bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2812: Macrophage Migration Inhibitory Factor (MIF) regulates monocytic MDSC abundance to contribute to tumor growth and metastasis.
Authors: Simpson Kendra D. , Templeton Dennis J. , Cross Janet V. 
Published: August 2014

Abstract
The inflammatory cytokine, Macrophage Migration Inhibitory Factor (MIF) is a critical mediator of numerous inflammatory disease processes. In addition, MIF is overexpressed in many cancers and the degree of expression correlates with tumor aggressiveness. We identified MIF as a target for inhibition by sulforaphane (SFN), a cancer chemopreventive agent prevalent in broccoli. Based on this observation and the correlation between MIF expression and poor prognosis in human patients, we set out to determine how MIF might contribute to tumor growth and progression.
We hypothesized that, as an inflammatory cytokine, MIF may regulate the interaction between the tumor and the host immune response, rather than impacting an intrinsic property of the tumor cells. We are exploring these questions using the syngeneic 4T1 model of breast carcinoma. This model recapitulates many aspects of human breast tumor progression, including spontaneous metastasis from the mammary fat pad to similar target organs. We found that MIF expression in the tumor cells increases tumor growth and metastasis in an orthotopic tumor model. Importantly, the MIF dependent growth differences are only manifested in vivo, as the MIF depleted cell line is not compromised in growth or colony formation in vitro, suggesting that MIF may be contributing to the interaction between the tumor and the host immune response. This was confirmed by demonstrating that MIF depleted and MIF containing tumors exhibit similar growth and metastasis properties in immunodeficient animals. Evaluation of the immune cell infiltrates in the MIF containing and MIF deficient tumors reveal that the abundance of monocytic MDSC within the tumor is dependent on MIF expression. Finally, we demonstrate that depletion of MDSCs abolishes the impact of MIF on tumor growth, suggesting that these cells are critical for MIF to mediate its effects. We are currently exploring the mechanisms by which MIF controls the abundance of monocytic MDSCs in the tumor microenvironment and how this relates to promotion of tumor metastasis. Our work establishes MIF as a potentially valuable therapeutic target in tumor metastasis and supports a potential alternative mechanism for chemoprevention in which SFN may target the inflammatory tumor microenvironment through inhibition of this cytokine.
Citation Format: Kendra D. Simpson, Dennis J. Templeton, Janet V. Cross. Macrophage Migration Inhibitory Factor (MIF) regulates monocytic MDSC abundance to contribute to tumor growth 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 2812. doi:10.1158/1538-7445.AM2013-2812
Abstract 2819: Role of endothelin 3 in melanoma progression and metastasis.
Authors: Chin Nikeisha L. , Gallegos Juan Carlos , Cruz Rosy , Garcia Ruslan , Gonzalez Andrea , Borobia Manuel , Kos Lidia 
Published: August 2014

Abstract
G-protein coupled receptors have been identified as important factors in melanoma progression including growth and proliferation of tumorigenic cells, as well as facilitating metastasis. Upregulation of the G-protein coupled receptor Endothelin receptor b (Ednrb) and its ligand Endothelin 3 (Edn3) has been implicated in melanoma progression in several ‘in vitro’ experiments. In this study we investigated the putative role of Edn3 over-expression in melanoma progression in vivo. Tg(Grm1) Epv mice over-expressing metabotropic glutamate receptor 1 (Grm1) under the Dopachrome tautomerase promoter that spontaneously produce melanocytic lesions in the ears and tails with limited metastatic capability, were crossed with transgenic mice that over-express Edn3 under the keratin 5 promoter (K5-Edn3). The Tg(Grm1)Epv/K5-Edn3 mice tumors appeared ∼ 3 months earlier and grew at a rate 3-4 times faster than the Tg(Grm1)/Epv control mice. Ninety-five percent of Dct-Grm1/ K5-Edn3 mice also displayed pigmented lesions in distant organs such as the lungs. Real Time PCR analysis showed higher expression levels of angiogenic related genes such as Hif-1α in the Dct-Grm1/K5-Edn3mice, when compared to controls. Our studies demonstrate that Edn3 over-expression enhances melanoma progression to a fully malignant state. Our preliminary data also suggests that Edn3 may be involved in tumor angiogenesis leading to faster melanoma tumor development.
Citation Format: Nikeisha L. Chin, Juan Carlos Gallegos, Rosy Cruz, Ruslan Garcia, Andrea Gonzalez, Manuel Borobia, Lidia Kos. Role of endothelin 3 in melanoma progression 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 2819. doi:10.1158/1538-7445.AM2013-2819
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2828: miR-19a-3p inhibits breast carcinoma metastasis via reversing M2 phenotype of TAMs.
Authors: Yang Jian , Li Na , Zhang Zhuhong , Si Qin , Chen Chong , Liu Yan , Reisfeld Ralph A. , Sun Peiqing , Stupack Dwayne , Xiang Rong , Luo Yunping 
Published: August 2014

