bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4138: Integrating SNPs, epigenetics and transcriptomics to better understand the inherited predisposition to breast cancer metastasis
Authors: Shukla Anjali , Bai Ling , Yang Howard , Doran Anthony , Hu Ying , Geiger Thomas , Lee Maxwell , Keane Thomas , Hunter Kent W. 
Published: August 2015

Abstract
Breast cancer is the most frequent cancer and the second leading cause of cancer mortality in women. The vast majority of breast cancer mortality is due to metastatic disease since the primary tumor can be relatively easily surgically resected. More comprehensive understanding of biology of metastasis is therefore clearly warranted to unveil novel metastasis-associated molecules and cellular processes that might be targeted for clinical intervention. Previously we demonstrated that like cancer incidence, metastatic progression has a significant inherited component. Using mouse complex trait mapping strategies we have been isolating metastasis susceptibility genes from backcross analysis. However, studies suggest that many of these QTL peaks are the result of the contribution of multiple genes, suggesting that causal genes are not being identified. To increase our ability to detect causal genes we have implemented a new integrated strategy. Whole genome sequencing of appropriate high or low metastatic mouse strains is performed to identify variants, which are then filtered for those within DNAse hypersensitive sites (DHS), based on the hypothesis that most inherited phenotypes are due to expression differences rather than missense variants. The genes associated with polymorphic DHS are then screened through mouse and human tumor expression databases to identify those genes associated with development of metastatic disease. This strategy was able to identify genes previously associated with metastatic breast cancer in both mouse and humans and new genes have also been validated. The results further suggest that inherited variation in cellular mediated immune response may be an important contributor to metastatic disease.
Citation Format: Anjali Shukla, Ling Bai, Howard Yang, Anthony Doran, Ying Hu, Thomas Geiger, Maxwell Lee, Thomas Keane, Kent W. Hunter. Integrating SNPs, epigenetics and transcriptomics to better understand the inherited predisposition to breast cancer 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 4138. doi:10.1158/1538-7445.AM2015-4138
Abstract 4143: Discrete clones cooperate to promote tumor progression through a non-cell-autonomous mechanism in intestinal cancers
Authors: Leystra Alyssa A. , Wisinger Amanda M. , Zahm Christopher D. , Matkowskyj Kristina A. , Sievers Chelsie K. , Schwartz Alex , Albrecht Dawn M. , Clipson Linda , Deming Dustin A. , Newton Michael A. , Halberg Richard B. 
Published: August 2015

Abstract
Background: The process of tumor evolution has often been described as a single initiated cell propagating a tumor with subclones of that cell acquiring distinct molecular changes and competing for dominance within the tumor. However, colon tumors are now known to often be derived from multiple initiated progenitor cells. Distinct initiated clones might cooperate or alternatively compete during tumorigenesis, progression, and therapy.
Methods: Mice carrying the Min allele of Apc and expressing an oncogenic form of PI3K in a subset of colonic epithelial cells develop multiple adenomas and adenocarcinomas in the colon. We utilized cell lineage tracing to follow the progeny of individual progenitor cells through tumor establishment, progression, and treatment with GDC 0941, a PI3K inhibitor.
Results: Nearly half (44%; 30/68) of the tumors were derived from at least two progenitor clones, one of which expressed the oncogenic form of PI3K and one of which did not. The presence of both types of clones correlated to an increased frequency of either clone becoming invasive (p = 0.0002). Additionally, the presence of both clones appeared to protect susceptible clones from targeted therapy.
Conclusions: Taken together, these data indicate that genetically distinct tumor progenitors can establish a single lesion, and moreover cooperation amongst diverse clonal populations provides a fitness advantage during tumor progression and therapy.
Citation Format: Alyssa A. Leystra, Amanda M. Wisinger, Christopher D. Zahm, Kristina A. Matkowskyj, Chelsie K. Sievers, Alex Schwartz, Dawn M. Albrecht, Linda Clipson, Dustin A. Deming, Michael A. Newton, Richard B. Halberg. Discrete clones cooperate to promote tumor progression through a non-cell-autonomous mechanism in intestinal 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 4143. doi:10.1158/1538-7445.AM2015-4143
Abstract 4153: Investigating the role of Fn14 in EGFRvIII-driven glioblastoma
Authors: Roos Alison , Mayo Zachary , Pineda Michael , Winkles Jeffery A. , Berens Michael E. , Tran Nhan L. 
Published: August 2015

