has been performed. One minute before harvest tumor tissue sections, Hoechst 33342 was injected and make frozen section. Tumor tissue were observed under 365nm microscope and photographed at x40. Each tumor image was constituted by 15∼35 pieces of view.
Through MTT assay, it was shown cell growth inhibitory effects of As4O6 on TC-1 cell lines. Cell proliferation reduced to 52.74%, when treat 4.00 uM As4O6, IC50 value was 4.05 uM after 24 hours treatment. There were also many changes on morphology after 24hours of As4O6 treatment, include: cell number was reduced, cell membrane became weak, and cytoplasm got scarce. In TC-1 cells challenged C57BL/6 mice, As4O6 delayed tumor growth. 3 weeks after As4O6 treatment, the tumor volume suppressed nearly 89.8% compared with control group (p&lt;0.05). Hoechst 33342 can stain tumor area which has vasculature. We detected that Hoechst 33342 stained areas was significantly disappeared in the central of the tumor tissue from one hour after As4O6 injection. While non-treated tumor tissue was 100% stained, one hour treated As4O6 tumor tissue was stained only 12.5 %.
Conclusion: This study shows that As4O6 can make strong vascular shutdown effects on TC-1 cells implanted mice.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1377.
Abstract 1384: Prevention of angiogenesis by aldose reductase inhibition
Authors: Saxena Ashish , Tammali Ravinder , Reddy Aramati BM , Srivastava Satish K. , Ramana Kota V. 
Published: February 2011

Abstract
We have recently shown that Aldose Reductase (AR) known to be involved in oxidative stress-signaling, initiated by inflammatory markers, prevents human colon cancer cell growth in culture as well as in nude mice xenografts. Inhibition of AR also prevents azoxymethane-induced aberrant crypt foci formation in mice. In order to understand the chemopreventive mechanism of AR inhibition in colon cancer, we have investigated the role of AR in the mediation of angiogenic signals in vitro and in vivo models. Using human umbilical vein endothelial cells (HUVEC), we have investigated the effect of AR inhibition on VEGF- and bFGF- induced tube as well as spheroid formation in in vitro angiogenesis. We have also determined the invasion and migration of HUVEC by inhibition of AR. Further, to determine the in vivo efficacy of AR inhibition on angiogenesis, matrigel plug assay was performed using a rat model. Our results show that inhibition of AR significantly prevented the VEGF- and bFGF -induced proliferation and generation of reactive oxygen species in HUVEC. Further, AR inhibition also prevented the VEGF- and bFGF- induced secretion/expression of IL-6, MMP1, MMP9, ICAM, and VCAM. Matrigel plug model of angiogenesis in rats showed that inhibition of AR prevented the infiltration of blood cells, invasion, migration and formation of capillary like structures, and expression of blood vessels markers CD31 and vWF. Thus, our results demonstrate that AR inhibitors could be novel drugs for cancer chemoprevention by inhibiting angiogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1384.