Abstract
Tumor-associated macrophages (TAMs), most of which exhibit M2 phenotype, function as immunosuppressive cells in tumor microenvironment (TME). Polarization of TAMs from a pro-immune (M1 like) phenotype to an immune-suppressive (M2-like) phenotype is one of the hallmarks of malignancy, but their molecular basis is still remains unknown. It has been reported that microRNAs are involved in monocyte-macrophage differentiation. In this study, we found that miR-19a-3p, broadly conserved in vertebrate, could reverse the M2 phenotype of RAW macrophage cells. When mouse breast tumor cells such as 4T1, 4TO7 and EMT6 were co-cultured with RAW macrophage cells which over express miR-19a-3p, the invasion capacity was suppressed. Meanwhile, when the conditional medium of RAW cells which were transfected with miR-19a-3p mimic was added into culturing medium of tumor cells, the migration capacity of 4T1 and EMT6 breast cancer cells was inhibited. Moreover, when miR-19a-3p was injected intratumor, consistent with the in vitro experiments, we found that the M2 phenotype of TAMs was suppressed significantly. Although 4T1 xengraft breast tumor growth was not affected by miR-19a-3p, lung metastasis of tumor cells was significantly suppressed. Taken together, our findings indicate that miR-19a-3p is down-regulated in M2 phenotype RAW macrophage and TAMs in TME. The low expression of miR-19a-3p plays an important role in inducing M2 macrophage polarization and promoting migration and invasion capacity and metastasis.
Citation Format: Jian Yang, Na Li, Zhuhong Zhang, Qin Si, Chong Chen, Yan Liu, Ralph A. Reisfeld, Peiqing Sun, Dwayne Stupack, Rong Xiang, Yunping Luo. miR-19a-3p inhibits breast carcinoma metastasis via reversing M2 phenotype of TAMs. [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 2828. doi:10.1158/1538-7445.AM2013-2828
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2829: Patient-derived primary melanoma cells that differentially express melano-specific antigens as a model for vaccines.
Authors: Suriano Robert , George Andrea L. , Rajoria Shilpi , Geliebter Jan , Tiwari Raj K. , Wallack Marc 
Published: August 2014

Abstract
Transformation of pigment producing melanocytes into melanoma is a complex multi-step process involving the generation and/or over expression of various immunotherapeutic antigens. Several of these melanoma associated antigens (MAAs) are directly involved in melanin biosynthesis and melanosome biogenesis. The precise contribution of proteins involved in melanin synthesis to the MAA associated immune response is poorly understood. To this end, we have developed primary cell lines from human patients and xenograft models to analyze melanin synthesis and antigen expression. In vitro, from the perspective of melanin production, these primary cell lines express essential proteins associated with melanin synthesis, namely tyrosinase, Trp-1, Trp-2, and gp100, all of which are immunotherapeutic targets in melanoma. When grafted in nude mice, these cell lines were capable of producing solid pigmented tumors in vivo. However, three out of the five cell lines that produced melanin in vivo failed to produce melanin in vitro, even when cultured with supplementation of either α-melanocyte stimulating hormone (MSH), basic fibroblast growth factor (bFGF), or matrigel. Despite expression of tyrosinase, Trp-1, Trp-2, and gp100, two of the five cell lines failed to grow in nude mice or produce melanin in vitro. These patient derived primary cells and xenografts were also analyzed for expression of various other significant MAAs, which included MART-1 (Melan-A), MAGE-A1, and NY-ESO-1 as well as antigens not classified as MAAs but essential for tumor progression such as CD71 (transferring receptor) and CD146 (MCAM or melanoma cell adhesion molecule). All of the antigens analyzed in our cell lines, such as gp100, NY-ESO-1, MART-1, MAGE-A1, have been the targets of clinical trials but our results clearly indicate that these antigens are differentially expressed by our primary melanoma cells. Therefore, we believe that in order to develop a clinically effective immunotherapeutic vaccine, multiple cell lines expressing a combination of melano-specific antigens and a repertoire of MAAs that allows for minimal immune evasion may be necessary. To this end, we are exploring a vaccinia virus antigen retrieval technology, which incorporates multiple primary cell lines to develop such a pan-antigen melanoma vaccine.
Citation Format: Robert Suriano, Andrea L. George, Shilpi Rajoria, Jan Geliebter, Raj K. Tiwari, Marc Wallack. Patient-derived primary melanoma cells that differentially express melano-specific antigens as a model for vaccines. [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 2829. doi:10.1158/1538-7445.AM2013-2829
Abstract 2831: Induction of CXCL9/Mig expression in the tumor microenvironment promotes protective antitumor immune responses.
Authors: Gorbachev Anton , Kish Danielle , Fairchild Robert 
Published: August 2014