Abstract
Glioblastoma Multiforme (GBM) is the most common malignant brain tumor in adults. Most GBM patients succumb to the disease less than one-year post diagnosis due to the highly invasive nature of the tumor, which prevents complete surgical resection and gives rise to tumor recurrence. The invasive phenotype also confers radio-and chemoresistant properties to the tumor cells; therefore, there is a need to develop new therapeutics that target drivers of GBM invasion. Amplification of EGFR is observed in over 50% of GBM tumors, of which half concurrently overexpress the variant EGFRvIII, and expression of both receptors confers a worse prognosis. EGFR and EGFRvIII cooperate to promote tumor progression and invasion, in part, through activation of the JAK/STAT-signaling pathway. Here we report that GBM cells expressing EGFRvIII show increased expression of a previously established mediator of glioma cell invasion and survival, fibroblast growth factor-inducible 14 (Fn14), at the mRNA and protein level. Treatment with a STAT3, STAT5, or JAK inhibitor decreased Fn14 mRNA and protein expression. Finally, knockdown of Fn14 levels in the EGFRvIII-expressing glioma cells decreased both cell survival after temozolomide (TMZ) treatment and cell invasion, which suggests that Fn14, in part, mediates the oncogenic phenotypes conferred by EGFRvIII signaling. Since EGFR inhibitors display limited therapeutic efficacy in GBM patients, we hypothesize that Fn14-targeted therapies could potentially limit invasiveness and chemoresistance in these tumor subtypes.
Citation Format: Alison Roos, Zachary Mayo, Michael Pineda, Jeffery A. Winkles, Michael E. Berens, Nhan L. Tran. Investigating the role of Fn14 in EGFRvIII-driven glioblastoma. [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 4153. doi:10.1158/1538-7445.AM2015-4153
Abstract 4158: Novel PAK4-mediated regulation of endothelial CXCL1/CXCR2 signaling and angiogenesis in glioblastoma
Authors: Kesanakurti Divya , Xu Jihong , Canella Alessandro , Nagarajan Prabhakaran , Kaur Balveen , Puduvalli Vinay K. 
Published: August 2015

