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The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1β
Elizabeth R. Lawlor1,3,
Lamorna Brown-Swigart1,, and
Gerard I. Evan1,4
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 asa pivotal requirement for the evolution of macroscopic tumors,the events that trigger onset of tumor angiogenesis remain largelyobscure. The pervasive Myc oncoprotein is itself a potent inducerof angiogenesis in a wide range of tissues. We have used a reversiblyswitchable mouse transgenic model of Myc-dependent β-cellcarcinogenesis to delineate the kinetics and causal sequenceof angiogenic processes following acute Myc activation. We showthat onset of endothelial cell proliferation is induced shortlyafter Myc-induced cell cycle entry of β cells. Endothelialcell proliferation is not indirectly induced by local tissuehypoxia but instead via a diffusible angiogenic signal producedby Myc-expressing β cells. This signal triggers the releaseof pre-existing, sequestered VEGF from the islet extracellularmatrix, that then homes to the endothelial compartment whereit induces endothelial cell proliferation. Myc activation inβ cells rapidly induces expression and release of the proinflammatorycytokine interleukin 1β (IL-1β). We show that IL-1βis the principal effector downstream of Myc responsible fortriggering rapid onset of islet angiogenesis. Together, ourdata delineate a complete pathway in vivo by which the highlypleiotropic Myc oncoproteins elicits coexpansion of the vascularcompartment during tumorigenic progression.