bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1545: Education of macrophages through modulation of NF-kappaB: an opportunity for targeted therapy.
Authors: Barham Whitney , Tikhomirov Oleg , Chen Lianyi , Ortega Ryan , Gleaves Linda , Onishko Halina , Sherrill Taylor , Connelly Linda , Blackwell Timothy S. , Yull Fiona E. 
Published: August 2014

Abstract
Macrophages are a plastic cell type, capable of adapting to numerous signals within their environment. As part of the innate immune system, macrophages were traditionally considered anti-tumor (M1), but it has been well established that macrophages can also help to create a pro-tumor, pro-metastatic tumor niche (M2). NF-κB transcription factors can regulate both pro- (MMP's, VEGF) and anti-tumor (iNOS) downstream targets within macrophages, suggesting that modulation of NF-κB may play a role in the two different macrophage phenotypes. However, our understanding of NF-κB signaling specifically within macrophages during tumor progression is limited. To this end, we have developed murine transgenic models that enable us to induce expression of an activator or dominant inhibitor of NF-κB in macrophages by adding doxycycline to the drinking water of mice. We have combined these novel transgenics with the polyoma model of mammary cancer for our studies.
We have recently shown that activation of NF-κB in macrophages significantly limits metastasis in a tail vein model of tumor progression. In this model, constitutive IKK2 activity within macrophages leads to an anti-tumor immune response including altered immune cell populations within the lung microenvironment, changes in chemokine and cytokine expression and rapid killing of tumor cells during the seeding phase mediated by reactive oxygen species. Our current work has extended these findings to an orthotopic mammary tumor model. Again, we find that activation of NF-κB in macrophages results in decreased primary tumor growth and decreased tumor seeding into the blood. To model this activation in vitro, we have utilized immortalized bone marrow derived macrophages from IκBα knock-out mice compared to a wild type line. IκBα KO macrophages display changes in morphology and adhesion relative to wild type macrophages. This correlates with increased cytotoxic behavior in co-culture with polyoma tumor cells, mirroring the in vivo phenotype of the cIKK2 expressing macrophages. Given these findings, we believe that targeted activation of NF-κB signaling in macrophages could be harnessed to overcome the education of macrophages by tumor cells, and could be exploited as a novel targeted therapy.
Citation Format: Whitney Barham, Oleg Tikhomirov, Lianyi Chen, Ryan Ortega, Linda Gleaves, Halina Onishko, Taylor Sherrill, Linda Connelly, Timothy S. Blackwell, Fiona E. Yull. Education of macrophages through modulation of NF-kappaB: an opportunity for targeted therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1545. doi:10.1158/1538-7445.AM2013-1545
Abstract 1568: Evaluate the efficacy of new therapeutics using advanced metastatic mouse models.
Authors: Zhang Juan , Guo Sheng , Cai Jie , Sun Yanmei , Mao Guanping , Wang Zhun , Zhang Lan , Jin Ying , Shi Qian , Chen Taiping 
Published: August 2014

Abstract
Metastasis, the spread and growth of tumor cells to distant organs, is usually a final and fatal step in the progression of solid malignancies. Preclinical test of the new anti-cancer therapies that could mimic the disease present in most clinical trials asks for robust metastatic models than just the subcutaneous models. We sought to establish and validate a panel of experimental (i.v. inoculation) and spontaneous (orthotopic inoculation) mouse models with high metastatic potential and varied tissue tropism in different types of cancer models, covering colorectal, liver, prostate, breast, pancreatic cancer and melanoma. The responsiveness of metastasis to several therapies that are proved to be clinically effective or ineffective was investigated. A higher predictive power of the metastatic models was demonstrated compared with the corresponding subcutaneous models. By means of the transcriptomic analysis of the paired primary tumor population and the distant lung metastasis population in 5 orthotopic tumor models, we identified the gene signatures that differentiate the two populations in different tumor types. Our signature was also compared with the clinical relevant gene signatures correlated with lung metastasis risk. Several genes are concordantly expressed in both signatures and are biologically meaningful. Overall, given the higher predictive power and the clinical relevance, the use of the metastatic mouse models constitutes an effective and important strategy to preclinically evaluate the efficacy of new therapeutic regimens.
Citation Format: Juan Zhang, Sheng Guo, Jie Cai, Yanmei Sun, Guanping Mao, Zhun Wang, Lan Zhang, Ying Jin, Qian Shi, Taiping Chen. Evaluate the efficacy of new therapeutics using advanced metastatic mouse models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1568. doi:10.1158/1538-7445.AM2013-1568
Abstract 1584: Targeting the mitotic checkpoint with inhibition of MPS1 kinase enhances radiosensitivity of glioblastoma cancer cells.
Authors: Tandle Anita T. , Hanson Ryan , Maachani Uday B. , Meushaw Tamalee , Zhao Shuping , Shankavaram Uma , Tofilon Philip , Caplen Natasha J. , Camphausen Kevin 
Published: August 2014

