bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5213: RUNX2 modulates the angiogenic potential of human neuroblastoma cells
Authors: Gnanamony Manu , Mohanam Indra , Mohanam Sanjeeva 
Published: August 2015

Abstract
Neuroblastoma is the most common extracranial pediatric solid tumor with an undifferentiated status and characterized by heterogeneous clinical courses ranging from spontaneous regression to a very aggressive malignant progression. The RUNX gene family comprises RUNX1, RUNX2, and RUNX3 transcription factors and plays pivotal roles in development, differentiation and tumorigenesis. Hypoxia is known to be a significant physiological stress in the tumor microenvironment and is associated with tumor malignant phenotype. In this study, we examined the effects of hypoxia on the Runx2 expression in human neuroblastoma cells and the role of RUNX2 on angiogenic potential of neuroblastoma cells. Runx2 has two isoforms, Runx2-I and Runx2-II. Isoform I is controlled by the P2 proximal promoter whereas isoform II is transcribed from the P1 distal promoter. Increased expression of mRNAs of isoform I and II as well as intact isoform of RUNX2 was observed in NB1691 cells exposed to hypoxia. Furthermore, hypoxia enhanced the activity of a luciferase reporter containing Runx2 P1 promoter in NB1691 cells. Hypoxic exposure caused an increase in protein levels of RUNX2 as well as survivin, a RUNX2 downstream target gene in NB1691 cells. Hypoxia also stabilized RUNX2 protein levels in NB1691 cells without altering the stability of RUNX2 mRNA. Hypoxia enhanced angiogenic potential of NB1691 cells. Knockdown of Runx2 significantly decreased VEGF mRNA and protein in NB1691 cells exposed to hypoxia. A decrease in angiogenesis was observed in chorioallantoic membrane assay performed using conditioned medium collected from RUNX2 siRNA treated hypoxic NB1691 cells compared with control. Further, transcript levels were measured by PCR array of human angiogenesis pathway and the analysis showed down regulation of EDN1, FIGF, TEK and VEGF A mRNAs in hypoxic NB1691 cells treated with RUNX2 siRNA. In conclusion, our study suggests that hypoxia upregulates RUNX2 expression in NB1691 cells and knockdown of RUNX2 decreases the angiogenic potential of hypoxic NB1691 cells.
Citation Format: Manu Gnanamony, Indra Mohanam, Sanjeeva Mohanam. RUNX2 modulates the angiogenic potential of human neuroblastoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5213. doi:10.1158/1538-7445.AM2015-5213
Abstract 5215: Loss of Rpl22 promotes tumor progression through regulation of angiogenesis
Authors: Rao Shuyun , Stadanlick Jason E. , Cai Kathy Q. , Wiest David L. 
Published: August 2015

Abstract
Mutations in ribosomal proteins (RP) often cause bone marrow syndromes associated with increased risk for cancer development. We have shown that Rpl22 is a haploinsufficient tumor suppressor in T acute lymphoblastic leukemia (T-ALL). Indeed, loss of one Rpl22 allele accelerates T-cell lymphomagenesis in the murine Akt transgenic mouse model, by inducing the stem cell factor Lin28B in an NFκB-dependent manner. Moreover, mice lacking both Rpl22 alleles exhibited significantly increased thymic tumor size, which was associated with poor survival and markedly enhanced angiogenesis relative to Rpl22 heterozygous mice or wild type. The increased angiogenesis in the mediastinal mass was linked to upregulation of VEGFA and downregulation of S1P1. Loss of S1P1 is sufficient to block egress of lymphoma cells from thymus. Rpl22-deficient thymic lymphoma lines also exhibit enhanced growth upon adaptation to growth in vitro, and this is reversed by ectopic expression of Rpl22. Rpl22 expression also represses the expression of proteins that promote traversal of the cell cycle. Collectively, the increased tumor growth and angiogenesis, and the blockade of thymic egress contribute to the enlarged mediastinal masses observed in Rpl22-deficient mice. Rpl22-mutant T-ALL are a molecularly distinct subtype exhibiting increased aggression and treatment resistance. Accordingly, our identification of a number of signaling pathways controlled by Rpl22 may enable the development of novel strategies, such as targeting angiogenesis, in such cases of T-ALL.
Citation Format: Shuyun Rao, Jason E. Stadanlick, Kathy Q. Cai, David L. Wiest. Loss of Rpl22 promotes tumor progression through regulation of angiogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5215. doi:10.1158/1538-7445.AM2015-5215
Abstract 5216: Potential use of saliva and hair samples to identify genetic markers for anti-VEGF therapy
Authors: Xue Gloria R. , Xue Crystal R. , Shen Fei , Schneider Bryan P. 
Published: August 2015

