bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 386: Inhibiting the CSF-1 receptor on tumor-infiltrating monocytes may enhance the efficacy of radiotherapy for glioblastoma multiforme.
Authors: Stafford Jason H. , Chernikova Sophia , West Brian , Brown J. Martin 
Published: August 2014

Abstract
Glioblastoma (GBM) is the most common brain tumor and is one of the most deadly forms of cancer with median survival only 15 months after diagnosis. Ionizing radiation (IR) is the most effective treatment for GBM, but the prognosis remains poor because the tumors invariably recur. We have previously shown that bone marrow-derived monocytes promote GBM recurrence after radiotherapy by homing to the irradiation site and stimulating the growth of new tumor blood vessels in a process referred to as vasculogenesis. We found that this infiltration of monocytes can be prevented and tumor recurrences delayed by inhibition of the SDF-1/CXCR4 chemokine axis.1 Here we present data that suggest Colony Stimulating Factor-1 (CSF-1) may also play an important role in this phenomenon. CSF-1 is a potent chemokine secreted by several different types of solid tumors and is also the main growth factor regulating the differentiation of monocytes into macrophages. RT-PCR analysis of U251 GBM tumors growing in mice revealed a more than 2.5-fold increase in expression of CSF-1 after treatment with a single dose of 12 Gy IR. Increased CSF-1 expression in these tumors correlated with increased recruitment of CD11b+ monocytes. Immunohistochemistry (IHC) and fluorescence activated cell sorting (FACS) showed that the number of CD11b+ monocytes in GBM tumors had approximately doubled within 2 weeks of IR treatment. F4/80 staining indicated that the majority of the CD11b+ cells were mature macrophages. Treatment with 40 mg/kg/day PLX3397, which inhibits the receptor for CSF-1 (CSF-1R), effectively blocked the recruitment of monocytes/macrophages to the irradiated tumors. Moreover, bioluminescence imaging (BLI) of intracranial U251-luciferase tumors growing in mice showed that combined treatment with IR and PLX3397 was more effective at inhibiting tumor growth than IR alone. Eighty percent of mice treated with IR and PLX3397 were alive at 50 days post-irradiation whereas there were no survivors among groups receiving monotherapy. These results suggest inhibition of CSF-1R may prevent post-irradiation recurrence of GBM by blocking the recruitment of tumor-infiltrating monocytes/macrophages.
Citation Format: Jason H. Stafford, Sophia Chernikova, Brian West, J. Martin Brown. Inhibiting the CSF-1 receptor on tumor-infiltrating monocytes may enhance the efficacy of radiotherapy for glioblastoma multiforme. [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 386. doi:10.1158/1538-7445.AM2013-386
Abstract 3878: Bach1 promotes liver metastasis of colorectal cancer cells by regulating c-Myc and SOX4.
Authors: Yun Jieun , Jo Yeong Nang , Park Song-Kyu , Kim Jin-Ah , Yang Junguk , Lee Chang Woo , Yoon Won Kee , Lee Ok-Jun , Han Sang-Bae , Doebele Robert C. , Kang Jong Soon 
Published: August 2014

Abstract
Bach1 is a basic leucine zipper transcription factor that binds to Maf recognition elements (MAREs) and has recently been identified as the regulator of breast cancer metastasis. Bach1 promotes breast cancer metastasis to bone by directly upregulating MMP1 and CXCR4 and it is critical for the cell transformation and tumor growth induced by activated H-RasV12. Here, we demonstrate the oncogenic mechanisms of Bach1 in colorectal cancer. Ectopic expression of Bach1 increases invasion of colorectal cancer cells, whereas knockdown of Bach1 significantly reduces the invasive efficiency of the cancer cells. In a mouse model, suppression of Bach1 expression significantly inhibits intravasation and liver metastasis of colorectal cancer cells. The mechanism involves upregulation of c-Myc and SOX4 expression by Bach1 maintaining ERK signaling. Finally, we confirmed the expression of Bach1 is high in the patient samples of colorectal cancer and metastasis, unlike normal colon tissues. These results suggest Bach1 as a novel target for cancer therapeutic strategy.
Citation Format: Jieun Yun, Yeong Nang Jo, Song-Kyu Park, Jin-Ah Kim, Junguk Yang, Chang Woo Lee, Won Kee Yoon, Ok-Jun Lee, Sang-Bae Han, Robert C. Doebele, Jong Soon Kang. Bach1 promotes liver metastasis of colorectal cancer cells by regulating c-Myc and SOX4. [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 3878. doi:10.1158/1538-7445.AM2013-3878
Abstract 3884: Targeting ATX and LPA receptors melanoma invasion and metastasis.
Authors: Tigyi Gabor , Fujiwara Yuko , Lee SueChin , Liu Jianxiong , Patil Renukadevi , Gupte Renuka , Miller Duane D. , Oravecz Tamas , Balazs Louisa 
Published: August 2014

