bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3363: Resistin promotes tumor angiogenesis and lymphangiogenesis through c-Src/PI3K/AKT signaling pathway in human chondrosarcoma cells
Authors: Chi Meng-Ju , Tsai Hsiao-Chi , Tang Chih-Hsin 
Published: July 2016

Abstract
Chondrosarcoma is a kind of commonly found bone malignant tumor. The development of distant metastasis often leads to a significant decline in overall survival, and there are no specific therapeutic methods for it until today. For tumors to metastasize, angiogenesis and lymphangiogenesis are both important steps in the early periods. Resistin was discovered as an adipocyte-secreting adipokine, which may play a critical role in modulating cancer pathogenesis. However, the role of resistin in the angiogenesis and lymphangiogenesis of human chondrosarcoma is largely unknown. In our lab, we found that the expression of resistin was higher in chondrosarcoma biopsy tissues than in normal cartilage. We also confirmed that treated cells with resistin increased VEGFA and VEGFC expression, promoting angiogenesis as well as lymphangiogenesis in human chondrosarcoma cells. Moreover, the inhibitors and siRNAs of c-Src, PI3K, and AKT reduced the resistin-increased cell angiogenesis and lymphangiogenesis. Our results indicate that resistin promotes chondrosarcoma angiogenesis and lymphangiogenesis by the increasing VEGFA and VEGFC expression through the activation of the c-Src/PI3K/AKT signaling pathway expression. Therefore, resistin may represent a potential novel molecular therapeutic target for chondrosarcoma therapeutic treatment.
Citation Format: Meng-Ju Chi, Hsiao-Chi Tsai, Chih-Hsin Tang. Resistin promotes tumor angiogenesis and lymphangiogenesis through c-Src/PI3K/AKT signaling pathway in human chondrosarcoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3363.
Abstract 3364: Adaptive mechanisms upon LRP1 repression: Impact on sphingosine-1-phosphate-mediated signalling and migration of brain endothelial cells
Authors: Vézina Amélie , Charfi Cyndia , Zgheib Alain , Annabi Borhane 
Published: July 2016

Abstract
Switches in the sphingolipid metabolism have recently been associated with oncogenic transformation, and a role for the low density lipoprotein receptor related protein (LRP1) in the sphingosine-1-phosphate (S1P) proangiogenic signalling inferred. Although S1P is a key determinant of blood-brain barrier (BBB) permeability, the interdependent signalling crosstalk with LRP1 in brain endothelial cells (EC) remains unclear. Here, we tested whether any adaptive LRP1/S1P interdependence mechanisms are required in a SV40-immortalized human brain microvascular EC (HBMEC) model which closely mimics the brain tumor endothelium phenotype. Transient LRP1 silencing and stable LRP1-/- HBMEC were generated and increased expression of CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor which regulates the transcription of all five S1P receptors members, was observed upon stable but not transient LRP1 repression. Migration of EC isolated from Lrp1(EC)-/- mice and of stable LRP1-/- HBMEC became unresponsive to S1P, in part explained by altered ERK and p38 MAPK pathways, whereas it remained unaltered in transient in vitro LRP1 repression. Adaptive diminished expressions of S1P1, S1P3, and S1P5, and increased S1P2 were observed in stable LRP1-/- HBMEC and in brain EC isolated from Lrp1(EC)-/- mice. Finally, gene silencing strategies highlighted the need for S1P3 for proper S1P-mediated HBMEC migration. Collectively, our study highlights an unexpected adaptive transcriptional crosstalk between LRP1 and specific S1P receptors which accounts for S1P signalling in brain EC. Targeting of the LRP1/S1P signalling axis at the BBB may thus be considered in future therapeutic strategies.
Citation Format: Amélie Vézina, Cyndia Charfi, Alain Zgheib, Borhane Annabi. Adaptive mechanisms upon LRP1 repression: Impact on sphingosine-1-phosphate-mediated signalling and migration of brain endothelial cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3364.