Abstract
Anti-angiogenic therapy to block and disrupt tumor angiogenesis has been used in clinical treatment of various malignancies including: glioblastoma, colorectal, lung and kidney cancer. Currently, the most clinically effective anti-angiogenic agents are the humanized monoclonal antibody (bevacizumab) against vascular endothelia growth factor (VEGF) and the small molecule receptor-tyrosine-kinase inhibitors (RTKIs) of VEGF receptors. However, the therapeutic benefit varies substantially for many of these agents. Predictive biomarkers that are required for personalized treatment with these agents are currently not available. Recently the role of germline single-nucleotide polymorphisms (SNPs) has been investigated as potential biomarkers for anti-angiogenic treatments. The rationale is that these agents target the vasculature in host (vessels) rather than tumor tissue, which could mean that much of the variability is dictated by the host. Several studies reported the association of SNPs in VEGFA with differential outcomes from clinical trials with these agents. SNP genotyping assays in these studies used germline DNA extracted from blood. However, collection of peripheral blood is invasive. Saliva and hair that are known to contain genomic DNA can be used as noninvasive and convenient DNA sampling resources, but the limited quantity of DNA in the hair and the low quality of DNA in the saliva make genotyping assays non-reproducible.
We have sought to improve SNP genotype assays with DNA from saliva and hair by applying SNP target pre-amplification for genotyping five SNPs (rs699947, rs833061, rs1570360, rs201093, rs3025039) in VEGFA. The concordance of genotyping calls of individual SNP using DNA from blood, saliva and hair from the same volunteer was compared. Our preliminary results demonstrated that pre-amplification substantially improved genotyping calls with saliva DNA and hair DNA samples. The average genotyping call rate with saliva and hair samples was about 45% and 10%, respectively, without pre-amplification. The pre-amplification improved the call rate with saliva and hair samples to 100% and 94%, respectively. The current report may facilitate easier clinical sample collection for genetic tests for these SNPs.
Citation Format: Gloria R. Xue, Crystal R. Xue, Fei Shen, Bryan P. Schneider. Potential use of saliva and hair samples to identify genetic markers for anti-VEGF therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5216. doi:10.1158/1538-7445.AM2015-5216
Abstract 5220: Inflamed and wound recovered tumor microenvironment contributions to lymphatic-mediated metastasis
Authors: Fink Darci Marie , Connor Alicia L. , Kelley Philip M. , Tempero Richard M. , Hollingsworth Michael A. 
Published: August 2015