Abstract
Increased endothelial cell proliferation and aberrant neovascularization are pathological hallmarks of glioblastoma that correlate with clinical outcome. Recent studies have also implicated ionizing radiation (IR)-induced angiogenesis as a potential cause for tumor recurrence and metastases in several malignancies. Its impact in gliomas has not been characterized. Factors that drive endothelial proliferation, angiogenesis and interaction of endothelial cells with tumor cells in the context of radiotherapy are potentially novel targets for glioma therapy. Our previous studies demonstrated high levels of expression of p21-activated kinase 4 (PAK4) in gliomas; analyses of tumor cell medium (CM) prepared from shRNA-mediated PAK4-knockdown cells using an angiogenesis antibody array showed a significant decrease in key angiogenic factors including CXCL1. Treatment of human brain microvascular endothelial cells (HBMECs) with CM from PAK4-knockdown cells (PAK4-kd CM) significantly inhibited proliferation, migration and microtubule formation compared with CM from control and scrambled vector-expressing glioma cells. PAK4-kd CM treatment also suppressed CXCR2 activation and decreased the expression levels of p-STAT3, VEGF, MMP-2 and cyclinD1 in HBMECs. Additionally, treatment with CM from ionizing radiation (IR, 8 Gy)-treated cells resulted in elevated CXCL1, MMP-2 and VEGF levels in HBMECs, and induced high levels of endothelial capillary network formation on matrigel, indicating an IR-induced angiogenesis in these cells. Conversely, PAK4-kd inhibited IR-induced angiogenesis and decreased p-STAT3, VEGF and MMP-2 levels in IR-treated HBMECS. Further, in vivo experiments with orthotopic intracranial tumors in nude mice showed growth suppression in PAK4-knockdown tumors compared to control tumors. Immunohistochemical analyses of brain tumor sections revealed a significant decrease in CXCL1, VEGF and MMP-2 in PAK4.sh tumors. In summary, our studies emphasize a novel regulation of angiogenic switch and endothelial CXCL1/CXCR2 signaling by PAK4 in tumor cells, thereby, suggests the role of PAK4 as a critical mediator of tumor-endothelial cell interactions in glioblastoma. Abrogation of key angiogenic signaling after IR treatment and inhibition of in vivo tumor growth by PAK4 suppression indicates its therapeutic potential in the treatment of glioma.
Citation Format: Divya Kesanakurti, Jihong Xu, Alessandro Canella, Prabhakaran Nagarajan, Balveen Kaur, Vinay K. Puduvalli. Novel PAK4-mediated regulation of endothelial CXCL1/CXCR2 signaling and angiogenesis in glioblastoma. [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 4158. doi:10.1158/1538-7445.AM2015-4158
Abstract 4162: Interleukin–6 stimulates defective angiogenesis
Authors: Gopinathan Ganga , Milagre Carla , Pearce Oliver M.T , Reynolds Louise , Hodivala-Dilke Kairbaan , Leinster Andrew , Zhong Haihong , Hollingsworth Robert E. , Thompson Richard , Whiteford James R. , Balkwill Frances 
Published: August 2015

Abstract
The aim of this study was to investigate the effects of IL-6 in normal and tumour angiogenesis. In previous studies we found that elevated levels of the inflammatory cytokine interleukin-6, IL-6, were linked with poor prognosis in ovarian cancer patients by influencing tumour growth, invasion, angiogenesis and chemo-resistance. A clinical trial conducted in parallel with pre-clinical studies showed an anti-IL-6 antibody to have some activity in ovarian cancer patients and in xenograft models, with systemic and local reduction in pro-inflammatory and angiogenic factors such as TNF, IL-8 and VEGF.
IL-6 directly induced vessel sprouting in the ex vivo aortic ring model, as well as stimulated endothelial cell proliferation and migration, with similar potency to VEGF. However, IL-6 itself did not induce VEGF in the endothelial cells tested. In contrast to VEGF, IL-6-stimulated aortic ring vessel sprouts had defective pericyte coverage. The mechanism of the IL-6 action on pericytes involved stimulation of the Notch ligand Jagged1 as well as Angiopoietin 2. When peritoneal ovarian cancer xenografts were treated with an anti-IL-6 antibody, pericyte coverage of vessels was restored. In addition, in human ovarian cancer biopsies there was an association between levels of IL-6mRNA, Jagged1 and Angiopoeitin2. Our findings have implications for the use of cancer therapies that target VEGF or IL-6 and for understanding abnormal angiogenesis in cancers, chronic inflammatory disease and stroke.
Citation Format: Ganga Gopinathan, Carla Milagre, Oliver M.T Pearce, Louise Reynolds, Kairbaan Hodivala-Dilke, Andrew Leinster, Haihong Zhong, Robert E. Hollingsworth, Richard Thompson, James R. Whiteford, Frances Balkwill. Interleukin–6 stimulates defective 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 4162. doi:10.1158/1538-7445.AM2015-4162
Abstract 4163: Targetting VPAC1 for intestinal cancer prevention
Authors: Liu Shaohua , Zeng Yunjie , Ouyang Nengtai 
Published: August 2015