Abstract
ATX, a lysophospholipase D that generates LPA, is highly up-regulated in metastatic and chemotherapy-resistant carcinomas. Many cancers secrete ATX, and it contributes to their invasive properties. LPA produced by ATX activates LPA1-8 G protein-coupled receptors on the cell surface. Many cancers over-express multiple subtypes of LPAR and the overexpression of LPAR leads to malignant transformation, metastasis, and resistance to therapy. Therefore, ATX-LPA signaling axis is an emerging target for cancer therapy. We have previously shown that knockdown of ATX expression in B16F10 melanoma cells decreased tumor invasion in vitro and metastasis in vivo. In this study, we sought to understand the roles of the LPA GPCRs both in the tumor cells and tissues targeted by metastatic cancer cells. Using the in vivo B16 melanoma metastasis model syngeneic to the C57BL/6 mouse strain, we found that the incidence of lung metastasis was greatly reduced in the LPA5KO mice compared to WT, LPA1KO, and LPA2KO mice, respectively. In addition, we found that the selective inhibitor of LPA1&3, Ki16425 also reduced lung metastasis, suggesting that inhibition of LPA5 and LPA1 receptors in the target tissues may prevent cancer metastasis. B16 melanoma cells predominantly express LPA5 receptor. These cells do not invade across a matrigel layer in response to LPA. We found that siRNA knockdown of LPA5 receptors in B16 melanoma cells relieves this inhibition and resulted in an increase in invasion. These results suggest that the LPAR, in particular LPA5 receptors in tumor and stromal cells may play different roles in invasion and metastasis.
Citation Format: Gabor Tigyi, Yuko Fujiwara, SueChin Lee, Jianxiong Liu, Renukadevi Patil, Renuka Gupte, Duane D. Miller, Tamas Oravecz, Louisa Balazs. Targeting ATX and LPA receptors melanoma invasion and metastasis. [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 3884. doi:10.1158/1538-7445.AM2013-3884
Abstract 3885: FXR is implicated in matrix metalloproteinases regulation, tumor invasion and metastasis in breast cancer.
Authors: Alasmael Noura , Meira Lisiane B. , Swales Karen , Plant Nick 
Published: August 2014

Abstract
Metastatic breast cancer is a principle cause of female mortality. In general, metastatic cancers show poor response to current treatments and therefore the development of new therapies is essential. Metastasis is a multi-step process where cancer cells migrate from the primary tumour to other distant organs. For this to occur, degradation of the extracellular matrix is required, allowing cancer cells to invade the vasculature and migrate to distant sites. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that breakdown the extracellular matrix, with increased expression of MMP-2 and -9 associated with metastatic breast cancer. MMP activity is tightly regulated by the tissue inhibitors of metalloproteinases (TIMPs): TIMP-1 inhibits MMP-9 activity while TIMP-2 inhibits MMP-2 activity. Studies have shown that the nuclear receptor Farnesoid X-receptor (FXR) is involved in regulation of MMP and TIMP activity in hepatic and vascular tissues. As FXR is highly expressed in metastatic breast cancer, the aim of the current study was to investigate whether FXR is a novel regulator of MMP-2 and -9 in breast cancer cells. The viability of the breast cancer cell lines MCF7 (Estrogen receptor positive) and MDA-MB-468 (Estrogen receptor negative) was measured after exposure to the FXR agonists chenodeoxycholic acid (CDCA) and 3-[2-[2-Chloro-4-[[3-(2, 6-dichlorophenyl)-5-(1-methylethyl)-4 isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064). In both cases, these FXR ligands caused cell death in both cell lines, with reduction of cell viability being significantly higher in the triple negative MDA-MB-468 cells. mRNA and protein levels of MMP-2 and -9 within both cell lines did not change after FXR activation, as measured by real time PCR and Western blotting. However, GW4064 did increase secreted MMP activity, as measured by a fluorescent substrate, in a concentration dependent manner, whereas CDCA had no effect. Such data suggests that while FXR ligands may be cytotoxic to breast cancer cells, they may also increase the risk of invasion and metastasis.
Citation Format: Noura Alasmael, Lisiane B. Meira, Karen Swales, Nick Plant. FXR is implicated in matrix metalloproteinases regulation, tumor invasion and metastasis in 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 3885. doi:10.1158/1538-7445.AM2013-3885
Abstract 389: The functional relevance of decreased ANGPTL4 in human urinary bladder cancer.
Authors: Cardenas Eduardo , Horton Tiffani , Ghosh Rita 
Published: August 2014