Abstract
Despite intense efforts to design immunotherapeutic strategies, the success of cancer immunotherapy remains extremely limited. Major factors limiting immune responses to tumors include insufficient activation of tumor-reactive effector T cells, poor intra-tumor recruitment of effector T cells, and/or suppression of their functions within the tumor. One mediator involved in effector T cell activation and recruitment to inflammatory sites is the T cell chemoattractant chemokine CXCL9/Mig. Our recent studies in murine models of aggressive skin cancer (cutaneous sarcoma and melanoma) have indicated that these tumors cease the production of CXCL9/Mig as a result of immunoediting mediated by T cells and IFN-g. The consequence of Mig deficiency in the tumor microenvironment is the increased resistance of immunoedited Mig-deficient tumor variants to T cell-mediated immunity. Here we demonstrated that inducing constitutive expression of Mig within Mig-deficient tumors by delivery of Mig-encoding retroviral vector promotes protective anti-tumor immune responses and results in rejection of cutaneous tumors. This modulation of intra-tumor Mig expression induced potent tumor-specific CD4 and CD8 T cell-mediated responses capable of complete tumor elimination and subsequent protection to tumor re-challenge. Furthermore, the delivery of Mig-overexpressing tumor cells as a vaccine into mice with established cutaneous tumors induced systemic anti-tumor immune responses that suppressed growth of established tumors. This therapeutic effect correlated with the presence of dendritic cells (DC) in the tumor-draining lymph nodes (TDLN) that were very potent in the activation of tumor antigen-specific IFN-g producing T cells. These results suggest that besides the recruitment of effector T cells into the tumor, tumor-derived Mig enhances activation of these T cells possibly by affecting tumor-infiltrating DC that acquire tumor antigens and then migrate into TDLN to prime tumor-specific effector T cells. Therefore, Mig might be a potent component of vaccines aimed to boost anti-tumor immunity in patients with aggressive skin cancers deficient in the expression of this chemokine.
Citation Format: Anton Gorbachev, Danielle Kish, Robert Fairchild. Induction of CXCL9/Mig expression in the tumor microenvironment promotes protective antitumor immune responses. [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 2831. doi:10.1158/1538-7445.AM2013-2831
Abstract 2839: NK cell response and tumor debulking are associated to prolonged survival in recurrent glioblastoma treated by dendritic cells loaded with autologous tumor lysate.
Authors: Pellegatta Serena , Eoli Marica , Frigerio Simona , Antozzi Carlo , Bruzzone Maria Grazia , Cantini Gabriele , Nava Sara , Anghileri Elena , Cuppini Lucia , Cuccarini Valeria , Ciusani Emilio , Dossena Marta , Pollo Bianca , Mantegazza Renato , Parati Eugenio A. , Finocchiaro Gaetano 
Published: August 2014

