bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4957: Keratin 13 drives the dissemination of bone and brain metastases of human prostate and breast cancer cells
Authors: Yin Lijuan , Li Qinlong , Huang Jen-Ming , Lewis Michael , Garraway Isla P. , Li Quanlin , Bu Hong , Chung Leland W. K , Zhau Haiyen E. 
Published: July 2016

Abstract
Introduction and Objective: Bone and brain metastases are prevalent in human prostate and breast cancer patients. Keratin 13 (KRT13), a member of the intermediate filament proteins and an epithelial stem cell differentiation marker, induces cancer cell migration and progression toward increased malignant state. The objectives of this study are: 1) to determine KRT13 expression in human prostate and breast cancer and its clinical correlation; 2) to determine the functional cell signaling role of KRT13 in prostate and breast cancer cells using gene transfer technology.
Methods and Results: We evaluated KRT13 protein expression in primary prostate cancer tissues from 44 cases with well-documented overall survival by quantitative quantum dot immuno-labelling. We found that KRT13 expression in primary prostate cancer correlated with patient overall survival and bone metastasis (p&lt;0.05). We next evaluated KRT13 protein expression in 36 prostate and 58 breast cancer tissue specimens by immunohistochesmistry (IHC) and found that KRT13 is overexpressed in breast cancer bone (5/8) and brain (7/10) metastases and prostate cancer bone (6/12) metastasis specimens (p&lt;0.05). KRT13 expression in primary prostate and breast cancer specimens is associated with decreased patient overall survival based on our data as well as publicly available Oncomine gene expression datasets. To elucidate the mechanisms by which KRT13 promotes cancer invasion, migration and metastasis, we genetically overexpressed KRT13 in human prostate CWR22 Rv1 and LNCaP, and human breast MCF7 and MCF10A cells, with respectively high or low malignant potential. KRT13-overexpressing prostate and breast cancer cells increase differential expression of genes associated with epithelial to mesenchymal transition (EMT; E-Cadherin and Vimentin), stemness (Nanog), neuromimicry (Chromagranin A and Synaptophysin), osteomimicry (RANKL) related genes as analyzed by qRT-PCR, western blot, and IHC. KRT13 also promotes increased cancer cell proliferation, migration and invasion in vitro, and bone and brain metastases in vivo.
Conclusion: These results suggest that KRT13 drives prostate and breast cancer bone and brain metastases via osteomimicry and neuromimicry associated genes resulting in downstream cell signaling network convergence between EMT, stemness, cell growth, and survival pathways.
Funded in part by NCI-P01-CA098912
Citation Format: Lijuan Yin, Qinlong Li, Jen-Ming Huang, Michael Lewis, Isla P. Garraway, Quanlin Li, Hong Bu, Leland W. K Chung, Haiyen E. Zhau. Keratin 13 drives the dissemination of bone and brain metastases of human prostate and breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4957.
Abstract 5057: Mena at the nexus of chemotaxis and haptotaxis during tumor progression
Authors: Oudin Madeleine J. , Miller Miles A. , Kosciuk Tatsiana , Klazen Joelle , Lussiez Alisha , Lauffenburger Douglas , Bear James E. , Gertler Frank B. 
Published: July 2016

Abstract
Directed-cell migration is key step in the metastatic cascade, and multiple cues can promote local invasion. The most well studied mode of cell motility for metastasizing tumor cells is chemotaxis, the directional movement of cells attracted to a source of soluble cues. In contrast, haptotaxis, migration of cells on gradients of substrate-bound factors, remains poorly understood. Mena, an actin regulatory protein, plays an important role in cell motility and is upregulated in various cancers, driving migration in response to chemotactic and haptotactic cues. We have recently shown expression of the pro-metastatic isoform of Mena, MenaINV, increases sensitivity to growth factors (EGF, HGF and IGF) via dysregulation of the phosphatase PTP1B, as well as high concentrations of fibronectin (FN) via its interaction with the integrin α5β1. We hypothesized that MenaINV may also promote crosstalk between these two pathways to drive metastasis. First, we show that MenaINV-driven haptotaxis on FN gradients and FN-driven invasion requires crosstalk between α5β1 and EGFR. Indeed, we show evidence that MenaINV expression is associated high phosphorylation of EGFR in high FN environments in vitro and in human breast cancer databases. Second, we find that MenaINV promotes synergy between EGF and FN in vitro and in vivo, leading to hyper-invasive phenotypes that drive more invasion than which each cue alone. Finally, we show that MenaINV-driven haptotaxis, ECM reorganization and 3D invasion requires RCP-dependent recycling of α5β1 and EGFR. Together, our data demonstrate that MenaINV is a shared component of the machinery that mediates both haptotactic responses to FN and chemotactic responses to EGF, two pathways that promote tumor progression.
