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Research Projects

Current projects

The vascular bed is essential for survival of all multicellular organisms that are larger than a millimeter. Accordingly, all changes in the structure and function of tissues, which occur in health and disease, during development or degeneration, are accompanied and often induced by vascular changes. We have shown that the critical switch for induction of growth of dormant ovarian carcinoma tumors is not provided by angiogenesis per se (namely the recruitment of new endothelial capillaries). Rather, the switch for tumor progression involves a subsequent step in which maturation of the newly formed vessels is achieved by recruitment of host stroma fibroblasts and myofibroblasts. The communication between tumor and stroma cells in inducing and stabilizing tumor angiogenesis was manifested by unique signatures of vascular function and permeability that were detectable by MRI, and were attributed to uncoupling in the expression of vascular endothelial growth factor (VEGF) by the tumor cells and the expression of angiopoietin-1 by the host stroma cells (Gilad et al 2005).

Tracking the recruitment of tumor stroma cells by MRI was made possible by labeling the cells with biotin-BSA-GdDTPA (in collaboration with Leoni A. Kunz-Schughart, Regensburg; Granot et al 2005). Project 1

The same contrast material was also valuable in mapping the pathways of peritumor and intratumor lymphatic drain, linking angiogenesis with metastatic spread (in collaboration with Zaver M. Bhujwalla, Johns Hopkins; Dafni et al 2005, Pathak et al 2005).

Angiogenesis is essential for successful implantation of grafts, particularly when anastomosis occurs at the microcirculation level. A particular case is the implantation of ovarian fragments for preservation of fertility in cancer patients (in collaboration with Alex Tsafriri) Using MRI we have shown that perivascular mural cells are essential for preservation of vascular and follicular survival (Israely et al 2004). Angiogenic preparation of the implantation site can support vascular maintenance and improve follicular preservation (Israely et al 2006).

Uterine-maternal angiogenesis during the first hours of mouse embryo implantation often determines the success of pregnancy. The angiogenic response can be detected by MRI, and thus can be used for the study of genetic implantation disorders associated with failures in mounting fetal-induced maternal angiogenesis in genetically modified transgenic and knockout mice (in collaboration with Nava Dekel; Plaks et al 2006). Project 4

Significant changes of the extracellular matrix accompany angiogenesis. Tissue transglutaminase catalyzes covalent cross-linking of extracellular matrix proteins in regions of angiogenesis. A novel MRI contrast material was developed, which serves as a low molecular weight substrate of transglutaminase and thus can be covalently linked to sites of enzymatic activity (Mazooz et al 2005) .Project 6
Another important modification of the extracellular matrix during angiogenesis, catalyzed by hyaluronidase, is the conversion of antiangiogenic high molecular weight hyaluronan to proangiogenic fragments. We developed a novel contrast material in which relaxivity is quenched but can be recovered upon degradation by hyaluronidase (Shiftan et at 2005). During metastatic dissemination, ovarian carcinoma cells adhere to hyaluronan on mesothelial cells via cell surface CD44 receptors, and induce angiogenesis by secretion of hyaluronidase. Project 1

Regulation at the level of gene expression controls multiple steps of angiogenesis. Such regulation can be detected non-invasively in whole animals with the use of reporter genes. Ferritin, a key iron storage protein was applied as a candidate reporter for detection of gene expression by MRI (Cohen et al 2005). Tetracycline inducible expression of ferritin in C6 glioma tumor cells led to increased iron uptake. Enhanced water relaxation rates associated with ferritin expression were detectable by MRI in vitro and in vivo. Link to Ferritin as a reporter gene for MRI. Project 3