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Imaging of the tumor matrix microenvironment heparan mimetics

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Thèse de doctorat : Sciences de la Vie et de la Santé : Tours : 2014

Heparan sulfate proteoglycans (HSPG), like all proteoglycans (PG), consisting of a protein portion and a glycosaminoglycan (GAG), heparan sulphate (HS) for HSPG. They are part of the extracellular matrix (ECM). PG are able, through their GAG, to bind a number of partners such as growth factors, chemokines, cytokines or enzymes. They regulate the bioavailability of many soluble mediators and thus their biological activity. They are thus involved in the regulation of many processes such as proliferation, differentiation, tissue remodeling, angiogenesis... In addition, it was shown that the binding of proteins having a heparan binding site (HB) with HS of HSPG protect them from enzymatic degradation. However, HSPG are among the first components of the ECM to be digested by heparanase during cellular tissue damage. This digestion makes HB sites available and proteins are sensitive to proteolytic degradation. It is in order to protect the HSBP (heparan sulfate binding protein) that was developed technology heparan mimetics (HM) that will replace the degraded HS on available HB sites and protect proteins of middle injured. These HM, already used as a therapeutic agent of the ECM, are identified in this use under the symbol RGTA for regenerating agent because they increase the speed and quality of the tissue repair, potentially leading to a true tissue regeneration. During tumor development and metastasis, it has been shown that the enzymatic activity of heparanase is multiplied, leading to an increased degradation of HS. In this context, the HM will be able to fix this matrix injured hence the idea of their diagnostic use in oncology. Using labeled HM (HM*) with a radioisotope such as fluorine-18 (18F) and followed by molecular imaging PETScan (positon emission tomography with scanner associated) should allow a particularly efficient marking of the matrix surrounding metastatic and tumor cells. HM* could indeed target ECM involved, through its early degradation in the processes of tumor growth and tumor spread and become a new marker oncology in molecular imaging. To date, among the various studied cancer markers, none address the matrix compartment. The use of HM* should allow the detection of peri-tumor and find a place in the early diagnosis of cancer and the therapeutic monitoring.

  • Dates
    Published on December 16, 2014, Created on December 16, 2014