Abstract
Transitional cell carcinoma is the most common urothelial cancer in the US. Current therapeutic options have been unable to overcome issues with the highly recurrent nature of this tumor, which requires frequent follow-up making urinary bladder cancer, one of the most expensive solid tumors to manage. Microarray-based gene expression analysis in response to capsaicin treatment identified significant upregulation of angiopoietin-like 4 (ANGPTL4) compared with solvent-treated bladder cancer cells. The focus of this study was to determine the functional relevance of ANGPTL4 in normal urothelial and bladder cancer cells. The microarray data was validated in a panel of normal, immortalized and bladder cancer cells of increasing stage by real-time qPCR, immunoblotting, and ELISA. To determine the possible function of ANGPTL4, we knocked down and overexpressed ANGPTL4 in normal urothelial and bladder cancer cells respectively. The role of ANGPTL4 in growth, proliferation and angiogenesis was assessed. Our results show that normal urothelial cells have significantly higher levels of ANGPTL4 when compared to non-tumorigenic and bladder cancer cells. Upon capsaicin treatment ANGPTL4 levels increased in all cell lines tested. Overexpression of ANGPTL4 in the metastatic cell line TCCSUP, led to decrease in cell growth. Further, ANGPTL4 knockdown increased cell growth in the normal urothelial cell line. Capsaicin treatment decreased the expression of VEGF in bladder cancer cell lines UMUC-3 and T24 as well as reduced expression in normal urothelium, albeit initial results in ANGPLT4-knockdown in normal urothelium indicates no change in VEGF expression. Our results thus far suggest that the loss of ANGPTL4 expression may be involved in bladder cancer. The mechanism involved is under investigation. Capsaicin remains an attractive compound for further studies in bladder cancer. Supported by RO3 CA136058 (RG) and NIHT32 T32CA148724 (EC).
Citation Format: Eduardo Cardenas, Tiffani Horton, Rita Ghosh. The functional relevance of decreased ANGPTL4 in human urinary bladder 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 389. doi:10.1158/1538-7445.AM2013-389
Abstract 3891: Hornerin: a novel, non-VEGF mediated human tumor angiogenic protein.
Authors: Seaman Marc E. , Kelly Kimberly A. 
Published: August 2014

