Editors' ChoiceCancer

From Myc Activation to Angiogenesis

Science's STKE  26 Sep 2006:
Vol. 2006, Issue 354, pp. tw330
DOI: 10.1126/stke.3542006tw330

Myc is encoded by an oncogene that is frequently activated in cancer. Myc is a basic helix-loop-helix leucine zipper transcription factor that integrates cell proliferation with changes in the local environment to accommodate that growth. In tumor growth, this frequently involves stimulation of angiogenesis. Shchors et al. used a transgenic mouse model in which myc expression was inducibly activated in the presence of the apoptosis inhibitor Bcl-XL in pancreatic β cells. Within 3 days of Myc expression, β cells proliferated as did endothelial cells, despite the fact that Myc activity and abundance were only increased in the β cells. When Myc expression was induced in isolated islets, a factor--which was determined by immunofluorescence and enzyme-linked immunosorbent assay (ELISA) to be vascular endothelial growth factor A (VEGF A)--was secreted into the medium. Application of this conditioned medium to human umbilical vein endothelial cells stimulated proliferation and tubule formation. Myc did not directly stimulate the transcription of VEGF A. Instead, using immunofluorescence analysis of islets from mice in which expression of Myc was induced, the authors showed that β cell Myc led to a redistribution of VEGF A from diffusely distributed throughout the islet to present in discrete foci. These foci also contained endothelial cells and engaged VEGF A–VEGFR2 (VEGF receptor 2) complexes. An increase in matrix metalloproteinase (MMP) activity was observed in the islets at the time of VEGF A redistribution; however, once again, Myc did not stimulate the expression of any MMP genes. The angiogenic effects of Myc appear to be the result of stimulation of the gene encoding interleukin-1β (IL-1β), because not only was this gene’s expression increased, neutralizing antibodies inhibited the release of VEGF A from cultured islets and reduced the redistribution of VEGF A in vivo. Thus, before the onset of tissue hypoxia, which is also a trigger for angiogenesis, Myc stimulates the production of the proinflammatory IL-1β, which stimulates MMP activity and thereby allows release of matrix-sequestered VEGF A and stimulates angiogenesis. These results help clarify the sequence of events associated with vascularization of tumors and suggest that interfering with IL-1β may be a useful tool in the battle against cancer progression.

K. Shchors, E. Shchors, F. Rostker, E. R. Lawlor, L. Brown-Swigart, G. I. Evan, The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1β. Genes Dev. 20, 2527-2538 (2006). [Abstract] [Full Text]