A phosphodiesterase 4B-dependent interplay between tumor cells and the microenvironment regulates angiogenesis in B-cell lymphoma

Leukemia. 2016 Mar;30(3):617-626. doi: 10.1038/leu.2015.302. Epub 2015 Oct 27.


Angiogenesis associates with poor outcome in diffuse large B-cell lymphoma (DLBCL), but the contribution of the lymphoma cells to this process remains unclear. Addressing this knowledge gap may uncover unsuspecting proangiogenic signaling nodes and highlight alternative antiangiogenic therapies. Here, we identify the second messenger cyclic-AMP (cAMP) and the enzyme that terminates its activity, phosphodiesterase 4B (PDE4B), as regulators of B-cell lymphoma angiogenesis. We first show that cAMP, in a PDE4B-dependent manner, suppresses PI3K/AKT signals to downmodulate vascular endothelial growth factor (VEGF) secretion and vessel formation in vitro. Next, we create a novel mouse model that combines the lymphomagenic Myc transgene with germline deletion of Pde4b. We show that lymphomas developing in a Pde4b-null background display significantly lower microvessel density (MVD) in association with lower VEGF levels and PI3K/AKT activity. We recapitulate these observations by treating lymphoma-bearing mice with the FDA-approved PDE4 inhibitor, Roflumilast. Lastly, we show that primary human DLBCLs with high PDE4B expression display significantly higher MVD. Here, we defined an unsuspected signaling circuitry in which the cAMP generated in lymphoma cells downmodulates PI3K/AKT and VEGF secretion to negatively influence vessel development in the microenvironment. These data identify PDE4 as an actionable antiangiogenic target in DLBCL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aminopyridines / pharmacology
  • Animals
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / enzymology*
  • B-Lymphocytes / pathology
  • Benzamides / pharmacology
  • Cyclic AMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Cyclopropanes / pharmacology
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / drug therapy
  • Lymphoma, Large B-Cell, Diffuse / enzymology*
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mice
  • Mice, Transgenic
  • Neovascularization, Pathologic / enzymology*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / prevention & control
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphodiesterase 4 Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction
  • Tumor Microenvironment / drug effects
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism


  • Aminopyridines
  • Benzamides
  • Cyclopropanes
  • Myc protein, mouse
  • Phosphodiesterase 4 Inhibitors
  • Proto-Oncogene Proteins c-myc
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Roflumilast
  • Cyclic AMP
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4B protein, human