Abstract
Angiogenesis is vital to the growth, progression and ultimately metastasis of tumors. As such, many therapies have attempted to eradicate tumors through anti-angiogenic strategies. Most current and past preclinical and clinically approved therapies focus on the vascular endothelial growth factor (VEGF) pathway. Unfortunately, these VEGF therapies have not shown much success, leading oncologists and scientists to become pessimistic about the usefulness of targeting angiogenesis as an anti-tumor strategy. Compensatory pathways may explain the lack of efficacy. Therapies against novel and/or non-VEGF proteins could hold the key to effective anti-angiogenic cancer therapies. Therefore, we used an in vivo phage display screen to find new, non-VEGF mediated angiogenic proteins. After phage selection, non-VEGF binding phage clones were identified by screening on human umbilical vein endothelial cells (HUVEC) treated with tumor conditioned media, VEGF conditioned media or vehicle control. Those that bound tumor conditioned media, but not VEGF conditioned media were selected for binding partner identification via functional proteomics pioneered in our lab. The binding partner of one clone was identified as hornerin, a previously unknown player in tumor angiogenesis.
Subsequent validation of hornerin by mRNA expression, immunocytochemistry and immunohistochemistry showed that hornerin was indeed not induced by VEGF. Hornerin expression was 7-fold more in resected human PDAC tumor vasculature than adjacent normal pancreatic vasculature. Interestingly, hornerin expression was also detected in tumor cells of resected human PDAC and 20 other types of tumors, providing a potential new biomarker of pancreatic and other cancers. A functional role in angiogenesis was confirmed by intratumoral injection of short siRNA against endothelial hornerin; treated tumor growth was static and tumor vessels displayed a more physiologic phenotype. Combination therapy consisting of siRNA against hornerin and a VEGF inhibitor (AV-951) produced additive reduction of tumor growth, consistent with the existence of separate and/or compensatory pathways.
The discovery of novel, non-VEGF mediated angiogenic proteins provides the potential to develop therapies that synergize with current anti-VEGF therapies. One such protein, hornerin was identified by our in vivo phage screen and shown to be functionally important in angiogenesis. Future studies include identifying the growth factor responsible for endothelial expression, understanding hornerin's mechanism and role in pathologic angiogenesis, and designing new therapeutic strategies.
Citation Format: Marc E. Seaman, Kimberly A. Kelly. Hornerin: a novel, non-VEGF mediated human tumor angiogenic protein. [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 3891. doi:10.1158/1538-7445.AM2013-3891
Abstract 3894: A high phosphate environment induces angiogenesis, which is mediated by FOXC2.
Authors: Lin Yiming , Garneys Laura M. , Bennett Kelly E. , Beck George R. 
Published: August 2014

Abstract
Inorganic phosphate is a common dietary element that is critical to the human body on many levels however the effects of changes in serum phosphate on cell and tissue behavior are not well understood. Due, in part, to the increased consumption of processed foods, the amount of inorganic phosphate in the American diet continues to rise above levels already considered high by the FDA. There is a growing appreciation that changes in serum phosphate levels influence pathological states associated with aging such as cancer, bone metabolism, and cardiovascular function, even in individuals with normal renal function. The causes are only beginning to be elucidated but are likely a combination of endocrine, paracrine, autocrine, and cell autonomous effects. Recent studies in mice have demonstrated that a diet high in phosphate, relative to a reduced phosphate diet, increases tumorigenesis in the two-stage skin carcinogenesis model as well as the Kras lung cancer model. Using cell cultures models we have determined that high phosphate results in increased proliferation and transformation as measured by XTT, cell counts, soft agar and focus formation assays. Our in vitro studies have also identified specific signaling cascades induced by elevated extracellular phosphate which result in the temporal and dynamic regulation of hundreds of phosphate responsive genes. A subset of the Pi-responsive genes including the Forkhead box protein C2 (FOXC2), osteopontin (spp1), Cyr61, and Vegf among others, has been previously linked to stimulation of angiogenesis leading to the hypothesis that conditioned medium from phosphate treated cells would increase angiogenesis. We confirmed the phosphate-induced expression of these genes in a number of cancer cells including breast, colon, and lung. The increased expression of these genes was determined to be dependent on phosphate transport as well as FGF receptor and ERK1/2 signaling. Using human umbilical cord vascular endothelial cells (HUVECs) we determined that, in fact, conditioned medium from these phosphate treated cancer cells increased both migration and tube formation in the HUVEC model. Knockdown of FOXC2 inhibited phosphate induced gene expression in cancer cells as well as eliminating the stimulation of HUVEC migration in response to Pi-treated cancer cell conditioned medium. These results suggest that a cellular environment with elevated phosphate promotes multiple aspects of tumorigenesis including angiogenesis.
Citation Format: Yiming Lin, Laura M. Garneys, Kelly E. Bennett, George R. Beck. A high phosphate environment induces angiogenesis, which is mediated by FOXC2. [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 3894. doi:10.1158/1538-7445.AM2013-3894
Abstract 3898: Glioma stem cells promote brain endothelial cell motility: a new mechanism for the direct interaction of glioma stem cells with endothelial cells.
Authors: Burgett Monica E. , Huang Ping , Tipps Russell S. , Vasanji Amit , Lathia Justin D. , Li Meizhang , Bao Shideng , Rich Jeremy N. , Gladson Candece L. 
Published: August 2014

