bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5272: A novel organotypic 3D invasion platform to advance anticancer drug development
Authors: Tuomela Johanna M. , Seppänen Jani , Bernoulli Jenni , Salo Sirpa , Salo Tuula , Halleen Jussi 
Published: August 2012

Abstract
Tumor cell invasion is traditionally studied in three-dimensional (3D) organotypic models composed of type I collagen and fibroblasts, where various cell types and the extracellular matrix in the tumor microenvironment (TME) affects tumor cell behavior. As both molecular and cellular components of TME are cardinal participants in tumor progression, special attention should be addressed in the growth environment. As there is urgent need for more predictive models to be utilized in drug discovery and development, organotypic 3D in vitro assay provides an applicable platform. We characterized a novel organotypic model based on human uterine leiomyoma tissue to be used in drug development. To evaluate the general applicability of the myoma model, human tongue squamous cell carcinoma cells (HSC-3) and human triple negative breast cancer cells (MDA-MB-231(SA)-GFP) were cultured on top of human uterine leiomyoma tissue. Organotypic sections were examined by immunohistochemical stainings against cytokeratin and GFP, where invasion area and depth were measured. The organotypic myoma model also gives opportunity for ELISA, RIA and Western blotting analysis of the culture media. The used cell lines were found to invade in highly distinct patterns. This organotypic 3D myoma model provides a potent tool for analyzing the behavior of tumor cells. Moreover, we conclude that established organotypic 3D in vitro platform gives remarkable advantages to screen potential therapeutic options by producing totally new commercially usable models and innovative treatment approaches that target both the cancer cells and the TME components.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5272. doi:1538-7445.AM2012-5272
Abstract 5274: MicroRNA-214 /hepatoma-derived growth factor paracrine pathway contributes to hypervascularity of human hepatoma
Authors: Hsieh Sen-Yung 
Published: August 2012

Abstract
Background & Aims: Unusual hypervascularity is a hallmark of human hepatocellular carcinoma (HCC). Angiogenesis is essential for tumorigenesis and metastasis. While microRNA (miRNA) deregulation is implicated in carcinogenesis, the role of miRNAs in tumor angiogenesis remains unknown. Methods: MiRNAs deregulated in HCC were identified using array-based miRNA profiling. A luciferase reporter assay was used to confirm target association between miR-214 and hepatoma-derived growth factor (HDGF). Tube formation and in vivo angiogenesis assays were performed to validate the roles of miR-214 and HDGF in angiogenesis. Results: Downregulation of miR-214 was associated with HCC progression and poor clinical outcome. Ectopic expression of miR-214 suppressed cell proliferation and xenograft tumor growth and depressed the vascularity of the tumor and its surrounding tissues. The genes downregulated by ectopic expression of miR-214 were involved in the regulation of apoptosis, cell cycle, and angiogenesis. Integrated analysis implicated HDGF as a downstream target of miR-214. Conditioned medium of HCC cells contained bioactivity to stimulate tube formation of human umbilical vein endothelial cells, which was abolished by pretreatment of the conditioned media with HDGF antibodies, and silencing of HDGF expression or ectopic expression of miR-214 of the donor HCC cells. The angiogenic activity of the conditioned media lost by ectopic expression of miR-214 in the donor cells was restored by supplementation with recombinant HDGF. In vivo tumor angiogenesis assays showed significant suppression of tumor vascularity by ectopic expression of miR-214. Conclusions: A novel miR-214/HDGF paracrine pathway contributes to hypervascularity of HCC and is a candidate target for anti-HCC therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5274. doi:1538-7445.AM2012-5274
Abstract 5276: Roles of BMP-9 signals during the formation of tumor vessels
Authors: Watabe Tetsuro , Suzuki Yuka , Yoshimatsu Yasuhiro , Miyazono Kohei 
Published: August 2012