Abstract 3366: NCL targeting impairs the progression of pancreatic ductal adenocarcinoma and promotes tumor vessel normalization through Ang-2 inhibition
Authors: Gilles Maud-Emmanuelle , Maione Federica , Cossutta Mélissande , Carpentier Gilles , Caruana Laure , Di Maria Silvia , Destouches Damien , Shchors Ksenya , Prochasson Christopher , Couvelard Anne , Courty José , Giraudo Enrico , Cascone Ilaria 
Published: July 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor, mostly resistant to the standard treatments. NCL is overexpressed in cancers and its inhibition impairs tumor growth. Herein we described, that NCL was overexpressed in human specimens of PDAC, and low NCL staining patients had increased overall survival. Previously, we described a family of multivalent pseudopeptides binding to NCL and inhibiting tumour growth. Here, NCL antagonist N6L, strongly impaired tumor growth, liver metastasis formation and angiogenesis in an orthothopic mouse model of PDAC. N6L inhibited both human and mouse tumor cell proliferation and invasion. Proteome analysis of endothelial cell secreted proteins showed that NCL inhibition decreased Ang-2 levels and switched a pro-angiogenic signature. Importantly, Ang-2 levels were decreased in plasma of N6L-treated PDAC mice. The analysis of tumor vasculature revealed a strong increase of pericyte coverage and vessel perfusion in parallel to an inhibition of tumor hypoxia. As consequence of N6L-induced tumor vessel normalization, pre-treatment with N6L efficiently improved chemotherapeutic drug delivery and increased the anti-tumor properties of gemcitabine in PDAC mice.
In conclusion, NCL inhibition is a new anti-tumor therapeutic strategy that dually blocks tumor progression and normalizes tumor vessels improving the delivery and efficacy of chemotherapeutic drugs in PDAC cancers. Moreover, we identified Ang-2 as a potential target and suitable response biomarker for N6L treatment in PDAC.
Citation Format: Maud-Emmanuelle Gilles, Federica Maione, Mélissande Cossutta, Gilles Carpentier, Laure Caruana, Silvia Di Maria, Damien Destouches, Ksenya Shchors, Christopher Prochasson, Anne Couvelard, José Courty, Enrico Giraudo, Ilaria Cascone. NCL targeting impairs the progression of pancreatic ductal adenocarcinoma and promotes tumor vessel normalization through Ang-2 inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3366.
Abstract 3369: Tumor-microenvironment-dependent imprinting of endothelial cells in human colorectal carcinoma
Authors: Stürzl Michael , Liebl Andrea , Schellerer Vera S. , Schütz Manuela , Kölbel Patrick , Schaal Ute , Haep Lisa , Klein-Hitpass Ludger , Rau Timan T. , Dietel Barbara , Meniel Valerie , Clarke Alan R. , Merkel Susanne , Croner Roland S. , Hohenberger Werner , Naschberger Elisabeth 
Published: July 2016

Abstract
The tumor microenvironment (TME) and tumor cell heterogeneity contribute significantly to tumor pathogenesis. In contrast, potential stromal cell heterogeneity induced by the TME and its impact on human tumorigenesis has not been conclusively investigated. Therefore, pure tumor endothelial cells (TECs) from human colorectal carcinomas (CRCs) with differential TMEs (favorable Th1-TME and worse control-TME) were isolated and significantly different gene clusters reflecting the tumorigenic and angiogenic impact attributed to the respective TMEs were identified by transcriptome analysis. SPARCL1 - the most strongly upregulated gene in Th1-TME-derived TECs - was analyzed to prove this concept. SPARCL1 was expressed by endothelial cells (EC) in colon tissues, most prominently in mature normal vessels, similarly in CRC with Th1-TME and lost towards more aggressive and angiogenic control tumors. SPARCL1 was induced in confluent, quiescent EC in culture but absent or resolved in angiogenically active EC. SPARCL1 inhibited proliferation, migration and sprouting of cultivated EC in vitro. In human CRC tissues SPARCL1 expressing vessels were highly covered by mural cells and of larger vessel size (perimeter and area), indicting more progressed maturation. Similarly the vessels in the colon of wild type mice as compared to SPARCL1/Sc1 knockout mice exhibited a more mature vessel structure. In conclusion, exploiting cellular memory processes we demonstrated TME-dependent intratumoral TEC heterogeneity in CRC and identified SPARCL1 as novel EC-derived protein regulating vessel maturation and homeostasis.