Abstract
Despite the clinical importance of lymph node status in cancer staging, treatment decisions, and patient outcomes, little is known about the earliest events of lymphatic-mediated metastasis of tumor cells. Lymphatic vessels remodel dramatically in response to changes in the inflammatory status of a tissue. Inflammation induces lymphangiogenesis and the resolution of inflammation stimulates lymphatic vessel regression. This study addresses one of the fundamental questions in metastasis biology and places it in the context of a specific microenvironmental state: how does a tumor cell gain entrance to a lymphatic vessel to migrate to a regional lymph node and what is the contribution of inflammation to this process? We sought to better understand lymphatic-mediated metastasis of tumor cells during inflammatory lymphangiogenesis or the resolution of inflammation. We hypothesized that manipulating the inflammatory status of the tumor microenvironment would alter tumor cell and lymphatic endothelium biology to influence lymphatic-mediated metastasis. We have previously established a corneal model of sutured-induced inflammatory lymphangiogenesis and a complimentary experimental arm of inflammation resolution. We transitioned this platform into real-time live imaging studies by using this corneal model in our novel transgenic mouse model background that inducibly expresses fluorescent tdTomato protein in the lymphatic endothelium (LyveCreERT2tdT). CFSE-labeled syngeneic tumor cells were introduced systemically via tail vein injection or locally into a corneal micropocket. Two-color intravital fluorescent stereomicroscopy allowed us to simultaneously track the fate of CFSE+ tumor cells at single-cell resolution and the morphologic changes in the tdTomato+ corneal lymphatic vessels during inflammatory lymphangiogenesis and lymphatic vessel regression. One major finding was the low frequency of lymphatic-mediated metastasis during both inflammation and resolution. Ongoing work continues to explore the contributions of specific cytokines to tumor-lymphatic endothelium interactions and the unique properties of a wound-recovered tumor microenvironment.
Citation Format: Darci Marie Fink, Alicia L. Connor, Philip M. Kelley, Richard M. Tempero, Michael A. Hollingsworth. Inflamed and wound recovered tumor microenvironment contributions to lymphatic-mediated metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5220. doi:10.1158/1538-7445.AM2015-5220
Abstract 5221: Mammary tumor aggressiveness is exacerbated by endothelial HoxA5 expression
Authors: Northcott Josette , Layman Hans , Boudreau Nancy 
Published: August 2015

Abstract
Despite evidence showing a positive correlation between angiogenesis and solid tumor progression, anti-angiogenic therapies have yielded limited, and often, tissue-specific responses. Whereas colorectal and renal cancers show improved responses, anti-angiogenic therapy has not proven effective at clinically managing breast tumor progression or prolonging patient survival. Moreover, anti-angiogenic treatment may promote the emergence of tumors with increased aggression and resistance to standard chemotherapies. Our laboratory has shown that sustained endothelial expression of the anti-angiogenic HoxA5 homeodomain transcription factor reduces angiogenesis and delays progression of squamous cell carcinoma in the KRT14-HPV16 mouse model of skin cancer. We subsequently investigated, whether constitutive endothelial expression of HoxA5 could also impede mammary tumor growth and metastasis. Surprisingly, we observed that endothelial HoxA5 expression increased both primary tumor growth and lung metastasis in the MMTV-PyMT mouse model of breast cancer. Primary tumors from PyMT/HoxA5+ mice exhibited an increased number of large vessels but were significantly more hypoxic, as compared to tumors from control mice. Orthotopic injection of isolated mammary tumor cells from PyMT/HoxA5+ mice into wild-type animals also resulted in larger tumors, as compared to tumor cells isolated from PyMT mice of the same age. Interestingly, although metastasis was increased in the PyMT/HoxA5+ transgenic mice, we did not detect differences in circulating tumor cells, suggesting that tumor cells from PyMT/HoxA5+ mice have increased tumor initiating potential. Thus, while anti-angiogenic HoxA5 expression in the endothelium delays skin tumor progression, more aggressive tumors arise in the mammary gland. We are currently evaluating the response of breast tumors in PyMT/HoxA5+ mice to standard cancer chemotherapeutics, as well as evaluating novel approaches to potentially target more aggressive tumors emerging from chronic hypoxic conditions.
Citation Format: Josette Northcott, Hans Layman, Nancy Boudreau. Mammary tumor aggressiveness is exacerbated by endothelial HoxA5 expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5221. doi:10.1158/1538-7445.AM2015-5221
Abstract 5224: Non-canonical activity of threonyl-tRNA synthetase promotes angiogenesis and invasion in a mouse model of ovarian cancer
Authors: Wo Peibin , Wellman Theresa , Howe Alan , Francklyn Christopher , Lounsbury Karen M. 
Published: August 2015