Abstract
Angiogenesis plays critical roles during development and progression of cancer. Members of the bone morphogenetic protein (BMP) family are involved in TGF-beta superfamily, and have been implicated in the development and maintenance of vascular systems. While BMP-9 and 10 have been recently reported to bind to ALK-1 in endothelial cells, the roles of BMP-9/ALK-1 signaling in the regulation of endothelial cells have not yet been fully elucidated. Here, we examined the effects of BMP-9 on the proliferation of endothelial cells using various systems. Vascular tube formation from ex vivo allantoic explants of mouse embryos was promoted by BMP-9. BMP-9 also induced the proliferation of in vitro-cultured mouse embryonic stem cell-derived endothelial cells (MESEC) by inducing the expression of vascular endothelial growth factor receptor 2 and Tie2, a receptor for Angiopoietin-1. Decrease in ALK-1 expression and expression of constitutively active ALK-1 in MESEC abrogated and mimicked the effects of BMP-9 on the proliferation of MESEC, respectively, suggesting that BMP-9 promotes their proliferation via ALK-1. Furthermore, in vivo angiogenesis was promoted by BMP-9 in a Matrigel plug assay and a BxPC3 human pancreatic cancer xenograft model. In consistent with these in vivo findings, BMP-9 enhanced the proliferation of in vitro cultured normal endothelial cells from dermal tissues of adult mice and tumor-associated endothelial cells isolated from tumor xenografts in host mice. These findings suggest that BMP-9 signaling activates the endothelium via ALK-1. In this presentation, the roles of BMP-9 signals in the formation of lymphatic vessels will also be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5276. doi:1538-7445.AM2012-5276
Abstract 5280: Activation of sphingosine kinase 1 is necessary for angiopoietin 2-induced hemangiogenesis and lymphangiogenesis
Authors: Yamada Akimitsu , Nagahashi Masayuki , Ramachandran Subramaniam , Kim Eugene Y. , Allegood Jeremy C. , Rashid Omar M. , Milstien Sheldon , Spiegel Sarah , Takabe Kazuaki 
Published: August 2012

Abstract
INTRODUCTION: Sphingosine kinase 1 (SphK1) is one of the two isoenzymes that generate the potent bioactive sphingolipid mediator, sphingosine-1-phosphate (S1P). S1P promotes cancer cell survival, proliferation and hemangiogenesis. The angiopoietin2 (Ang2)-Tie2 axis also plays a significant role in hemangiogenesis and lymphangiogenesis. The aim of this study was to investigate the involvement of SphK1 in Ang2-induced hem- and lymphangiogenesis. METHODS: Human umbilical vein endothelial cells (HUVECs) and human lymphatic endothelial cells (HLECs) were treated without or with an isozyme-specific inhibitor of SphK1 (SK1-I) and qPCR, western blot, ELISA, and tube formation assays carried out. We also used a new method we developed to quantify both hem- and lymphangiogenesis in the same sample in vivo by combining Directed In Vivo Angiogenesis Assays (DIVAA) with Fluorescence Activated Cell Sorting (DIVAA/FACS). RESULTS: qPCR revealed that human HLECs like HUVECs express high levels of SphK1 and the S1PR1 receptor. S1P rapidly stimulated xocytosis of Ang2 from HLEC storage granules determined by ELISA. Ang2 activated Tie2 in HLECs as demonstrated by its rapid phosphorylation on Tyr992, a major site responsible for its activation. Similar to Ang2, S1P also stimulated phosphorylation of Tie2, which may be due to secretion of Ang2. S1P is a potent hem- and lymphangiogenic factor for HUVECs and HLECs, respectively, as demonstrated by enhanced tube formation. Ang2-induced hem- and lymphangiogenesis was mediated at least in part by SphK1 as shown by the inhibitory effect of SK1-I. Furthermore, both S1P and Ang2 significantly induced hem- and lymphangiogenesis in vivo determined by DIVAA/FACS. Similar to its effect on in vitro hem- and lymphangiogenesis, inclusion of SK1-I in the angioreactors together with Ang2 completely abolished its ability to stimulate both of these processes. CONCLUSION: Activation of SphK1 is necessary for Ang2-induced hemangiogenesis and lymphangiogenesis through the SphK1/S1P and Ang2/Tie2 axes. This work was supported by NIH (K12HD055881) and Susan G. Komen for the Cure (KG090510) to KT, NCI (R01CA61774) to SS, and Sumitomo Life Social Welfare Services Foundation grant to MN.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5280. doi:1538-7445.AM2012-5280
Abstract 5288: Glioma stem cells stimulate the motility of brain endothelial cells: Identification of cell-adhesion molecules mediating motility and direct interaction
Authors: Burgett Monica E. , Tipps Russell S. , Lathia Justin D. , Bao Shideng , Rich Jeremy N. , Gladson Candece L. 
Published: August 2012