Citation Format: Madeleine J. Oudin, Miles A. Miller, Tatsiana Kosciuk, Joelle Klazen, Alisha Lussiez, Douglas Lauffenburger, James E. Bear, Frank B. Gertler. Mena at the nexus of chemotaxis and haptotaxis during tumor progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5057.
Abstract 5102: Heparan sulfate modifying enzymes deliver cancer, stromal and macrophage-produced heparin-binding growth factors in the prostate cancer microenvironment
Authors: Brasil Fabio H. , Ferrer Valeria , Navone Nora M. , Farach-Carson Mary C. , Carson Daniel D. 
Published: July 2016

Abstract
We previously showed that the heparan sulfate proteoglycan, perlecan (PLN)/HSPG2, is deposited into the matrix of reactive stroma surrounding tumors, where it concentrates heparin binding growth factors (HBGFs) and cytokines at the tumor-stromal border both in primary prostatic tumors and bone metastatic lesions. Heparan sulfate (HS) modifying enzymes produced in tumor-associated stroma play key roles in the delivery of these perlecan-sequestered cancer, stromal and tumor macrophage-produced HBGFs and cytokines, serving to enhance tumorigenesis and recruit other bystander cells to sites of metastasis. Studies presented here focused on the production of secreted HS-modifying enzyme heparanase and the two extracellular sulfatases, SULF1 and SULF2, in the prostatic tumor microenvironment. Our studies showed that SULF1 and heparanase mRNA levels are elevated in prostate cancer (PCa) cells of the LNCaP lineage in the presence of stroma, indicating that both stroma and PCa cells can be sources of these enzymes. We are presently examining a number of PCa patient derived xenografts to determine the prevalence of SULF-1 and heparanase elevation in castrate resistant disease. To study function, we developed a modified 3D hyaluronate gel system that contains HS-bearing recombinant perlecan domain I (PlnDI) to retain and deliver HBGFs and cytokines to various PCa cells cultured with bone marrow stromal cells, osteoblasts, or tumor macrophages. We are using this system to study the expression and individual functions of heparanase and the two SULFs in promoting HBGF-dependent PCa progression in a physiologically relevant system. Overexpression and gene deletion techniques allow us to determine the role that heparanase or SULFs play in each relevant cell type present in the tumor microenvironment, and thus determine the need for co-targeting of both tumor and reactive stroma. (Supported by NIH P01 and CAPES).
Citation Format: Fabio H. Brasil, Valeria Ferrer, Nora M. Navone, Mary C. Farach-Carson, Daniel D. Carson. Heparan sulfate modifying enzymes deliver cancer, stromal and macrophage-produced heparin-binding growth factors in the prostate cancer microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5102.