Abstract
Despite clear connections between the tumor microenvironment and ovarian cancer invasion, the underlying molecular mechanisms remain elusive. We have recently shown that the protein synthesis regulator threonyl-tRNA synthetase (TARS) has a unique extracellular angiogenic activity separate from its canonical function. Secreted TARS promotes endothelial cell migration and tube formation, and a selective TARS inhibitor, BC194, disrupts normal vessel development in zebra fish and chick embryo models. TARS expression also correlates with tumor stage and angiogenesis in human ovarian cancer. The objective of this study was to validate the biological and clinical relationship between TARS and ovarian tumor progression using a syngenic mouse model of epithelial ovarian cancer. Tumors were initiated by intraperitoneal injection of ID8 mouse ovarian cancer cells, and tumors formed at 4-6 weeks were scored for invasiveness and analyzed by immunostaining for TARS expression and microvascular density. To test the hypothesis that overexpression of TARS promotes invasion, cells were stably transfected with a TARS expression plasmid prior to injection. To test the hypothesis that TARS inhibition reduces tumor invasion, animals harboring ID8 tumors were treated with the high-affinity TARS inhibitor BC194. We found that TARS levels were elevated in ovarian tumors as compared with normal ovarian tissue. Overexpression of TARS in ID8 cells also resulted in enhanced invasiveness and microvascular density of the resulting tumors (p = 0.026). Preliminary results also indicated that inhibition of TARS by BC194 treatment reduced tumor angiogenesis and growth (p = 0.005) without observed toxicities in the animals. Overall, these results show that modifying TARS expression or activity can affect in vivo ovarian tumor angiogenesis and progression. These results encourage further study of TARS as a regulator of the tumor microenvironment and as a possible target for diagnosis and treatment of ovarian cancer.
Citation Format: Peibin Wo, Theresa Wellman, Alan Howe, Christopher Francklyn, Karen M. Lounsbury. Non-canonical activity of threonyl-tRNA synthetase promotes angiogenesis and invasion in a mouse model of ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5224. doi:10.1158/1538-7445.AM2015-5224
Abstract 5228: mTORC2 mediates SDF-1α/CXCL12-induced angiogenesis
Authors: Ziegler Mary E. , Hatch Michaela M.S. , Hughes Christopher C.W. 
Published: August 2015

Abstract
Angiogenesis occurs when new blood vessels sprout from the existing vasculature and mature into an organized and functional circulatory system. Physiological angiogenesis is stringently regulated and occurs transiently. Numerous disease states, including chronic inflammation and cancer, induce pathological angiogenesis, which disrupts the stable vascular network by altering both positive and negative angiogenic regulators. The chemokine stromal-cell derived factor-1 (SDF-1α, also called CXCL12) and its receptor CXCR4 promote endothelial cell (EC) migration and tube formation. PI3K is a key downstream regulator of CXCR4-mediated chemotaxis and mammalian target of rapamycin (mTOR) is at the center of PI3K-mediated signal transduction. mTOR exists in two complexes: mTOR complex 1 (mTORC1) and 2 (mTORC2). Receptor induced mTORC1 signal transduction has been widely studied. In contrast, the signaling upstream of mTORC2 remains elusive. We hypothesized that the SDF-1 α/CXCR4/mTOR signaling axis contributes to the molecular mechanism of tumor angiogenesis. This study illustrates that SDF-1α activates a distinct molecular signaling cascade in EC that involves CXCR4, G protein, PI3K and mTORC2, but not mTORC1. CXCR4 inhibition blocks sprouting in a 3D in vitro angiogenesis model, and specific inhibition of each of the mTOR complexes reveals that sprouting angiogenesis requires mTORC2 signal transduction. In a mouse model, tumor angiogenesis is significantly reduced only when mTORC2 is targeted. An analysis of targets downstream of mTORC2 indicates that 6-phosphofructo-2-kinase (PFKFB3), which is a key regulator of glycolytic flux and sprouting angiogenesis, is reduced in vivo when mTORC2 is targeted and tumor angiogenesis is inhibited. This study provides evidence that mTORC2 is an important regulator of angiogenesis that is downstream of GPCR signaling and upstream of metabolic regulation. In addition, these data present a potential link between mTORC2, metabolism and angiogenesis.
Citation Format: Mary E. Ziegler, Michaela M.S. Hatch, Christopher C.W. Hughes. mTORC2 mediates SDF-1α/CXCL12-induced angiogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5228. doi:10.1158/1538-7445.AM2015-5228
Abstract 5229: Disruption of the acetylcholine signaling pathway suppresses the growth and angiogenesis of human lung cancers
Authors: Dasgupta Piyali , Brown Kathleen C. , Lau Jamie K. , Dom Aaron M. , Thornhill Brent A. , Crabtree Clayton M. , Witte Theodore R. , Hardman W E. , Stover Cody A. , Carpenter A B. , Chen Yi C. 
Published: August 2015