Abstract
Angiogenesis is a prominent characteristic of malignant glioma. Glioma stem cells (GSCs) reside adjacent to blood vessels in the perivascular niche, and recent evidence suggests a role for GSCs in promoting angiogenesis. Here we examined the interplay between GSCs and endothelial cells (ECs) on a laminin substrate, and the potential for GSC promotion of EC motility. In an in vitro 2D motility assay, we found that GSCs dramatically stimulated EC migration, and ECs also stimulated GSC migration. An antibody to integrin α6 blocked in part the motility of both GSCs and ECs. We also found that GSCs directly interact with ECs; therefore, we investigated which cell-adhesion molecules mediated the interaction. In a cell-cell binding assay, blocking antibodies to both L1-cell adhesion molecule (L1CAM) and integrin αvβ3 inhibited in part the direct contact between GSCs and ECs. In the motility assay, the combination of antibodies to L1CAM and αvβ3 significantly inhibited the motility and interaction of both cell types. These data suggest GSCs can promote angiogenesis by promoting EC migration, and indicate a role for the cell-adhesion receptors L1CAM and αvβ3 in the direct interaction between GSCs and ECs that may promote EC motility.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5288. doi:1538-7445.AM2012-5288
Abstract 5297: Autocrine stimulation of VEGFR-2 by leptin is associated with Notch signaling pathway and cancer stem cell marker expression
Authors: Guo Shanchun , Gillespie Corey , Liu Mingli , Gonzalez-Perez Ruben 
Published: August 2012

Abstract
Obesity-related cancer is an increasing health problem. Leptin, the major adipokine, has been suggested a major factor in these relationships. Leptin is a pro-inflammatory, pro-angiogenic and mitogenic factor for breast cancer cells. Recently, we described a comprehensive mechanism for leptin induction of VEGF, and unveiled a novel crosstalk between Notch, IL-1 and leptin (NILCO) in breast cancer. NILCO regulates VEGF/VEGR-2 in breast cancer cells and could represent the integration of developmental, pro-inflammatory and pro-angiogenic signals critical for leptin oncogenic actions. However, the specific mechanisms for leptin-induced VEGFR2 are unknown. To answer this question, we re-cloned mouse VEGFR-2 promoter and prepared VEGFR-2 luc, then analyzed VEGFR-2 regulation and expression by using several kinase inhibitors, leptin peptide antagonist 2 (LPrA2), a VEGFR-2 kinase inhibitor (SU5416), as well as siRNA against VEGFR-2, Notch1, Notch3 in 4T1 cells. Our results demonstrated that leptin-induced JAK2/STAT3, MAPK/ERK 1/2, PI-3K/AKT1, PKC, p38 and JNK signaling pathways may correlate with upregulated VEGFR-2. Moreover, leptin-induced activation of Notch/VEGFR-2 was linked to the upregulation of cancer stem cell markers CD44 and ALDH1. These leptin effects were inhibited by siRNA-Notch1&3, leptin signaling antagonist (PEG-LPrA2), VEGFR2-kinase inhibitor (SU5416) and siRNA-VEGFR-2. Our results show for the first time how leptin's molecular signals regulate VEGFR-2 (an autocrine survival process) that was associated to Notch and cancer stem cell marker expression. These novel findings may help to design new strategies for prevention/treatment of breast cancer through the abrogation of tumor angiogenesis and breast cancer stem cell renewal in an obesity context. [This work was supported in part by NIH/NCI1SC1CA138658-02; NIH/ARRA/3SC1CA138658-02S1 and the Georgia Cancer Coalition Distinguished Cancer Scholar Award (to RRGP)].
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5297. doi:1538-7445.AM2012-5297
Abstract 530: Circulating γδ T cells are activated and depleted during progression of high-grade gliomas: Implications for γδ T cells therapy of GBM
Authors: Beck Benjamin , Gillespie G Yancey , Lopez Richard D. , Cloud Gretchen A. , Langford Cathy , Kim Hyung , Harkins Lualhati , Lamb Lawrence S. 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) remains frustratingly impervious to any existing therapy. We have previously shown that GBM is sensitive to recognition and lysis by ex vivo activated γδ T cells, a minor subset of lymphocytes that innately recognize autologous stress-associated target antigens via the T cell receptor and/or NKG2D. However, circulating γδ T cell counts and function are significantly reduced in patients with GBM. We sought to determine the role of γδ T cells in the immune response to high-grade gliomas in C57BL/6 mice bearing GL261 cell line-derived intracranial gliomas. Examination of mice 15 days after intracranial tumor placement and prior to development of neurologic symptoms revealed small infiltrating high-grade gliomas near the injection site. Concurrently, the peripheral blood γδ T cell count was significantly increased when compared to control mice that received only the methylcellulose vehicle (p=0.0003). T cell expansion was confined to the γδ T cell compartment, and a substantial proportion of γδ T cells in tumor-bearing mice expressed Annexin-V (20%-45%) indicating progression to apoptosis. Annexin-V expression in control mice was confined to 2-5% of γδ T cells, significantly less than tumor-bearing mice (p&lt;0.0001). GL261-derived tumors expressed γδ T cell target stress-associated NKG2D ligands H60, MULT-1 and RAE-1, yet γδ T cells did not infiltrate the intracranial tumors. In a separate experiment, we found no survival advantage between wild-type (WT) mice over γδ T cell-deficient (C57BL/6α-/−) tumor-bearing mice. Based on this observation that activated γδ T cells did not invade the tumor, we treated mice with a stereotactic intracranial injection of 1.5 x 106 ex vivo expanded/activated γδ T cells approximately 15 minutes following placement of 5 x 106 GL261 glioma cells. Mice that received intracranial γδ T cells were protected from tumor development at site of injection, although distant tumors did eventually form. These data suggest that γδ T cells are stimulated in glioma-bearing mice and that depletion in γδ T cells observed in mouse glioma models and human GBM are likely due to activation-induced cell death in response to the tumor. Activated γδ T cells do not traffic to the tumor parenchyma; however, an antitumor effect can be achieved by direct placement of ex vivo activated γδ T cells in the vicinity of microscopic disease, suggesting a potential post-resection strategy for treatment of minimal residual GBM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 530. doi:1538-7445.AM2012-530
Abstract 5313: Sustained hypercalcemia primes non-invasive breast cancer cells for metastasis to high calcium microenvironments
Authors: Sakwe Amos M. , Koumangoye Rainelli B. , Ochieng Josiah 
Published: August 2012