Abstract 5239: Preventive effects of pentoxifylline on hepatic tumorigenesis in a novel mouse model of NASH-related liver cancer
Authors: Shirakami Yohei , Maruta Akinori , Obara Koki , Ideta Takayasu , Miyazaki Tsuneyuki , Sakai Hiroyasu , Kochi Takahiro , Kubota Masaya , Tanaka Takuji , Shimizu Masahito , Seishima Mitsuru 
Published: July 2016

Abstract
Overweight and obesity are becoming more prevalent worldwide. As the hepatic manifestation of the metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have received attention as major causes of liver disorder. In addition, hepatocellular carcinoma (HCC) associated with NASH becomes an important issue. Although no standard medicinal treatment for NASH is established, pentoxifylline (PTX), a medicine used to improve circulation, is reported to ameliorate histopathological appearance of NASH and is thought to be a candidate therapeutic agent for NASH. In the present study, we investigated effects of PTX on NAFLD/NASH and the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in monosodium glutamate (MSG)-treated mice, a novel mouse model of NASH-related hepatocarcinogenesis, and db/db obese and diabetic mice. Male MSG and db/db mice were administered DEN, and then they received drinking water containing PTX (100 mg/kg/day) throughout the experiment. At sacrifice, drinking water with PTX significantly inhibited the development of hepatic pre-neoplastic lesions compared with respective control groups. MSG mice were thought to be susceptible to liver tumorigenesis. Hepatic triglyceride contents in db/db mice were decreased by PTX administration. The serum levels of total cholesterol, triglyceride, free fatty acid, and alanine aminotransferase were all decreased by PTX treatment, as was the mRNA expression of pro-inflammatory cytokines (TNF-alpha and IL-1beta) the macrophage-inducing chemokine CCL2/MCP-1, and several lipogenic genes (FASN and SREBP1c) in the liver. In vitro studies also revealed that PTX treatment decreased the expression of several genes associated with de novo lipogenesis and CCL2/MCP-1 in hepatoma and hepatic stellate cell lines, respectively. These findings suggest that PTX prevents NAFLD/NASH-related liver tumorigenesis by attenuating chronic hepatic inflammation and decreasing lipogenic gene expression in the liver. PTX might be a promising and efficient agent for treatment of NAFLD/NASH patients, who have a higher risk for developing liver cancer.
Citation Format: Yohei Shirakami, Akinori Maruta, Koki Obara, Takayasu Ideta, Tsuneyuki Miyazaki, Hiroyasu Sakai, Takahiro Kochi, Masaya Kubota, Takuji Tanaka, Masahito Shimizu, Mitsuru Seishima. Preventive effects of pentoxifylline on hepatic tumorigenesis in a novel mouse model of NASH-related liver cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5239.
Abstract 614: Cytotoxic activity of enantia chlorantha, nauclea latifolia, and citrus medica extracts on carcinoma cells
Authors: Alford Chenel M. , Onyejiaka Alexandra , Myles Elbert L. 
Published: July 2016

Abstract
Over 562,340 Americans are expected to die of cancer, more than 1500 people a day. Cancer is the second most common cause of death in the US, exceeded only by heart disease. In the US, cancer accounts for nearly 1 of every 4 deaths. Our study focuses primarily on three plants never before investigated for antitumor activity. They were chosen based upon native ethno medicinal usages. Indigenous primarily to the southwestern region of Nigeria; Enantia chlorantha, Nauclea latifolia, and Citrus medica have all been traditionally used and studies have proven their noteworthy antibacterial, antimicrobial, and anti parasitical activities. These important characteristics provide the rationale behind studying these plants further for potential antitumor agents. Experimental: Methanolic leaf and bark extracts in a series of concentrations were taken from the previously stated plants and exposed to two breast and two colorectal cancer cells for 24 hours. Growth analysis is determined using a cell viability indicator alamar blue and a florescent plate reader. Results: Enantia chlorantha and Citrus medica demonstrated the most potential for containing novel antitumor compounds. However, E. chlorantha proved to be exceedingly toxic to the cellular proliferation of all four tumors cell lines at all concentrations. In addition to this, Nauclea latifolia extracts illustrated the least potential for antitumor activity. In most cases this extract showed little or no effect in reducing cellular proliferation. Conclusion: We conclude that leaf extracts from E. chlorantha and C. medica should be studied further to characterize their antitumor potential, investigate their main active compounds, and to better understand their mechanisms of action.
Citation Format: Chenel M. Alford, Alexandra Onyejiaka, Elbert L. Myles. Cytotoxic activity of enantia chlorantha, nauclea latifolia, and citrus medica extracts on carcinoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 614.
