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

A. N. Suhasini, L. Wang, K. N. Holder, A. P. Lin, H. Bhatnagar, S. W. Kim, A. W. Moritz, R. C T Aguiar

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)617-626
Number of pages10
JournalLeukemia
Volume30
Issue number3
DOIs
StatePublished - Mar 1 2016

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Type 4 Cyclic Nucleotide Phosphodiesterase
Cellular Microenvironment
Tumor Microenvironment
B-Cell Lymphoma
Lymphoma
Phosphatidylinositol 3-Kinases
Cyclic AMP
Vascular Endothelial Growth Factor A
Lymphoma, Large B-Cell, Diffuse
Microvessels
Phosphodiesterase 4 Inhibitors
Second Messenger Systems
Complementary Therapies
Transgenes
Enzymes

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

A phosphodiesterase 4B-dependent interplay between tumor cells and the microenvironment regulates angiogenesis in B-cell lymphoma. / Suhasini, A. N.; Wang, L.; Holder, K. N.; Lin, A. P.; Bhatnagar, H.; Kim, S. W.; Moritz, A. W.; Aguiar, R. C T.

In: Leukemia, Vol. 30, No. 3, 01.03.2016, p. 617-626.

Research output: Contribution to journalArticle

Suhasini, A. N. ; Wang, L. ; Holder, K. N. ; Lin, A. P. ; Bhatnagar, H. ; Kim, S. W. ; Moritz, A. W. ; Aguiar, R. C T. / A phosphodiesterase 4B-dependent interplay between tumor cells and the microenvironment regulates angiogenesis in B-cell lymphoma. In: Leukemia. 2016 ; Vol. 30, No. 3. pp. 617-626.
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