Abstract
Recurrent glioblastoma (GB) are highly aggressive tumors allowing 6-8 month survival. Here we evaluated the possible benefits of immunotherapy with mature dendritic cells (DC) loaded with autologous tumor lysate in 15 patients with recurrent GB. After a median follow-up of 8 months median progression free survival (PFS) was 4.4 months and median overall survival (OS) 8.0 months. Patients with small tumors at first vaccination (&lt; 20 cc; n = 8) had significantly longer PFS and OS than others: 6.0 vs 3.0 months (p = 0.01) and 16.5 vs 7.0 months (p = 0.003), respectively. Patients were analysed for CD8+ T cells, CD56+ NK cells and other relevant immunological parameters in peripheral blood before and after immunization, defining a vaccination/baseline ratio (V/B ratio). Increased V/B ratio of NK but not CD8+ T cells was significantly associated to longer PFS and OS. Patients showing NK cell responses had higher levels of IFN-γ and E4BP4, the NK cell transcription factor. Furthermore, NK V/B ratio was inversely correlated with TGF-β2 and VEGF V/B ratio. The results suggest that tumor-loaded DC may increase survival of recurrent GB after effective tumor debulking and emphasize the role of NK cell responses in this therapeutic setting.
Citation Format: Serena Pellegatta, Marica Eoli, Simona Frigerio, Carlo Antozzi, Maria Grazia Bruzzone, Gabriele Cantini, Sara Nava, Elena Anghileri, Lucia Cuppini, Valeria Cuccarini, Emilio Ciusani, Marta Dossena, Bianca Pollo, Renato Mantegazza, Eugenio A. Parati, Gaetano Finocchiaro. NK cell response and tumor debulking are associated to prolonged survival in recurrent glioblastoma treated by dendritic cells loaded with autologous tumor lysate. [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 2839. doi:10.1158/1538-7445.AM2013-2839
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 284: Down-regulated Kruppel-like factor 4 induces the migration and epithelial-mesenchymal transition in human hepatoma cells.
Authors: Sung Ming-Ta , Lee Hsin-Chen , Hsia Cheng-Yuan , Chi Chin-Wen 
Published: August 2014

Abstract
The transcriptional factor Kruppel-like factor 4 (KLF4) plays important roles in development, stemness, and tumorigenesis. Several studies have suggested that KLF4 is important in various tumors; however limited information is available on the detailed function of KLF4 in hepatocellular carcinoma. The objective of this study was to examine the functional roles of KLF4 in metastasis of hepatoma cells. In order to investigate the role of KLF4 in the progression of hepatocellular carcinoma, we used lentiviral transduction method to down-regulate KLF4 expression in Hep3B and HA22T/VGH hepatoma cell lines. The effects of KLF4 on cell migration, invasion and the expression of epithelial-mesenchymal transition (EMT) related proteins were evaluated in KLF4-knockdown hepatoma cells. Transwell migration assay and matrigel invasion assay revealed the migration and invasion abilities were significantly increased in KLF4-knockdown Hep3B or HA22T/VGH cells. Knockdown KLF4 in hepatoma cells resulted in decreased mRNA and protein expression of E-cadherin, and a concomitant increase of vimentin, MMP2 and MMP9. These results corresponded well with our finding that overexpression of KLF4 in Mahlavu hepatoma cells led to significant inhibition of cell migration and invasion through up-regulating E-cadherin and down-regulating vimentin, MMP2 and MMP9. Snail and Bmi1, repressors of E-cadherin gene expression, were also markedly decreased in KLF4-overexpressing Mahlavu cells. Therefore, these results together suggested that KLF4 is tightly involved in the epithelial-mesenchymal transition and metastasis in the tumor progression of hepatocellular carcinoma.
Citation Format: Ming-Ta Sung, Hsin-Chen Lee, Cheng-Yuan Hsia, Chin-Wen Chi. Down-regulated Kruppel-like factor 4 induces the migration and epithelial-mesenchymal transition in human hepatoma 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 284. doi:10.1158/1538-7445.AM2013-284
Abstract 286: Cucurbitacin B inhibits epithelial-to-mesenchymal transition in breast cancer cells through Snail downregulation.
Authors: Gupta Parul , Srivastava Sanjay K. 
Published: August 2014