Abstract
Cigarette smoking bears a strong association with the development of lung cancer. Nicotine is the addictive component of cigarettes. Several convergent studies show that nicotine facilitates the growth and angiogenesis of human lung cancers. The biological activity of nicotine is mediated by nicotinic acetylcholine receptors (nAChRs). The endogenous ligand of nAChRs is acetylcholine (ACh). Data from our laboratory and other research groups show that lung cancers express all of the genes for synthesis, transport and degradation of ACh. These include nAChRs, choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), choline transporter (ChT1) and acetylcholinesterase (AChE). Nicotine upregulates the ACh-signaling loop in human lung cancer cells. Therefore, we conjectured that disruption of ACh-signaling pathway should suppress the growth of human cancers. We show that alpha7-nAChR antagonists robustly suppress angiogenesis in human lung and retinal microvascular endothelial cells. The anti-angiogenic activity of alpha7-nAChR antagonists was also observed in chicken chorioallantoic membrane (CAM) and nude mouse models. Similarly, vesamicol, a small molecule antagonist of VAChT, decreases nicotine-induced tumor growth in human NSCLCs. Our studies suggest that the acetylcholine signaling pathway may be have potential applications in the therapy of human lung cancers. Our results are also relevant to lung cancer patients who are exposed to nicotine via secondhand smoke, nicotine patches, gums or electronic cigarettes.
Citation Format: Piyali Dasgupta, Kathleen C. Brown, Jamie K. Lau, Aaron M. Dom, Brent A. Thornhill, Clayton M. Crabtree, Theodore R. Witte, W E. Hardman, Cody A. Stover, A B. Carpenter, Yi C. Chen. Disruption of the acetylcholine signaling pathway suppresses the growth and angiogenesis of human lung cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5229. doi:10.1158/1538-7445.AM2015-5229
Abstract 525: PHD3-mediated prolyl hydroxylation of non-muscle actin impairs polymerization and cell motility
Authors: Luo Weibo , Semenza Gregg L. 
Published: August 2015

Abstract
Actin filaments play an essential role in cell movement and many post-translational modifications regulate actin filament assembly. Here we report that prolyl hydroxylase 3 (PHD3) interacts with non-muscle actin in human cells and catalyzes hydroxylation of actin at proline residues 307 and 322. Blocking PHD3 catalytic activity, by either a pharmacological inhibitor or short hairpin RNA knockdown of PHD3 expression, decreases actin prolyl hydroxylation. Knockdown of PHD3 significantly increases filamentous F-actin assembly, which is reversed by PHD3 overexpression. PHD3 knockdown significantly increases cell velocity and migration distance. Inhibition of PHD3 prolyl hydroxylase activity by dimethyloxalylglycine also increases actin polymerization and cell migration. These data reveal a novel role for PHD3 as a negative regulator of cell motility through post-translational modification of non-muscle actins.
Citation Format: Weibo Luo, Gregg L. Semenza. PHD3-mediated prolyl hydroxylation of non-muscle actin impairs polymerization and cell motility. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 525. doi:10.1158/1538-7445.AM2015-525