02 BOOK OF ABSTRACTS .indd

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Angiogenesis independent growth mediated by glioma stem cells Per Oyvind Enger, Per Sakariassen, Lars Prestegaarden, Simone Niclou, Uro{ Raj~evi~, A.J.A Terzis and Rolf Bjerkvig NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Norway and Centre de Recherche Public - Santé, Luxembourg A highly infiltrative cancer stem cell phenotype was established by xenotransplantation of human primary glioblastomas in immuno-deficient nude rats. These tumors coopted the host vasculature and presented as an aggressive disease without signs of angiogenesis. The malignant cells expressed neural stem cell markers and showed a migratory behavior similar to normal human neural stem cells. The cells showed self-renewal capacity in vitro and gave rise to tumors in vivo. Serial animal passages, gradually transformed the stem cell tumors into an angiogenesis-dependent phenotype. This process was characterized by a reduction in stem cells markers. Pro-invasive genes were up-regulated and angiogenesis signaling genes were down-regulated in the stem cell tumors. In contrast, pro-invasive genes were downregulated in the angiogenesis-dependent tumors, derived from the stem cell tumors. By using gene arrays, proteomics and bioinformatics, we were able to identify two separate signaling pathways characterized by the two phenotypes. Moreover, based on our proteomics data, a set of molecular targets towards the cancer stem cells were identified. In conclusion, we describe a system where primary glioblastomas can be dissected into two separate malignant phenotypes. One that depends on angiogenesis and one that is characterized by angiogenesis independent growth. Our work points at two completely independent mechanisms that drive glioma progression. The present work underlines the need for developing therapies that specifically target the cancer stem cell pools in tumors. Examples of such targets will 62l44 be shown.
Tumor proteolysis: a multidimensional approach Kamiar Moin 1,2 , Donald Schwartz 2 , Mansoureh Sameni 1 , Stefanie R. Mullins 1,2 , Bruce Linebaugh 1 , Deborah Rudy 1 , Ching Tung 3 and Bonnie F. Sloane 1,2 1 Department of Pharmacology and 2 Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA; 3 Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA Despite the awareness that proteolysis is essential for cancer progression, and that proteases represent potential drug targets, clinical trials for cancer treatment with inhibitors of matrix metalloproteases have failed. Moreover, a broad and comprehensive strategy to identify potential protease targets has not been employed. We hypothesize that proteases are valid therapeutic and prevention targets in cancer and that imaging of protease activity and its inhibition in vivo will provide a means to confirm this hypothesis. In our laboratories we have developed functional optical imaging techniques to monitor tumor progression and tumor-host interactions based on proteolytic activity, both in vitro in live cells and in vivo. In vitro, we have used a 3-dimensional assay system to study tumor-stromal interactions in real time, utilizing confocal and multiphoton microscopy to document our observations. Using this system, we have found that both pericellular and intracellular proteolysis occur during tumor invasion. Furthermore, there is a high degree of interaction between tumor and stromal cells. Our results indicate that tumor cells actively recruit stromal cells and that these cells contribute significantly to the proteolytic events occurring in the tumor environment. l45 63 In order to identify the potential proteases, their endogenous inhibitors, and genes that interact with proteases in the tumor micronenvironment, we developed a dual species custom oligonucleotide microarray in conjunction with Affymetrix, Inc. The Hu/Mu ProtIn array contains 516 and 456 custom probes sets that survey 426 and 390 unique human and mouse genes of interest, respectively. Our goal is to determine tumor (human) and host (murine) contributions to the degradome in orthotopic xenograft models of