Citation Format: Michael Stürzl, Andrea Liebl, Vera S. Schellerer, Manuela Schütz, Patrick Kölbel, Ute Schaal, Lisa Haep, Ludger Klein-Hitpass, Timan T. Rau, Barbara Dietel, Valerie Meniel, Alan R. Clarke, Susanne Merkel, Roland S. Croner, Werner Hohenberger, Elisabeth Naschberger. Tumor-microenvironment-dependent imprinting of endothelial cells in human colorectal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3369.
Abstract 3376: Molecular drivers of endothelial hypoxic adaption during angiogenesis deciphered using the Berg Interrogative Biology® platform
Authors: Walshe Tony E. , Bourdelais Justin , Akmaev Viatcheslav R. , Rodrigues Leonardo O. , Lao Socheata , Gesta Stephane , Kiebish Michael A. , Vishnudas Vivek K. , Sarangarajan Rangaprasad , Narain Niven R. 
Published: July 2016

Abstract
Angiogenesis is a key feature of tumor progression providing oxygen and nutrients required for tumor cell growth, hypoxia being a major driver of this phenomenon. A systems biology approach using the Berg Interrogative Biology® platform was implemented to identify drivers of the endothelial cell (EC) angiogenic response to hypoxia. To determine the proteomic profile of proliferating ECs and non-proliferating confluent ECs exposed to normoxia or hypoxia, a functional proteomic approach employing activity-based probes and phosphorylation analysis was utilized. Kinases and ATPases were labeled with ATP-binding domain enrichment probes and titanium dioxide enrichment of phosphopeptides was employed for capture of protein phosphorylation events. Phenotypic assays including proliferation rates, apoptosis, mitochondrial superoxide and ROS/NO signaling were included as a measure of EC phenotype. Comparative proteomics, kinase activity, phosphoproteomics and assay data were integrated using an AI based Bayesian Network Inference approach to investigate causal signaling networks in order to elucidate the complexity and dynamics of angiogenesis and more specifically, the role of hypoxia in driving intracellular signaling in response to changes in oxygen tension. High confidence causal networks identified novel proteins that modulate the EC hypoxic response, validation of which are in process. Previously characterized proteins that are responsive to hypoxia were also identified in the hypoxic, but not normoxic signaling networks, namely Aldoc, Rac1, mTor, Cav-1 and Bax. Endothelial proliferation rate is closely related to both hydrogen peroxide and nitric oxide signaling, as has previously been reported. Novel regulatory networks that determine these interactions were identified. Using the Berg Interrogative Biology® platform, we are deciphering both the effects of the hypoxic microenvironment, and the unique characteristics of proliferating ECs by applying integrated functional proteomic assays and a systems approach to determine global changes in intracellular signaling in response to hypoxia.
Citation Format: Tony E. Walshe, Justin Bourdelais, Viatcheslav R. Akmaev, Leonardo O. Rodrigues, Socheata Lao, Stephane Gesta, Michael A. Kiebish, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain. Molecular drivers of endothelial hypoxic adaption during angiogenesis deciphered using the Berg Interrogative Biology® platform. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3376.
Abstract 3379: Tumor-induced remote extracellular matrix network orientation steers angiogenesis
Authors: Danen Erik H. 
Published: July 2016

Abstract
Tumor angiogenesis promotes tumor growth and metastasis. Here, we use automated sequential microprinting of tumor and endothelial cells in extracellular matrix (ECM) scaffolds to study its mechanical aspects. Quantitative reflection microscopy shows that tumor spheroids induce radial orientation of the surrounding collagen fiber network up to a distance of five times their radius. Across a panel of ∼20 different human tumor cell lines, remote collagen orientation is correlated with local tumor cell migration behavior. Tumor induced collagen orientation requires contractility but is remarkably resistant to depletion of collagen-binding integrins. Microvascular endothelial cells undergo directional migration towards tumor spheroids once they are within the tumor-oriented collagen fiber network. Laser ablation experiments indicate that an intact physical connection of the oriented network with the tumor spheroid is required for mechanical sensing by the endothelial cells. Together our findings show that remote physical manipulation of the ECM network by the tumor steers angiogenesis.
