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Lymphoma

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

Leukemia volume 30, pages 617–626 (2016)Cite this article

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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.

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Acknowledgements

We thank the Cancer Therapy and Research Center at UTHSCSA Core Pathology Tissue Bank for procurement of the primary DLBCL samples. We acknowledge Patricia Dahia for insightful suggestions during the execution of this project. This work was supported by CPRIT awards RP110200 and RP150277 (to RCTA), a grant from the William and Ella Owens Medical Research Foundation (to RCTA), and a Cancer Center support grant P30 CA054174.

Author contributions

ANS designed and conducted experiments, and analyzed the data; LW conducted animal experiments; A-PL conducted experiments, HB performed animal husbandry; S-WK conducted experiments; AM and KH performed pathological analyses; RCTA designed and coordinated the study, analyzed data and wrote the manuscript, which was reviewed by all authors.

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Author notes

  1. S-W Kim

    Present address: 5Current address: Department of Biological Sciences, Pusan National University, 63 Beon-gil 2, Busandaehag-ro, Geumjeong-gu, Pusan 609–735, Republic of Korea.,

  2. L Wang and K N Holder: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    A N Suhasini, L Wang, A-P Lin, H Bhatnagar, S-W Kim & R C T Aguiar

  2. Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    K N Holder & A W Moritz

  3. Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, TX, USA

    R C T Aguiar

  4. South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, TX, USA

    R C T Aguiar

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Correspondence to R C T Aguiar.

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Suhasini, A., Wang, L., Holder, K. et al. A phosphodiesterase 4B-dependent interplay between tumor cells and the microenvironment regulates angiogenesis in B-cell lymphoma. Leukemia 30, 617–626 (2016). https://doi.org/10.1038/leu.2015.302

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