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The role of innate immunity in tumor angiogenesis: identification of downstream mediators in the IL-12 mediated anti-angiogenic activity of Angiostatin.
No full textThe numerous studies on Angiostatin (AST) mechanisms of angiogenesis inhibition have focused on the potential receptor-mediated interactions with endothelial cells. Although these studies have provided potential mechanisms, no single receptor system has been definitively shown to mediate AST activity. Recent studies have shown that inflammatory cells, in particular macrophages and neutrophils, are also targets of AST. These cells are part of a network that generates one of the most powerful anti-angiogenic cytokines: interleukin-12 (IL-12). We show that in in vivo preclinical studies, IL-12 is an essential mediator of AST antiangiogenic activity. Function blocking antibodies to IL-12 revert angiogenesis inhibition induced by AST. Further, AST is unable to exert angiogenesis inhibition in mice with gene targeted deletions of the IL-12 receptor IL-12R2, specific for IL-12, or in mice gene targeted for the IL- 12 p40 subunit. However, AST retains anti-angiogenic activity in IFNgene targeted mice, suggesting an IFNindependent angiogenesis inhibition mechanism as previously observed. We also identified a short synthetic peptide localized to the lysine binding domain that completely reproduces the IL-12 dependent anti-angiogenic properties of AST. Since endothelial cells do not express the IL-12 receptor, nor do they essentially change gene expression patterns when treated with AST in vitro, our data show that the immune system forms an integral part of the anti-angiogenic effects of AST, by both responding to AST and providing downstream signals to the endothelium. AST induced IL-12 synthesis by human macrophages polarized toward M1 phenotype in vitro. We also identified a short synthetic peptide with potential application in oncological therapy, that reproduced the IL-12 dependent anti-angiogenic properties of angiostatin
Indici e metriche per la valutazione della qualità delle acque lacustri italiane attraverso la comunità macrofitica.
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Synthesis and conformational analysis of peptidomimetics containing unnatural amino acids based on a piperazinone and g-butyrolactone scaffolds.
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Molecular mechanisms of novel angiopreventive compounds.
No full textIn this thesis I have been studied 2 agents that have shown promising results as cancer chemopreventive.
These 2 compounds are:
-N-acetyl-cysteine (NAC)
-Triterpenoid CDDO-Me (synthetic derived of olanoleic acid)
NAC has been widely studied and has already been reported is chemopreventive activity due to its anti-oxidant activity. Here for the first time it has been reported its ability to reduce the expression of an endothelial membrane protein (E-selectin).
E-selectin is expressed on endothelial cells and can be used by metastatic cells as ‘docking site’ during metastatic spreading. This proprety of NAC could be a suitable tool for preventive approach of metastatization. CDDO-Me is actually in phase I Clinical trial. It has already been reported its antitumoral proprety. Here we show for the first time its potent antiangiogenic and angiopreventive activity through its interaction with inflammatory and endothelial cells