Citation Format: Erik H. Danen. Tumor-induced remote extracellular matrix network orientation steers angiogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3379.
Abstract 338: A novel small molecule inhibitor of the Notch transcription activation complex
Authors: Lehal Rajwinder , Frismantas Viktoras , Loubéry Sylvain , Reinmuller Viktoria , Turcatti Gerardo , Gonzalez-Gaitan Marcos , Bourquin Jean-Pierre , Radtke Freddy 
Published: July 2016

Abstract
NOTCH signaling is a developmental pathway known to play critical roles during embryonic development as well as for the regulation of self-renewing tissues. Aberrant activation of NOTCH signaling leads to deregulation of the self-renewal process resulting in sustained proliferation, evasion of cell death, loss of differentiation capacity, invasion and metastasis, all of which are hallmarks of cancer. Over activation of NOTCH in human cancers can be a consequence of over expression of NOTCH ligands/receptors, GOF mutations in NOTCH receptors as well as chromosomal translocations leading to constitutive activation of the pathway. Given the importance of Notch signaling in human cancers, several therapeutic approaches have been utilized to block NOTCH signaling. Two of these strategies are; a) the use of monoclonal blocking antibodies (Mabs) against NOTCH ligands and receptors and b) the use of small molecule γ-secretase inhibitors (GSIs). However, these approaches can only be effective if tumor cells express full-length ligand or receptor molecules. On the contrary, in human cancers harbouring NOTCH gene fusion due to chromosomal translocations, the use of Mabs and GSIs will have very limited clinical benefits. A third, yet not fully explored approach could be the blockage of NOTCH signalling by targeting the most downstream event in the NOTCH cascade i,e NOTCH transcriptional activation complex using small molecule inhibitors.
Here we report discovery and identification of a novel, orally-active small molecule inhibitor, named CB-103, of the NOTCH pathway that blocks NOTCH signaling by targeting the NOTCH transcriptional activation complex in the nucleus. CB-103 has shown the ability to block NOTCH signalling in human cancer cell lines, induce neurogenic phenotype in drosophila, induce muscle cell differentiation and inhibit NOTCH dependent cellular processes in mice. In addition, CB-103 exhibit anti-tumor efficacy in a xenograft model of human triple negative breast cancer resistant to GSIs and Mabs against NOTCH ligands/receptors. Furthermore, CB-103 has shown a remarkable activity in PDX models of human T-ALL harbouring activation of the NOTCH pathway. Additional studies are underway on several analogs of CB-103 to determine ADME/PK/PD profile and nominate a development candidate for further clinical development of this novel inhibitor of the NOTCH pathway.
Citation Format: Rajwinder Lehal, Viktoras Frismantas, Sylvain Loubéry, Viktoria Reinmuller, Gerardo Turcatti, Marcos Gonzalez-Gaitan, Jean-Pierre Bourquin, Freddy Radtke. A novel small molecule inhibitor of the Notch transcription activation complex. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 338.
Abstract 3382: A physiological model of the tumor microenvironment for screening drug delivery systems
Authors: Tang Yuan , Soroush Fariborz , Deosarkar Sudhir , Wang Bin , Prabhakarpandian Balabhaskar , Kiani Mohammad 
Published: July 2016

Abstract
Tumor drug delivery is a complex phenomenon affected by several elements in addition to drug or delivery vehicle's physico-chemical properties. Tumor microvasculature has many unique features including unusual transport characteristics, high interstitial pressure, and enhanced permeability and retention (EPR) effect. Current in vitro models of tumor drug delivery are oversimplified and, as a result, show poor correlation with in vivo performance. The objective of this study is to develop and characterize a synthetic 3D solid tumor - endothelium model in a novel microfluidic platform that mimics the tumor microenvironment observed in vivo.