Abstract
During the cell cycle, genomic stability requires accurate chromosome segregation. Errors in this process can cause aneuploidy and lead to tumorigenesis. To ensure faithful chromosome segregation, cells develop a mechanism called the spindle assembly checkpoint (SAC). Cancer cells are addicted to the components of SAC machinery for a faithful entry of the cell into anaphase. Thus, targeting the molecular mechanisms required for the growth of aneuploid cells may be a more cancer cell specific therapeutic approach applicable to broader tumor histologies. Previously, using a siRNA based RNAi screen we identified MPS1 kinase, (also known as TTK) as an important kinase for GBM cell survival. MPS1 is an essential SAC enzyme aberrantly overexpressed in a wide range of tumors and necessary for tumor cell proliferation.
We observed inhibition of GBM cell growth when MPS1 was downregulated by number of MPS1 specific siRNAs. This was further validated using a selective and orally bioavailable MPS1 inhibitor NMS-P715 in various in-vitro cell assays. The inhibition of cell death was induced partly by apoptosis; however, the major mechanism was mitotic catastrophe. Cells treated with NMS-P715 showed an increase in cells in G2-M phase of cell cycle compared to control cells followed by mitotic catastrophe. Moreover, inhibition of MPS1 resulted in radiosensitization of GBM cells. We observed decrease in DNA damage repair and significant retention of γH2AX foci after combination of radiation (RT) with NMS-P715 compared to individual treatments. Next, radiation in combination with NMS-P715 inhibited cell survival ability of GBM cells in a colony formation assay. Further, NMS-P715 could inhibit GBM tumor growth in an orthotopic brain tumor model. Finally, in order to determine MPS1 associated molecular pathways, we compared gene expression profile in MPS1 knockdown cells compared to the control by microarray analysis. Ingenuity pathway and Gene Set Enrichment Analysis were used to investigate the biological relevance of the MPS1 modulated genes. We identified genes important in cell assembly, cell organization, DNA repair and cell death pathways. Thus, inhibiting MPS1 kinase in combination with radiation could represent a promising new approach to GBM therapy.
Citation Format: Anita T. Tandle, Ryan Hanson, Uday B. Maachani, Tamalee Meushaw, Shuping Zhao, Uma Shankavaram, Philip Tofilon, Natasha J. Caplen, Kevin Camphausen. Targeting the mitotic checkpoint with inhibition of MPS1 kinase enhances radiosensitivity of glioblastoma cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1584. doi:10.1158/1538-7445.AM2013-1584
Abstract 1614: Murine matrigel plug assay for quick evaluation of anti-angiogenesis drugs.
Authors: Sun Yanmei , Song Xiaoming , Li Nan , Cai Jie , Shi Qian , Chen Taiping 
Published: August 2014