Abstract
Metastasis is a primary cause of about 90% of cancer related deaths worldwide. It is associated with epithelial to mesenchymal characteristics transition (EMT), which helps in attaining migratory phenotype by tumor cells. Cucurbitacin B (CuB), a triterpenoid steroidal compound has been shown to suppress JAK/STAT3 signaling and cause G2/M arrest in cancer cells. However, the role of CuB as an anti-metastatic agent still remains to be elucidated. In the present study, we investigated the effects of CuB on EMT in breast cancer cells. These cells are known to exhibit significant mesenchymal properties that endow aggressive nature. Our results show that CuB significantly suppressed cell migration of MDA-MB-231 cells in wound healing assay. In addition, we also observed reduced cell invasion with CuB treatment using transwell invasion assay. To elucidate the mechanism of these effects, western blotting was performed using whole cell lysates from CuB treated MDA-MB-231 cells. We observed significantly reduced expression of snail and twist with CuB treatment. Snail and twist are known to be repressors of E-cadherin. Generally upregulation of snail and twist mark the initiation of EMT, and eventually leads to loss of epithelial signature of cells. Furthermore, with CuB treatment upregulation of E-cadherin was observed. Transforming growth factor β is known to induce EMT in malignant breast cancer cells. We further investigated the role of CuB on TGFβ induced EMT. Interestingly, we observed that TGFβ induced snail expression was reversed by CuB in MDA-MB-231 cells. Moreover, CuB treatment also contributed protection to the loss of E-cadherin caused by TGFβ treatment. Taken together our results indicate reversal of EMT by CuB treatment in breast cancer cells, which lead to suppression of metastasic ability. However, further in vitro and in vivo mechanistic studies are under progress. [Supported in part by R01 grant CA129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: Parul Gupta, Sanjay K. Srivastava. Cucurbitacin B inhibits epithelial-to-mesenchymal transition in breast cancer cells through Snail downregulation. [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 286. doi:10.1158/1538-7445.AM2013-286
Abstract 2861: A novel negative regulation principle between DAPK and STAT3 in inflammation-associated carcinogenesis.
Authors: Chakilam Saritha , Gandesiri Muktheswar , Rau Tilman , Neufert Clemens , Agaimy Abbas , Mahadevan Vijayalakshmi , Ivanovska Jelena , Wirtz Ralph , Benderska Natalya , Schulze-Lührmann Jan , Wittkopf Nadine , Chellappan Ajithavalli , Ruemmele Petra , Vieth Michael , Rave-Fränk Margret , Christiansen Hans , Hartmann Arndt , Atreya Raja , Becker Christoph , Steinberg Pablo , Schneider-Stock Regine 
Published: August 2014

Abstract
It has been shown that the TNF-IL-6-STAT3 pathway plays a crucial role in promoting ulcerative colitis associated carcinoma (UCC). As inflammation compromises gut homeostasis and is associated with cancer progression, it is important to understand the role of key signalling molecules that are involved in the activation of the inflammatory cascade. Interestingly, we found that intestinal epithelial cells (IEC) of UCC in comparison to ulcerative colitis (UC) show high expression level of the anti-inflammatory Death associated protein kinase (DAPK) but only low levels of pSTAT3. Accordingly, epithelial DAPK expression was enhanced in STAT3IEC-KO mice. To unravel a possible regulatory mechanism we used an in vitro model of TNF-treated IEC. We identified a new function of DAPK in suppressing TNF-induced STAT3 activation as DAPK si knockdown and treatment with a DAPK inhibitor potentiated STAT3 activation and IL-6 secretion. DAPK attenuated STAT3 activity directly by physical interaction shown in a 3D structural model. This model suggests that DAPK induced conformational changes in the STAT3 dimer masked its nuclear localization signal. Vice versa, pharmacologic inactivation of STAT3 led to an increase in DAPK mRNA and protein levels. Chromatin immunoprecipitation data showed that STAT3 restricted DAPK expression by promoter binding, thereby reinforcing its own activation by inducing IL-6. This novel negative regulation principle was confirmed in an AOM-DSS-colon carcinogenesis mouse model. It might balance TNF-induced inflammation and seems to play an important role in the inflammation-associated transformation process. DAPK as a negative regulator of STAT3 emerges as therapeutic option in the treatment of UC and UCC.
Citation Format: Saritha Chakilam, Muktheswar Gandesiri, Tilman Rau, Clemens Neufert, Abbas Agaimy, Vijayalakshmi Mahadevan, Jelena Ivanovska, Ralph Wirtz, Natalya Benderska, Jan Schulze-Lührmann, Nadine Wittkopf, Ajithavalli Chellappan, Petra Ruemmele, Michael Vieth, Margret Rave-Fränk, Hans Christiansen, Arndt Hartmann, Raja Atreya, Christoph Becker, Pablo Steinberg, Regine Schneider-Stock. A novel negative regulation principle between DAPK and STAT3 in inflammation-associated carcinogenesis. [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 2861. doi:10.1158/1538-7445.AM2013-2861
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.