Summary Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide, with an overall 5-year survival rate of only 10–15% 1. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras 2. p53 is also frequently inactivated in NSCLC and, since oncogenic Ras can be a potent trigger of p53 3, it seems likely that oncogenic Ras signalling plays a major and persistent part in driving the selection against p53. Hence, pharmacological restoration of p53 is an appealing therapeutic strategy for treating this disease 4. Here, we model the likely therapeutic impact of p53 restoration in a spontaneously evolving mouse model of NSCLC initiated by sporadic oncogenic activation of endogenous Kras 5. Surprisingly, p53 restoration failed to induce significant regression of established tumours although it did result in a significant decrease in the relative proportion of tumours classed as high grade. This is due to selective activation of p53 only in the more aggressive tumour cells within each tumour. Such selective activation of p53 correlates with marked up regulation in Ras signal intensity and induction of the oncogenic signalling sensor p19ARF 6. Our data indicate that p53-mediated tumour suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumour evolution and to the efficacy of therapeutic p53 restoration to eradicate cancers.

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...

No abstract

Bax and Bak comprise the mitochondrial gateway for apoptosis induced by diverse stimuli. Loss of both bax and bak is necessary to block cell death induced by such stimuli, indicating a great degree of functional overlap between Bax and Bak. Apoptosis is the major intrinsic pathway that limits the oncogenic potential of Myc. Using a switchable mouse model of Myc-induced apoptosis in pancreatic ␤ cells, we have shown that Myc induces apoptosis in vivo exclusively through Bax but not Bak. Furthermore, blockade of Myc-induced apoptosis by the inactivation of Bax, but not Bak, eliminates all restraints to the oncogenic potential of Myc, allowing the rapid and synchronous progression of invasive, angiogenic tumors.