Abstract 615: Scaffold-based perfusion bioreactor system for in vitro maintenance of primary breast cancer tissue microenvironment suitable for personalized medicine
Authors: Muraro Manuele Giuseppe , Muenst Simone , Mele Valentina , Quagliata Luca , Tzankov Alexandar , Weber Walter P. , Spagnoli Giulio C. , Soysal Savas D. 
Published: July 2016

Abstract
INTRODUCTION Two-dimensional (2D) in vitro culture systems and in vivo animal models are the primary tools used to test cancer cell responses to drugs but they are not suited for the development of immune-mediate therapies. Here we present an innovative method for in vitro culture primary breast cancer (BrCa) tissues in porous 3D scaffolds by using a perfusion-based bioreactor system (U-CUP).
MATERIALS & METHODS Freshly excised breast cancer specimens were fragmented and cultured in a 3D “sandwich-like format” between collagen porous scaffolds under perfusion flow. DMEM/F12, supplemented with 10% autologous human serum, was used as a culture medium. Malignant and non-malignant cells survival, expansion into the scaffold and the ability to recapitulate features of the original BrCa specimens were histologically assessed. For estrogen receptor (ER) positive tissues we tested the response to hormonal therapy by adding the anti-ER drug Fulvestrant. Furthermore, the maintenance of immune-infiltrating cells allowed testing immune blockade therapy in vitro using anti PD-L1 on PD-L1 positive samples. Response to treatment was evaluated by histology and qRT-PCR for markers of immune-response.
RESULTS By culturing BrCa using the U-CUP we were able to preserve viability and to promote the expansion of breast cancer cells from surgical specimens together with accompanying stromal and immune cells into the porous scaffold. Expanding cancer cells were viable after 21 days and recapitulating the initial histology with formation of glands. Administration of anti-ER treatment was associated with decreased expansion of cancer tissue into the scaffold after 21 days. After 7 days of anti PD-L1 antibody treatment we observed a reduced number of tumor cells due to the activation of infiltrating lymphocytes, as shown by increased expression of IFNg and decreased expression of IL10.
CONCLUSIONS The scaffold-based perfusion bioreactor represents a successful organotypic tumor model allowing in vitro long-term culture of breast cancer specimens. Our findings shed the light on a promising system for selecting personalized treatment based on a patient's tumor specific microenvironment.
Citation Format: Manuele Giuseppe Muraro, Simone Muenst, Valentina Mele, Luca Quagliata, Alexandar Tzankov, Walter P. Weber, Giulio C. Spagnoli, Savas D. Soysal. Scaffold-based perfusion bioreactor system for in vitro maintenance of primary breast cancer tissue microenvironment suitable for personalized medicine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 615.
Abstract 654: Impact of epithelial cell-specific deletion of mPGES-1 on colon carcinogenesis
Authors: Nakanishi Masako , Rosenberg Daniel W. 
Published: July 2016

Abstract
Activation of the COX-2/mPGES-1/PGE2 signaling axis is a hallmark of many cancers, including colorectal cancer (CRC), prompting the implementation of cancer prevention strategies targeting COX-2 activity. We have shown that targeting the downstream terminal PGE2 synthase, mPGES-1, specifically reduces inducible PGE2 formation without disrupting synthesis of other essential prostanoids. Additionally, global deletion of mPGES-1 (gKO) confers dramatic protection against intestinal cancer development in several mouse models, including the AOM+DSS inflammation-associated colon cancer model. Understanding the role of PGE2 under inflammatory conditions, however, is complicated by the diverse cellular sources and context-dependence of inducible PGE2. To clarify the relative contribution of inducible PGE2 synthesis within distinct cell compartments in colon, we have recently created an mPGES-1 conditional knockout mouse (cKO), where exon 3 of the mPGES-1 gene (mPtges) is floxed for tissue-specific Cre-mediated deletion. To test the role of epithelial-derived PGE2 synthesis on inflammation-associated cancer, we crossed the cKO mice with carbonic anhydrase 1 (Car1)-controlled Cre mice (cKO:Car1), thereby inactivating mPGES-1 function specifically within colonic epithelial cells. Based on our recent observation that global inactivation mPGES-1 sensitizes the colonic mucosa to direct environmental injury, we first examined the sensitivity of the cKO:Car1 mice to DSS-induced acute colitis. Two days after a five-day treatment with 0, 0.5 or 1% DSS, clinical signs of colitis, including the extent of colonic ulceration were determined. Both cKO:Car1 and cKO:WT control mice showed a comparable extent of colonic ulceration, covering ∼60% of the epithelial surface. We next examined the impact of epithelial-specific deletion of mPGES-1 on DSS-induced colon carcinogenesis. KO:Car1 and cKO:WT control mice were treated with a single injection of AOM (10 mg/kg bw) followed by five days of 0, 0.5 or 1% DSS, and colons were examined five weeks after the end of DSS treatment. Surprisingly, epithelial deletion of mPGES-1 in the cKO:Car1 mice failed to provide against cancer development in comparison to the cKO:WT mice. This is the first study to show that genetic inactivation of inducible PGE2 formation within a specific cell lineage (e.g. epithelial cells) does not affect both the extent of acute colonic inflammation nor subsequent inflammation-associated carcinogenesis.