Abstract
Angiogenesis plays important roles in disease processes such as tumor development and progression, as well as many physiological conditions. A few cancer drugs were successfully approved based on anti-angiogenesis mechanisms. More candidates are in different evaluation stages, including clinical phase II stages. Among many assays used for angiogenesis evaluation, Murine Matrigel Plug Assay (MMPA) is a relatively simple, highly effective in vivo assay to evaluate anti-angiogenesis responses of the test articles. Because of its simplicity and short assay duration, the assay is scalable for efficient screening of large number of test articles. However, the analysis of the plugs, usually with H&E staining and microvessel counting, is time consuming and error prone, hampers the usage of this method as a general screening assay for test articles. Here, we set out to test a number of combinations of assay conditions, including mouse strains, angiogenesis inducers, varying days of treatment, and different routes of SOC drug treatments. More importantly, we tested plug analysis methods including H&E staining, CD31 IHC staining, as well as hemoglobin concentration analysis. We demonstrated that hemoglobin concentration analysis results are corroborated by IHC staining as well as H&E staining, in most of the conditions tested. Hemoglobin assay is less time consuming and easier to scale up. Thus MMPA followed by hemoglobin analysis may be suitable for large scale screening studies for angiogenesis modulators. Interestingly, CTX, one of the popular anti-cancer therapeutics, was shown in MMPA as a good anti-angiogenesis agent. In conclusion, the MMPA described may greatly facilitate the preclinical development of cancer therapeutics that target the angiogenesis.
Citation Format: Yanmei Sun, Xiaoming Song, Nan Li, Jie Cai, Qian Shi, Taiping Chen. Murine matrigel plug assay for quick evaluation of anti-angiogenesis drugs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1614. doi:10.1158/1538-7445.AM2013-1614
Abstract 1619: Combination of VEGFR inhibitor lenvatinib (E7080) and Met/EphB4 inhibitor golvatinib (E7050) overcomes VEGFR inhibitor-resistant tumor vascular.
Authors: Kawano Satoshi , Nakagawa Takayuki , Nakazawa Yuya , Sato Yoshiaki , Matsushima Tomohiro , Funahashi Yasuhiro 
Published: August 2014

Abstract
Vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for the treatment of several types of tumors, however, some tumor shows intrinsic resistance to VEGFR inhibitors. In addition, patients initially responding develop acquired resistance to VEGFR inhibitors after varying periods of time. Thus it is urgent to develop strategy to overcome anti-VEGF therapy resistance. Hepatocyte growth factor (HGF)/Met signaling is activated in various types of tumors. Recently, it is reported that HGF/Met signaling contributes to resistance to tyrosine kinase inhibitors such as EGFR, BRAF, ALK inhibitors. This suggests that Met inhibitors may be promising in treating HGF/Met activated anti-VEGF therapy-resistant tumors. We have identified lenvatinib (E7080) as a highly-potent VEGFR inhibitor and phase III trial is ongoing in thyroid cancer. Lenvatinib inhibited the growth of HUVEC induced by VEGF, however, addition of HGF to HUVEC conferred resistance to lenvatinib. This resistance was cancelled by the addition of golvatinib (E7050) which is identified as a potent Met/EphB4 inhibitor and phase I trial of the lenvatinib/golvatinib combination therapy is ongoing. In mouse models bearing various tumor cell lines expressing VEGF and HGF, treatment with lenvatinib alone demonstrated only moderate antitumor activity, however, combination with golvatinib demonstrated synergistic antitumor activity with decrease of tumor vessel density. Furthermore, it is reported that EphB4 has critical roles in tumor vessel development and maturation. Our unique in vitro assay systems, endothelial cells/pericyte 2D co-culture assay and endothelial cells/pericyte 3D co-culture sprouting assay, suggested that EphB4 inhibitory activity of golvatinib disrupted anti-VEGF therapy-resistant tumor vascular in the combination with lenvatinib. Together, these data demonstrated that combination therapy with golvatinib may be promising to overcome anti-VEGF therapy resistance.
Citation Format: Satoshi Kawano, Takayuki Nakagawa, Yuya Nakazawa, Yoshiaki Sato, Tomohiro Matsushima, Yasuhiro Funahashi. Combination of VEGFR inhibitor lenvatinib (E7080) and Met/EphB4 inhibitor golvatinib (E7050) overcomes VEGFR inhibitor-resistant tumor vascular. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1619. doi:10.1158/1538-7445.AM2013-1619
Abstract 1621: Short-time exposure to high concentrations of sunitinib causes tumor cell death.
Authors: Rovithi Maria , Poel Dennis , Voortman Jens , Labots Mariette , Dekker Henk , Gotink Kristy J. , Broxterman Henk J. , Verheul Henk M.W. 
Published: August 2014

