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Sci. Signal., 6 November 2012
Vol. 5, Issue 249, p. ra79
[DOI: 10.1126/scisignal.2003257]

RESEARCH ARTICLES

Key Roles for the Lipid Signaling Enzyme Phospholipase D1 in the Tumor Microenvironment During Tumor Angiogenesis and Metastasis

Qin Chen1*, Tsunaki Hongu2*, Takanobu Sato2, Yi Zhang1, Wahida Ali1,3, Julie-Ann Cavallo1,3, Adrianus van der Velden4, Huasong Tian5{dagger}, Gilbert Di Paolo5, Bernhard Nieswandt6, Yasunori Kanaho2, and Michael A. Frohman1,3{ddagger}

1 Department of Pharmacological Sciences and Center for Developmental Genetics, Stony Brook University, Stony Brook, NY 11794–5140, USA.
2 Department of Physiological Chemistry, Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Ten-nohdai, Tsukuba 305-8575, Japan.
3 Graduate Program in Molecular and Cellular Pharmacology, Stony Brook University, Stony Brook, NY 11794–8651, USA.
4 Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794–5120, USA.
5 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
6 University Hospital and Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.

* These authors contributed equally to this work.

{dagger} Present address: Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

Abstract: Angiogenesis inhibitors, which target tumor cells, confer only short-term benefits on tumor growth. We report that ablation of the lipid signaling enzyme phospholipase D1 (PLD1) in the tumor environment compromised the neovascularization and growth of tumors. PLD1 deficiency suppressed the activation of Akt and mitogen-activated protein kinase signaling pathways by vascular endothelial growth factor in vascular endothelial cells, resulting in decreased integrin-dependent cell adhesion to, and migration on, extracellular matrices, as well as reduced tumor angiogenesis in a xenograft model. In addition, mice lacking PLD1 incurred fewer lung metastases than did wild-type mice. Bone marrow transplantation and binding studies identified a platelet-derived mechanism involving decreased tumor cell–platelet interactions, in part because of impaired activation of αIIbβ3 integrin in platelets, which decreased the seeding of tumor cells into the lung parenchyma. Treatment with a small-molecule inhibitor of PLD1 phenocopied PLD1 deficiency, efficiently suppressing both tumor growth and metastasis in mice. These findings reveal that PLD1 in the tumor environment promotes tumor growth and metastasis and, taken together with previous reports on the roles of PLD in tumor cell–intrinsic adaptations to stress, suggest the potential use of PLD inhibitors as cancer therapeutics.

{ddagger} To whom correspondence should be addressed. E-mail: michael{at}pharm.stonybrook.edu

Citation: Q. Chen, T. Hongu, T. Sato, Y. Zhang, W. Ali, J.-A. Cavallo, A. van der Velden, H. Tian, G. Di Paolo, B. Nieswandt, Y. Kanaho, M. A. Frohman, Key Roles for the Lipid Signaling Enzyme Phospholipase D1 in the Tumor Microenvironment During Tumor Angiogenesis and Metastasis. Sci. Signal. 5, ra79 (2012).

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