cancer and demonstrate the utility, versatility and specificity of the custom probe sets. To validate the utility of the array, we profiled human MDA231 and MDA435 breast carcinoma cells derived from in vitro cultures or orthotopically implanted xenografts, as well as normal mouse mammary fat pads. We also profiled MCF-10A breast cell lines, grown in the 3D Matrigel overlay model, as well as xenografts of the MCF-10DCIS.com line, a line that forms DCIS lesions that progress to invasive carcinomas in mice. We have identified genes that were either significantly up or down regulated in DCIS.com as compared with MCF10A or were derived from host cells that have infiltrated into the DCIS.com xenografts. We are currently validating genes of interest by both Q-RT-PCR and immunohistochemistry in human breast samples. In vivo, we have utilized quenched fluorescent probes that are activated by proteases. We have found that upon injection of these probes into tumor-bearing mice, the
Page 2 and 3:
Co-chairs of the conference: Scient
Page 4 and 5:
Contents Conference programme 5 Lis
Page 6 and 7:
Differential effects of Cathepsin L
Page 8 and 9:
17.25 - 17.50 Golzio Muriel, IPBS C
Page 10 and 11:
List of lectures: L1. Teissiè Just
Page 13 and 14: Abstracts of lectures 13
Page 15 and 16: Proteases and their inhibitors duri
Page 17 and 18: Biochemical characterization and cl
Page 19 and 20: Assessment of cathepsin B activity
Page 21 and 22: Differential effects of Cathepsin L
Page 23 and 24: anecdotally and within a clinical t
Page 25 and 26: Tumor cell- and macrophage-derived
Page 27 and 28: The selection of serological marker
Page 29 and 30: Cathepsins and their inhibitors in
Page 31 and 32: Matrix metalloproteinase expression
Page 33 and 34: l18 33 Complement resistance impair
Page 35 and 36: Classical tumor vaccine potently st
Page 37 and 38: CpG oligonucleotides admixed with i
Page 39 and 40: Electrochemotherapy in veterinary o
Page 41 and 42: studies were able to provide a deta
Page 43 and 44: threshold and electric field intens
Page 45 and 46: Gene delivery systems in cancer gen
Page 47 and 48: Electropermeabilization: a non vira
Page 49 and 50: Visible light microscopy, efficient
Page 51 and 52: Progress in tumour vascular targeti
Page 53 and 54: The Fer kinas: a novel target for p
Page 55 and 56: Targeting of plasminogen activation
Page 57 and 58: Functional interdependence of natur
Page 59 and 60: Antiprotease therapy in cancer: hot
Page 61: Functional genomics and systems bio
Page 65 and 66: Stem cell therapy for liver insuffi
Page 67 and 68: Increased plasma DNA concentration
Page 69 and 70: List of poster presentations P1. Ab
Page 71 and 72: Abstracts of posters 71
Page 73 and 74: Tumor VEGF modulates host proteolyt
Page 75 and 76: New inhibitors of human hydroxyster
Page 77 and 78: Cytotoxicity and antitumour effecti
Page 79 and 80: Quantification of lysosomal fusion
Page 81 and 82: Spatiotemporal relevance of tumor c
Page 83 and 84: Electrogene therapy with p53 alone
Page 85 and 86: Do organophosphorous pesticides pla
Page 87 and 88: Molecular analysis of lymphoprolife
Page 89 and 90: Humoral response in pleural space t
Page 91 and 92: In conclusion, this study shows tha
Page 93 and 94: Angiogenesis correlates with cycloo
Page 95 and 96: Inhibition of mouse uPA activity by
Page 97 and 98: Cathepsin X interacts with integrin
Page 99 and 100: Annexin-V apoptosis analysis of hum
Page 101 and 102: Tissue swelling at the site of elec
Page 103 and 104: p30103 The Bcl-2 family members: me
Page 105 and 106: p32105 Proteomics of astrocytic neo
Page 107 and 108: Correlation of chromosomal abnormal
Page 109 and 110: Optimization of treatment parameter
Page 111 and 112: The effect of xantohumol on normal
Page 113 and 114:
Cappabianca Lucia University of Aqu
Page 115 and 116:
Jevnikar Zala University of Ljublja
Page 117 and 118:
Mesojednik Suzana Institute of Onco
Page 119 and 120:
Rols Marie-Pierre Institute of Phar
Page 121 and 122:
Author Index Abramovi} Zrinka 72 Ak
Page 123 and 124:
Paridaens R. 31 Parker Katharine 99
Page 125 and 126:
125
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