Citation Format: Masako Nakanishi, Daniel W. Rosenberg. Impact of epithelial cell-specific deletion of mPGES-1 on colon carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 654.
Abstract 661: Establishment of transgenic mice with liver-specific BRAF V600E mutation
Authors: Tanaka Hiroki , Yamamoto Masahiro , Yamazaki Kosuke , Shimizu Keiko , Ogawa Katsuhiro 
Published: July 2016

Abstract
Diethylnitrosamine (DEN) is often used to induce hepatocarcinogenesis in rodents to investigate the pathogenesis of hepatocellular carcinoma (HCC). BrafV637E mutation, corresponding to the human BRAFV600E mutation, is highly frequent in DEN-induced hepatic tumors depending on mouse strains.
To investigate the role of BrafV637E mutation in DEN-induced hepatocarcinogenesis, we established the transgenic mice (Alb-Cre/BRAFV600E), in which human BRAFV600E mutation is specifically expressed in the liver, and compared the properties of DEN-induced hepatic tumors and the livers of the transgenic mice. The hepatic tumors were induced by neonatal treatment with DEN, isolated at various time points, and stored as frozen or paraffin-embedded materials. For production of the transgenic mice, we obtained homozygous male BRAFV600E mice, in which a LoxP-flanked cassette containing the human BRAF exons 15-18 cDNA, mouse polyadenilation sequences and the neo gene was inserted into the mouse Braf intron 14 upstream of the human BRAF exon 15 cDNA that encodes the BRAFV600E mutation, and crossed them with female Alb-Cre mice by in vitro fertilization.
RT-PCR and cDNA sequencing revealed that the liver of Alb-Cre/BRAFV600E mice expressed mRNA derived both from normal mouse and mutated human BRAF exon 15. The transgenic mice showed 20% decrease in body weight compared to normal mice, but 5 fold-increase in the liver/body weight. Histological examination revealed that the liver was entirely consisted of basophilic hepatocytes resembling to those in DEN-induced foci of cellular alteration at 8 weeks of birth, and bile duct cells were further increased at 10-12 weeks. The Ki-67 labeling index of hepatocytes in the Alb-Cre/BRAFV600E mice was 3 times higher than normal mice. Immunoblot analysis revealed that the liver of Alb-Cre/BRAFV600E mice expressed the BRAFV600E protein and showed hyperphosphlylation of ERK1 and AktS473 like the DEN-induced hepatic tumors. Furthermore, immunohistochemical staining detected increased C5/C5a expression in the hepatocytes of Alb-Cre/BRAFV600E mice, and by immunoblot analysis C5a, a protease-cleaved form of C5, was specifically detected in Alb-Cre/BRAFV600E liver like DEN-induced tumors. These results indicate that the liver specific expression of mutationally-activated BRAF led to the hepatocytic phenotype mimicking the DEN-induced hepatic tumors.
Citation Format: Hiroki Tanaka, Masahiro Yamamoto, Kosuke Yamazaki, Keiko Shimizu, Katsuhiro Ogawa. Establishment of transgenic mice with liver-specific BRAF V600E mutation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 661.