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Loss of fibulin-5 binding to beta1 integrins inhibits tumor growth by increasing the level of ROS.

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 that are required for pro-tumorigenic activities such as angiogenesis. Fibulin-5 (Fbln5) is a matricellular protein that was 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 is suppressed in Fbln5-null (Fbln5(-/-)) mice compared with 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 that is dependent on beta1 integrins. These results were validated in Fbln5(RGE/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 Fbln5(RGE/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.

Pubmed ID: 20197418


  • Schluterman MK
  • Chapman SL
  • Korpanty G
  • Ozumi K
  • Fukai T
  • Yanagisawa H
  • Brekken RA


Disease models & mechanisms

Publication Data

April 29, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA118240
  • Agency: NICHD NIH HHS, Id: R01 HD064824
  • Agency: NHLBI NIH HHS, Id: R01 HL070187
  • Agency: NHLBI NIH HHS, Id: R01 HL07115
  • Agency: NHLBI NIH HHS, Id: R01 HL071157

Mesh Terms

  • Animals
  • Antigens, CD29
  • Antioxidants
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Embryo, Mammalian
  • Endothelial Cells
  • Extracellular Matrix Proteins
  • Fibroblasts
  • Fibronectins
  • Mice
  • Neovascularization, Pathologic
  • Oxidative Stress
  • Pancreatic Neoplasms
  • Protein Binding
  • Reactive Oxygen Species
  • Recombinant Proteins