Novel Function for Fibulin-5 in Controlling Integrin-Induced ROS Production: Implications on Angiogenesis and Cancer

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Novel Function for Fibulin-5 in Controlling Integrin-Induced ROS Production: Implications on Angiogenesis and Cancer

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dc.contributor.advisor Brekken, Rolf A. en
dc.creator Schluterman, Marie Kay en
dc.date.accessioned 2011-09-30T18:56:13Z en
dc.date.available 2012-12-01T18:56:13Z en
dc.date.issued 2010-01-12T18:56:13Z en
dc.identifier.other 761307641 en
dc.identifier.uri http://hdl.handle.net/2152.5/911 en
dc.description.abstract Tumor survival depends in part on the ability of tumor cells to transform the surrounding extracellular matrix (ECM) into an environment conducive to tumor progression. Matricellular proteins are secreted into the ECM and impact signaling pathways required for pro-tumorgenic activities such as angiogenesis. Fibulin-5 (Fbln5) is a matricellular protein recently shown to regulate angiogenesis, however its effect on tumor angiogenesis and thus tumor growth is currently unknown. We report that the growth of pancreatic tumors and tumor angiogenesis was suppressed in Fbln5 null (Fbln5-/-) mice compared to wild-type (WT) littermates. Furthermore, we observed an increase in the level of reactive oxygen species (ROS) in tumors grown in Fbln5-/- animals. Increased ROS resulted in elevated DNA damage, increased apoptosis of endothelial cells within the tumor and represented the underlying cause for the reduction in angiogenesis and tumor growth. In vitro, we identified a novel pathway by which Fbln5 controls ROS production through a mechanism dependent on _1 integrins. These results were validated in Fbln5RGE/RGE mice, which harbor a point mutation in the integrin-binding RGD motif of Fbln5 preventing its interaction with integrins. Tumor growth and angiogenesis was reduced in Fbln5RGE/RGE mice, however treatment with an antioxidant rescued angiogenesis and elevated tumor growth to WT levels. These findings introduce a novel function for Fbln5 in the regulation of integrin-induced ROS production and establish a rationale for future studies to examine whether blocking Fbln5 function could be an effective anti-tumor strategy, alone or in combination with other therapies. [Keywords: Fibulin-5; reactive oxygen species; angiogenesis; pancreatic cancer; tumor microenvironment; matricellular] en
dc.language.iso en en
dc.subject Pancreatic Neoplasms en
dc.subject Reactive Oxygen Species en
dc.subject Extracellular Matrix Proteins en
dc.title Novel Function for Fibulin-5 in Controlling Integrin-Induced ROS Production: Implications on Angiogenesis and Cancer en
dc.type Thesis en
thesis.degree.grantor Graduate School of Biomedical Sciences en
thesis.degree.name Doctor of Philosophy en
thesis.degree.level Ph.D. en
thesis.degree.discipline Integrative Biology en

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