The novel synthetic tumor model consists of a vascular network of tumor derived endothelial cells forming a complete lumen in communication with 3D solid tumors. Primary human breast tumor associated endothelial cells (HBTAECs) were co-cultured under physiological fluid flow conditions with 3D tumor cells from metastastic (MDA-MB-231) or non-metastatic (MCF-7) origins to study the effect of metastatic potential on the integrity of the adjacent endothelial cell lining. Extravasation of fluorescently labeled liposomes across the endothelium to the tumors was measured following HBTAECs treatment with normal media, tumor conditioned media (TCM), or TNF-α. Tight junction formation was characterized using ZO-1 immunostaining.
MDA-MB-231 cells quickly invaded into the vascular network from their primary culture location whereas MCF-7 cells rarely grew beyond the boundary of tumor origin. Permeability of liposomes across the endothelium was significantly higher with TCM treatment compared to both control and TNF-α treated cells (P &lt; 0.01, one-way ANOVA). ZO-1 staining indicated strong tight junction formation when HBTAECs were treated with normal media as compared to TCM or TNF-α.
We have successfully established an in vitro 3D tumor - endothelial cell co-culture model in a novel microfluidic platform that closely mimics the tumor microenvironment in vivo. This system reproduces the tumor permeability and retention (EPR) effect on a chip. This realistic in vitro model can have great potential in applications such as cell-cell/cell-drug carrier interaction studies, drug delivery carrier screening, and drug efficacy testing.
Citation Format: Yuan Tang, Fariborz Soroush, Sudhir Deosarkar, Bin Wang, Balabhaskar Prabhakarpandian, Mohammad Kiani. A physiological model of the tumor microenvironment for screening drug delivery systems. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3382.
Abstract 3385: Identification of tumor endothelium-related genes in colorectal cancer
Authors: Yorozu Akira , Yamamoto Eiichiro , Maruyama Reo , Kai Masahiro , Nishidate Toshihiko , Furuhata Tomohisa , Sugai Tamotsu , Suzuki Hiromu 
Published: July 2016

Abstract
Background and Aims:
Angiogenesis is a hallmark of cancer development that has been considered an attractive therapeutic target. In this study, we aimed to unravel the molecular mechanism of tumor angiogenesis in colorectal cancer (CRC).
Materials and Methods:
We isolated endothelial and epithelial cells from surgically resected 14 human CRC tissues by using antibodies against endothelial (CD146) and epithelial markers (EpCAM). RNA sequencing was carried out using 3 pairs of normal and tumor endothelial cells. Expression of the genes was validated using quantitative RT-PCR, immunohistochemistry. Functions of a selected gene were carried analyzed by tumor conditioned medium (TCM) experiments, tube formation assay, gene expression microarray and cell cycle analysis.
Results:
Through RNA-seq analysis, we identified 18 genes, which were upregulated in the endothelial cells isolated from CRC tissues. We further validated the results by performing quantitative RT-PCR and immunohistochemical analysis in a larger series of clinical samples, and identified gene A as a novel candidate of the tumor endothelium-related gene. Expression of gene A was also upregulated in human umbilical vein endothelial cells (HUVECs) treated with TCM obtained from CRC cell lines. Knockdown of gene A in HUVECs suppressed in vitro tube formation and induced G1 cell cycle arrest. Microarray analysis revealed that gene A knockdown induced expression changes of approximately 300 genes in HUVECs, and gene ontology analysis showed that genes related to cell cycle or cell division were significantly enriched in the affected genes. To confirm our findings in vivo, we co-transplanted CRC cells with HUVECs into nude mice. We found that gene A knockdown in HUVECs resulted in reduced micro vessel formations in the xenograft tissues.
Conclusion:
We identified elevated expression of gene A in tumor endothelial cells of primary colorectal cancer tissues. Our results suggest that gene A may play an important role in the angiogenesis in colorectal cancer, and that it could be a potential therapeutic target.
Citation Format: Akira Yorozu, Eiichiro Yamamoto, Reo Maruyama, Masahiro Kai, Toshihiko Nishidate, Tomohisa Furuhata, Tamotsu Sugai, Hiromu Suzuki. Identification of tumor endothelium-related genes in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3385.