Abstract
Breast cancer frequently spreads to calcium-rich organs/metastatic sites such as skeletal tissues but the role of hypercalcemia in breast cancer progression remains poorly understood. While patients with metastatic or end-stage cancer are likely to become hypercalcemic, up to 30% of breast cancer patients develop cancer-induced hypercalcemia (CIH) in the absence of metastases or bone diseases. The resulting high extracellular ionized calcium (Ca2+) activates the calcium sensing receptor (CaSR) that not only promotes the proliferation of breast cancer cells but also the secretion of parathyroid hormone-related protein by the tumor cells. This suggests that CIH may promote both the vicious osteolytic cycle and breast cancer progression. In this study, we examined whether sustained hypercalcemia primes breast cancer cells for metastasis to high Ca2+ microenvironments. We demonstrate that sustained hypercalcemia enables Ca2+-sensitive non invasive breast cancer cells such as MCF-7 to become high Ca2+-adapted and that this adaptation is accompanied by increased motility and more aggressive growth (increased proliferation). Consistent with this observation, invasive and metastatic breast cancer cells are high Ca2+-adapted cells that efficiently grow over a wide range of Ca2+ concentrations (up to 10 mM). Interestingly, we also show that at high Ca2+ (5 mM) breast cancer cells expressing the Q1011E CaSR variant that is common among African Americans proliferate faster than those expressing the A986S CaSR variant that is common among Caucasians. These data suggest that differences in the adaptation of breast cancer cells to hypercalcemia due in part to the expression of distinct CaSR variants underlie the distinct race-related breast cancer outcomes. This work is funded by the following grants made available to JO: DOD-W81XWH-07-1-0254 and 1SC1CA134018-01
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5313. doi:1538-7445.AM2012-5313
Abstract 5376: Immunosuppressive T regs and MDSCs in human melanoma
Authors: Jordan Kimberly R. , McCarter Martin D. 
Published: August 2012

Abstract
Despite the ability to elicit active immune responses, most immunotherapies fail to eliminate tumors in human cancer patients. One reason immunotherapy has not met expectations may be due to immunosuppression in the local environment of the tumor. We have previously reported that untreated advanced-stage melanoma patients have increased numbers of peripheral T regs. In addition, exposure to melanoma cells in vitro expands T regs from normal human peripheral blood mononuclear cells (PBMCs). We have shown that melanoma-conditioned media have increased levels of TGF-beta, which may be responsible for the expansion of these suppressive cells in culture. Here we show that the number of peripheral T regs directly correlates with the amount of TGF-beta in the plasma of late-stage melanoma patients. We also show that melanoma patients have increased numbers of other suppressive cells, known as myeloid-derived suppressor cells (MDSCs). These MDSCs may further contribute to immunosuppression in advanced-stage melanoma patients. Finally, we show that the tumor-induced T regs and the T regs and MDSCs from the peripheral blood of melanoma patients suppress T cell responses in vitro, including proliferation, cytokine production, and cytotoxic activity. We are currently investigating whether MDSCs from melanoma patients contribute to the accumulation of T regs and whether immunotherapies used in the treatment of advanced-stage melanoma patients, particularly IL-2 and ipilimumab, affect their frequency or function. An understanding of the potential interaction between melanoma, MDSCs, and regulatory T cells will further our goal in identifying ways of blocking the function of these suppressive cells in melanoma patients to improve the effectiveness of future therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5376. doi:1538-7445.AM2012-5376