Abstract
Background: Sunitinib, although initially developed as an antiangiogenic agent, has been shown to exert direct anti-tumor effects. Previously we demonstrated that sunitinib inhibits proliferation of various tumor cell lines in a dose-dependent manner. We here studied whether short exposure to high peak concentrations of sunitinib would induce tumor cell death.
Methods: 786-O renal cancer cells were incubated with increasing concentrations of sunitinib (5, 10 and 20 μM) for various time intervals (1 hour, 3, 6, 9, 24, 48, 72 hours). At prespecified time points, sunitinib was removed and cells were subsequently allowed to grow in drug-free culture medium. Viability of these cells one week after short time sunitinib exposure and sensitivity of recovered cells after repetitive treatment with high sunitinib concentrations were determined by MTT assays. Flow cytometry with Propidium Iodide staining was employed to determine apoptosis.
Results: Short-time exposure to high concentrations of sunitinib significantly induced cell death. Exposure to 20 μM of sunitinib for 9 hours provoked cell death in a manner identical to the prolonged exposure of 24, 48 or 72 hours. Flow cytometry confirmed the significant increase in cell death (60%) after 9-hour treatment with 20 μM sunitinib, compared to the untreated control (2%). Tumor cells that were repetitively treated with high concentrations of sunitinib retain their sensitivity to the drug identical to its parental cell line. Analysis of the key signaling pathways involved in sunitinib-induced cell death is ongoing.
Conclusion: We here report that repetitive short-time exposure to high concentration sunitinib causes cell death without inducing resistance. Interestingly, single-dose sunitinib up to 300 mg was previously reported to be well tolerated by patients. Based on these findings, administration of high dose intermittent sunitinib may result in cytotoxic antitumor activity irrespective of angiogenesis inhibition. A phase I trial to test this hypothesis in patients with cancer will start shortly.
Citation Format: Maria Rovithi, Dennis Poel, Jens Voortman, Mariette Labots, Henk Dekker, Kristy J. Gotink, Henk J. Broxterman, Henk M.W. Verheul. Short-time exposure to high concentrations of sunitinib causes tumor cell death. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1621. doi:10.1158/1538-7445.AM2013-1621
Abstract 1625: Crosstalk between breast cancer and stromal cells occurs via exosomes and gap junctions in bone metastatic breast cancer.
Authors: Bussard Karen M. , Marini Frank C. 
Published: August 2014

Abstract
Breast cancer preferentially metastasizes to the bone, where the five-year relative survival rate falls from 90% to &lt;10%. Although the precise mechanism underlying preferential metastasis is unknown, the bone likely provides a hospitable environment that both attracts breast cancer cells and allows them to colonize and grow. Besides affects osteoblast and osteoclast properties, we have evidence that metastatic breast cancer cells further create a unique bone niche by orchestrating extensive crosstalk with osteoblasts that may be involved in creating a niche permissive for breast cancer cell dormancy.
MC3T3-E1 murine osteoblasts were grown to confluence, then MDA-MB-231 human breast cancer cells added at a ratio of 1 breast cancer cell to 10 osteoblasts. Co-cultures were subsequently fixed and stained for Cx43 expression. Next, MC3T3-E1 cells and MDA-MB-231 cells were grown to confluence. Culture supernatants were removed and processed through a series of ultra-centrifugation, purification, and concentration steps to purify for exosomes. Finally, MC3T3-E1 cells were grown to various stages of maturity: 4 (growth) and 10 days (early differentiation) and incubated with conditioned medium from human MDA-MB-231 cells. qPCR was used to assay for changes in osteoblast-derived inflammatory cytokine expression.
Expression of the gap junction protein Cx43 was localized between breast cancer cells and osteoblasts. Both MC3T3-E1 and MDA-MB-231 cells expressed exosomes, which were visualized using a transmission electron microscope. Osteoblast-derived cytokines increased in the presence of MDA-MB-231 breast cancer cell conditioned medium included MCP-1 (CCL2), LIX (CXCL5), LIF, and NFATc2.
Overall, these data suggest that suggest there is extensive crosstalk directly between osteoblasts and breast cancer cells, and that osteoblasts are an important source of cytokines in breast cancer bone metastasis. Thus, these findings implicate the bone microenvironment and cancer cell manipulation thereof in orchestrating metastatic tumor cell dormancy, colonization, and survival. Supported in part by the National Institutes of Health; 1RC1 CA146381, 1R01NS06994, P50 CA083639 for FCM; Ruth L. Kirschstein Institutional Research Service Award (NRSA) T32 CA079448 for KMB.
Citation Format: Karen M. Bussard, Frank C. Marini. Crosstalk between breast cancer and stromal cells occurs via exosomes and gap junctions in bone metastatic breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1625. doi:10.1158/1538-7445.AM2013-1625
Abstract 1635: MiR-21/Smad 7 signaling determines TGF-β1-induced cancer associated fibroblast (CAF) formation.
Authors: Li Qiong , Wang Yongbin , Xiong Wujun , Mi Jun 
Published: August 2014

