Involvement of the Syk-mTOR pathway in follicular lymphoma cell invasion and angiogenesis

Leukemia. 2012 Apr;26(4):795-805. doi: 10.1038/leu.2011.248. Epub 2011 Sep 16.

Abstract

Follicular lymphoma (FL) is the second-most common non-Hodgkin's lymphoma. The disease affects the lymph nodes, and 50% of patients present with bone marrow infiltration; however, the mechanisms involved in dissemination of the disease are not yet known. We previously reported that FL cells display an overexpression of Syk, a tyrosine kinase involved in many cellular processes including cell migration. Therefore, we sought to explore its role in the invasive process. Here, we show that FL patients display higher matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF) levels than healthy donors. Moreover, using Syk small interfering RNA and the Syk inhibitor R406, we demonstrate that, in FL cells, Syk is involved in the regulation of MMP-9 and VEGF expression, and that invasion and angiogenesis is mediated through a phosphatidylinositol-3 kinase (PI3K)-mammalian target of rapamycin module. Finally, using a FL xenograft mouse model we observe that fostamatinib (R788), inhibits MMP-9 expression and angiogenesis in vivo. Altogether, this study provides strong evidence that Syk represents an encouraging therapeutic target in FL and suggests the potential use of fostamatinib as an anti-invasive and anti-angiogenic drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Humans
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Lymphoma, Follicular / pathology*
  • Matrix Metalloproteinase 9 / genetics
  • Mice
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic / etiology*
  • Phosphatidylinositol 3-Kinases / physiology
  • Protein-Tyrosine Kinases / physiology*
  • Proto-Oncogene Proteins c-akt / physiology
  • Signal Transduction / physiology*
  • Syk Kinase
  • TOR Serine-Threonine Kinases / physiology*
  • Vascular Endothelial Growth Factor A / physiology

Substances

  • Intracellular Signaling Peptides and Proteins
  • Vascular Endothelial Growth Factor A
  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Syk protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Matrix Metalloproteinase 9