Abstract
Vasoactive intestinal peptide (VIP) is a neurotransmitter that primarily functions as a vasodilator. VIP plays its role through binding to its receptors known as VIP/pituitary adenylate cyclase-activating peptide receptors (VPACs). In this study, we examined the expression of VPAC1 in human colon cancer tissues, analyzed the relationship between VPAC1 expression and cancer malignancy, and explored the possible mechanisms using immunohistochemistry and immunofluorescence double staining. The results showed that: 1) poorly-differentiated colon cancers have significantly higher VPAC1 expression than well-differentiated colon cancers do (p&lt;0.01); 2) phospho-EGFR overexpression/activation in the cytoplasm of cancer cells is related to VPAC1 overexpression; 3) blood vessels surrounding colon cancer have significantly more VPAC1-positive than normal colon mucosa does; 4) Tumor-Associated Macrophages (TAMs) of colon cancer have a higher level of VPAC1 expression than macrophages in normal colon mucosa do. These data suggest that VPAC1 overexpression is associated with poorer differentiation of colon cancer, which is likely caused by subsequent EGFR activation in cancer cells. In addition, VPAC1 overexpression in both blood vessels and macrophages in tumors may also play an important role in the development of aggressive cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Shaohua Liu, Yunjie Zeng, Nengtai Ouyang. Targetting VPAC1 for intestinal cancer prevention. [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 4163. doi:10.1158/1538-7445.AM2015-4163
Abstract 4167: Snai2(Slug) regulates tumor angiogenesis through the induction of EndoMT
Authors: Wu Nan , Welch-Reardon Katrina , Hughes Christopher 
Published: August 2015

Abstract
Anti-angiogenic therapy remains an attractive option in the treatment of cancer since it has the potential to both control growth of the primary tumor and limit metastasis. However, many current anti-angiogenic cancer drugs fail to deliver long-term efficacy, likely due to adaptation of the tumor to utilize alternative angiogenic pathways. The high level of cross talk between pro-angiogenic pathways makes targeting the downstream effectors a potentially more beneficial strategy.
We have recently demonstrated that the transcription factor Slug (Snai2), a master regulator of epithelial-to-mesenchymal transition (EMT), is expressed in angiogenic endothelial cells (EC) and can augment sprouting angiogenesis in vitro, likely by inducing a partial endothelial-to-mesenchymal transition (EndoMT). Slug is induced by many pro-angiogenic pathways (e.g. TGFβ, Notch, VEGF) and can directly regulate several key steps in angiogenesis, such as migration and proliferation, making it an attractive anti-angiogenic drug target.
In this study we used Slug knockout mice, which are viable but runted, to test the hypothesis that Slug regulates pathological angiogenesis in vivo by inducing an EndoMT. Using a Matrigel plug assay we found that angiogenesis was reduced in Slug knockout mice compared to littermate controls. Initial analysis suggests this is the result of impaired vascular recruitment. In addition, a syngeneic subcutaneous tumor model showed that the growth of wild type tumor cells is reduced by over 50% in Slug knockout mice compared to controls. In an in vitro angiogenesis assay Slug overexpression induces hypersprouting and an increased number of disconnected cells, suggesting the complete loss of cell-cell junctions, consistent with a full EndoMT. RNA-seq comparing Slug overexpressing EC to wild type EC revealed targets that are implicated in both autocrine and paracrine regulation of tumor angiogenesis. In conclusion, these data suggest that EC expression of Slug regulates tumor angiogenesis, and that the level of slug expression may set the threshold between a partial and a full EndoMT.
Citation Format: Nan Wu, Katrina Welch-Reardon, Christopher Hughes. Snai2(Slug) regulates tumor angiogenesis through the induction of EndoMT. [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 4167. doi:10.1158/1538-7445.AM2015-4167
Abstract 4168: Robo1 promotes angiogenesis through CDC42/Rho GTPases signaling pathway in hepatocellular carcinoma
Authors: Sun Hui-Chuan , Ao Jian-Yang , Chai Zong-Tao , Zhang Yuan-Yuan 
Published: August 2015

