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RESEARCH PAPERS

The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1β

¹ Cancer Research Institute and Department of Cellular and Molecular Pharmacology, University of California at San Francisco Comprehensive Cancer Center, San Francisco, California 94143, USA; ² Biotraces, Inc., Herndon, Virginia 20171, USA

Although induction of blood vessel growth is acknowledged as a pivotal requirement for the evolution of macroscopic tumors, the events that trigger onset of tumor angiogenesis remain largely obscure. The pervasive Myc oncoprotein is itself a potent inducer of angiogenesis in a wide range of tissues. We have used a reversibly switchable mouse transgenic model of Myc-dependent β-cell carcinogenesis to delineate the kinetics and causal sequence of angiogenic processes following acute Myc activation. We show that onset of endothelial cell proliferation is induced shortly after Myc-induced cell cycle entry of β cells. Endothelial cell proliferation is not indirectly induced by local tissue hypoxia but instead via a diffusible angiogenic signal produced by Myc-expressing β cells. This signal triggers the release of pre-existing, sequestered VEGF from the islet extracellular matrix, that then homes to the endothelial compartment where it induces endothelial cell proliferation. Myc activation in β cells rapidly induces expression and release of the proinflammatory cytokine interleukin 1β (IL-1β). We show that IL-1β is the principal effector downstream of Myc responsible for triggering rapid onset of islet angiogenesis. Together, our data delineate a complete pathway in vivo by which the highly pleiotropic Myc oncoproteins elicits coexpansion of the vascular compartment during tumorigenic progression.

[Keywords: Myc; angiogenesis; interleukin 1β; tumor]

Received June 6, 2006; revised version accepted July 26, 2006.

⁴ Corresponding author.

E-MAIL gevan{at}cc.ucsf.edu; FAX (415) 514-0878.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1455706.

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