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

Abstract

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 ␤-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 ␤ cells. Endothelial cell proliferation is not indirectly induced by local tissue hypoxia but instead via a diffusible angiogenic signal produced by Myc-expressing ␤ 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 ␤ cells rapidly induces expression and release of the proinflammatory cytokine interleukin 1␤ (IL-1␤). We show that IL-1␤ 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. Induction of blood vessel growth is a pivotal requirement for the evolution of macroscopic tumors. However, the precise molecular mechanisms that trigger angiogenesis in tumors remains largely obscure. Some initial studies in experimental tumor models supported the notion that early tumors are innately incompetent for angiogenesis and, consequently, restricted in size by hypoxia and nutrient privation. The capacity for angiogenesis then arises sporadically during the course of tumor evolution, presumably through the aleatory acquisition of proangiogenic mutations. Recently, however, several studies have indicated that pervasive dominant oncogenes such as Myc and Ras can directly instruct angiogenesis in tissues in which they are activated (Watnick et al. 2003;Knies-Bamforth et al. 2004). Since oncogene activation is likely to be an early and obligate event in tumorigenesis, this intimates that angiogenesis can be an inherent attribute of many tumors from the outset. Deregulated expression of the basic helix-loop-helixleucine zipper (bHLH-LZ) transcription factor Myc is frequent in human cancers. Myc is a pivotal coordinator of a large number of diverse transcriptional programs that coordinate the cellular processes of growth, metabolism, proliferation, and intrinsic tumor suppression. In addition, Myc also regulates various processes by which proliferating cells communicate with, and instruct, appropriate changes in surrounding tissues and stroma, including angiogenesis, invasion, and tissue organization. In this way, Myc integrates intracellular processes required for cell expansion with requisite changes in the local soma...

Myc heterozygosity attenuates the phenotypes of APC deficiency in the small intestine

“…Therefore, both studies underline the importance of c-Myc levels for intestinal tumour progression and there may be multiple key tumour-promoting mechanisms that c-Myc impinges on. This link between Myc and angiogenesis had been observed previously in pancreatic islet tumour growth driven by c-Myc overexpression and appears dependent on changes in c-Myc levels within the epithelial cells (Shchors et al, 2006).…”

Estrogen regulation of vascular endothelial growth factor in breast cancer in vitro and in vivo: the role of estrogen receptor α and c-Myc

“…Recent studies also indicated that VEGF expression levels are also controlled by c-Myc (Barr et al 2000, Knies-Bamforth et al 2004 and that c-Myc is essential for angiogenesis (Baudino et al 2002). Other studies have revealed that c-Myc plays a central role in the angiogenic switch in tumors (Knies-Bamforth et al 2004, Shchors et al 2006.…”

Angiogenesis in pre-malignant conditions

“…In a mouse transgenic model of Myc-dependent b-cell carcinogenesis, the onset of endothelial cell proliferation was noted to begin shortly after Myc-induced cell cycle entry of pancreatic b cells. Subsequent endothelial proliferation was not caused by local tissue hypoxia but through the release of pre-existing sequestered VEGF from the ECM by MMPs mediated by the production and release of the proinflammatory cytokine IL-1b (Shchors et al, 2006).…”