Abstract
Tumor-secreted growth factors such as TGF-β1 transform adjacent normal fibroblasts into cancer-associated fibroblasts (CAF) which is a major source of CAF. TGF-β1 has canonical and noncanonical Smad pathway, which pathway mediates TGF-β1 signaling during the CAF formation and how TGF-β1 activates regulatory Smad proteins is not entirely understood. To investigate whether the miR-21/Smad 7 signaling determines TGF-β1-induced CAF formation, the in vitro TGF-β1-induced CAF model was successfully established and the function of fibroblasts knocked down or overexpressed miR-21 or Smad 7 were finally identified in the xenografted mice, with or without TGF-β1 stimulation. Our data showed that the mature miR-21 is increased in fibroblast after TGF-β1 treatment, and miR-21 regulates Smad 7 protein level through the translation inhibition instead of the mRNA decay. Moreover, our data showed Smad 3 was phosphorylated 2 hours early than Smad 2 after TGF-β1 stimulation and Smad
7 knockdown enhanced Smad 2 and 3 phosphorylation; both of their phosphorylations were abolished by the TGFR kinase inhibitor. Most important, both of the over-expression of miR-21 or the knockdown of Smad 7 promoted CAF formation, even without TGF-β1 stimulation while the miR-21 knockdown or the Smad 7 overexpression as well as Smad 2, 3 and Smad 4 knock down blocked the TGF-β1-induced CAF formation.
These observations suggest that TGF-β1 induces CAF formation through the canonical pathway, miR-21/Smad 7 is a critical mediator.
Citation Format: Qiong Li, Yongbin Wang, Wujun Xiong, Jun Mi. MiR-21/Smad 7 signaling determines TGF-β1-induced cancer associated fibroblast (CAF) formation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1635. doi:10.1158/1538-7445.AM2013-1635
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1638: Imaging the interaction of αv integrin-GFP in osteosarcoma cells with RFP-expressing host stromal cells and tumor scaffold collagen in nude mice.
Authors: Tome Yasunori , Uehara Fuminori , Maehara Hiroki , Miwa Shinji , Tsuchiya Hiroyuki , Tomita Katsuro , Kanaya Fuminori , Bouvet Michael , Hoffman Robert M. 
Published: August 2014

Abstract
Human 143B osteosarcoma cells were stably transfected with an αv integrin-GFP vector. Confocal microscopy demonstrated that αv integrin immunofluorescence staining co-localized with αv integrin-GFP fluorescence. The αv integrin-GFP expressing tumors were established in transgenic nude mice ubiquitously expressing red fluorescent protein (RFP). The primary tumors acquired RFP-expressing stroma and were passaged orthotopically in the tibia in non-colored nude mice, which maintained the RFP stroma. The interaction of αv integrin-GFP expression in 143B cells with RFP-expressing host stromal cells was observed by confocal microscopy using the Olympus FV1000. Collagen fibers were imaged simultaneously in reflectance mode. The RFP-expressing stroma included cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in the tumors which persisted even 3 weeks after passage. CAFs expressing RFP were aligned between collagen fibers and cancer cells expressing αv integrin-GFP. Six weeks after transplantation, pulmonary metastases expressing αv integrin-GFP could be identified. TAMs expressing RFP accompanied osteosarcoma cells expressing αv integrin-GFP in the lung. The present study demonstrates the importance of αv integrin interaction with stromal elements.
Citation Format: Yasunori Tome, Fuminori Uehara, Hiroki Maehara, Shinji Miwa, Hiroyuki Tsuchiya, Katsuro Tomita, Fuminori Kanaya, Michael Bouvet, Robert M. Hoffman. Imaging the interaction of αv integrin-GFP in osteosarcoma cells with RFP-expressing host stromal cells and tumor scaffold collagen in nude mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1638. doi:10.1158/1538-7445.AM2013-1638