Abstract
Angiogenesis, the development of a neovasculature, is a key histologic feature of malignant glioma. It occurs through multiple mechanisms, including sprouting and migration of existing endothelial cells (ECs), and is driven by signals in the microenvironment. Glioma stem cells (GSC) inhabit a region near ECs (perivascular niche). Here we examined the hypothesis that GSCs interact directly with ECs and promote EC motility. In 4 of 5 glioblastoma biopsies we found that ∼40% of GSCs were localized within 25 μm of ECs, based on double-labeling for Sox2 and vWf. We then examined the effect of GSCs on EC motility when plated on a 2D laminin substrate, and found a significant increase in EC motility in the presence of GSCs as well as a direct interaction. In a 3D assay, EC migration was enhanced by GSC-conditioned media, but the physical presence and interaction between ECs and GSCs further increased EC migration through a laminin-coated, 3-μm pore filter, as compared to GSC-conditioned media. Integrin αvβ3 and L1CAM have been reported to be upregulated on ECs and GSCs, respectively, in GBM tumors, and integrin αvβ3 can bind the RGD-peptide in L1CAM. We examined the effect of blocking or downregulating integrin αvβ3 or L1CAM on EC interaction with GSCs. In a cell-cell binding assay, blocking or downregulating the integrin β3 subunit significantly inhibited EC-GSC direct contact, as did an RGD peptide and an antibody to L1CAM. Furthermore, downregulation of integrin β3 on ECs significantly reduced EC migration in the presence of GSCs in the transwell migration assay and reduced EC association with GSCs in mouse brain slices in organotypic culture, analyzed by 2-Photon-LSM. These data suggest GSCs promote angiogenesis in part by promoting EC motility, and that the EC-GSC direct interaction mediated by integrin αvβ3 on ECs and L1CAM on GSCs also stimulates EC motility.
Citation Format: Monica E. Burgett, Ping Huang, Russell S. Tipps, Amit Vasanji, Justin D. Lathia, Meizhang Li, Shideng Bao, Jeremy N. Rich, Candece L. Gladson. Glioma stem cells promote brain endothelial cell motility: a new mechanism for the direct interaction of glioma stem cells with endothelial 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 3898. doi:10.1158/1538-7445.AM2013-3898
Abstract 3904: uPAR-regulated nuclear translocation of hand-1 mediates vascular radiosensitivity in medulloblastoma tumors.
Authors: Asuthkar Swapna , Velpula Kiran Kumar , Nalla Arun Kumar , Gogineni Venkateswara Rao , Dasari Venkata Ramesh , Gorantla Bharathi , Rao Jasti S. 
Published: August 2014

Abstract
Urokinase-type plasminogen activator (uPAR) is overexpressed in the tumor-stromal invasive microenvironment in many human cancers including medulloblastoma. The role of uPAR in tumor progression and angiogenesis has been well characterized. Most recently, in medulloblastoma cells, we showed that ionizing radiation (IR)-induced uPAR is a potent activator of cancer stem cell (CSC)-like properties and is associated with various transcription factors that are involved during embryonic development and cancer. In this study, we show that the uPAR protein is a cytoplasmic sequestration factor for a novel basic helix-loop-helix (bHLH) transcription factor, Hand-1. The Hand-1 protein plays an essential role in differentiation of trophoblast giant cells and cardiac morphogenesis, and yet its precise cellular function and its contributions to cancer remain mostly unknown. In the present study, we observed that Hand-1 protein is upregulated in uPAR shRNA-treated medulloblastoma cells and accompanies sustained cell growth and angiogenesis. Furthermore, IR-induced uPAR overexpression negatively regulates Hand-1 activity and results in the stabilization of angiogenesis promoting molecules, such as HIF-1 alpha. Finally, uPAR overexpression and its association with Hand-1 after IR treatment indicate that uPAR is capable of regulating Hand-1 and that uPAR has a role in the process of IR-induced tumor angiogenesis.
Citation Format: Swapna Asuthkar, Kiran Kumar Velpula, Arun Kumar Nalla, Venkateswara Rao Gogineni, Venkata Ramesh Dasari, Bharathi Gorantla, Jasti S. Rao. uPAR-regulated nuclear translocation of hand-1 mediates vascular radiosensitivity in medulloblastoma tumors. [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 3904. doi:10.1158/1538-7445.AM2013-3904