Abstract
Angiogenesis is essential for cancer growth and metastasis. Since present anti-angiogenesis strategies could not fulfill the expected clinical efficacy in hepatocellular carcinoma (HCC), novel key regulatory molecules involving this process are still under investigation. It has been reported that the axon guidance receptor gene Robo1 is involved in tumor angiogenesis. Here, we report the function of Robo1 in human umbilical vein endothelial cells (HUVEC) as well as the hepatocellular carcinoma endothelial cells. High Robo1 expression in the tumor vessels associated with a poor survival in patients. Over-expression of Robo1 in HUVEC cell lines results in increased proliferation, migration and tube formation in HUVECs. These changes could be reversed by knockdown of Robo1. Moreover, we show that Robo1 expression promoted CDC42 and Rho expression in HUVEC. We demonstrated that Robo1/CDC42/Rho signaling axis in HUVECs, which is important for function of HUVECs. Taken together, our results showed that Robo1 promoted angiogenesis in hepatocellular carcinoma and provide new target for anti-angiogenesis therapy in HCC
Note: This abstract was not presented at the meeting.
Citation Format: Hui-Chuan Sun, Jian-Yang Ao, Zong-Tao Chai, Yuan-Yuan Zhang. Robo1 promotes angiogenesis through CDC42/Rho GTPases signaling pathway in hepatocellular carcinoma. [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 4168. doi:10.1158/1538-7445.AM2015-4168
Abstract 4172: Differential angiogenesis-related cytokines release in tumor interstitial fluid and plasma in ER-positive and triple-negative breast cancers overexpressing VEGF
Authors: Dore-Savard Louis , Lee Esak , Popel Aleksander S. , Bhujwalla Zaver M. 
Published: August 2015

Abstract
Interstitial fluid (IF) is a key component of the tumor microenvironment (TME) that has been largely overshadowed by proteomic and genomic analysis of the cancer cell and stromal compartments of the TME. Early studies of tumor IF by Gullino and colleagues showed elevated protein and lactic acid levels and the absence of glucose. Modern analytical methods allow for comprehensive characterization of IF proteins to better understand the TME. We modified Gullino's model and created a collection chamber adapted to collect IF from mouse tumors. We used ER-positive MCF-7 and triple negative MDA-MB-231 breast cancer cells in SCID mice. Additionally, we created VEGF-overexpressing cells from each cell line to evaluate the effect of VEGF overexpression on angiogenic cytokines in tumor IF. The chamber was implanted with small tumor pieces in the subcutaneous space until the tumor encompassed the chamber (4 to 12 weeks depending on cell types). The tumor was then removed and the tumor IF (approximate volume 40μl) and blood plasma were collected. IF and plasma samples were analyzed using a multiple cytokine immunoassay (Proteome Profiler Human Angiogenesis Kit, R & D Systems Inc., Minneapolis MN). Among the 55 human angiogenesis-related cytokines tested, only 4 were detected in MCF-7 tumors IF, and 24 were detected in MDA-MB-231 IF sample. As anticipated, high VEGF levels were detected in MCF-7 overexpressing cells. Additionally, we observed a tendency to an elevated level of TIMP metallopeptidase inhibitor 1 (TIMP-1). All 4 cytokines detected in MCF-7 IF were also detected in MDA-MB-231 IF. VEGF overexpression had minimal effect on the tested cytokines. However, decreased levels of angiogenin and endostatin were observed. In plasma of tumor-bearing mice, 5 cytokines were detected. For instance, Serpin E1 (PAI-1) and TIMP-1 were detected in the plasma of both MCF-7 and MDA-MB-231, at lower levels than in IF. However, urokinase plasminogen activator was present only in mice with triple negative MDA-MB-231 tumors. We anticipate that a better understanding of the TME, via the characterization of the IF, will help identify new targets for diagnosis and therapy of cancer. We intend to examine correlations between the present data and human databanks to confirm the relevance of our model systems.
Citation Format: Louis Dore-Savard, Esak Lee, Aleksander S. Popel, Zaver M. Bhujwalla. Differential angiogenesis-related cytokines release in tumor interstitial fluid and plasma in ER-positive and triple-negative breast cancers overexpressing VEGF. [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 4172. doi:10.1158/1538-7445.AM2015-4172