The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1beta.
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 beta-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 beta cells. Endothelial cell proliferation is not indirectly induced by local tissue hypoxia but instead via a diffusible angiogenic signal produced by Myc-expressing beta 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 beta cells rapidly induces expression and release of the proinflammatory cytokine interleukin 1beta (IL-1beta). We show that IL-1beta 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.
Shchors
Ksenya
K
Cancer Research Institute and Department of Cellular and Molecular Pharmacology, University of California at San Francisco Comprehensive Cancer Center, 94143, USA.
Shchors
Elena
E
Rostker
Fanya
F
Lawlor
Elizabeth R
ER
Brown-Swigart
Lamorna
L
Evan
Gerard I
GI
D000818:Animals; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D066298:In Vitro Techniques; D007340:Insulinoma / Q000098:blood supply* / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D007375:Interleukin-1 / Q000502:physiology*; D007515:Islets of Langerhans / Q000098:blood supply; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D051020:bcl-X Protein / Q000235:genetics
C494812:Bcl2l1 protein, mouse; D007375:Interleukin-1; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein; C467480:vascular endothelial growth factor A, mouse