Cancer is a disease in which inherent genetic flexibility allows cells to progressively evolve functions that promote cell growth, disable cell death mechanisms and evade immune surveillance and therapy. During tumorigenesis, normal growth mechanisms are deregulated and safeguards that eliminate abnormal cells by apoptosis are disabled. Tumor cells must also increase nutrient uptake and angiogenesis to support the upregulation of metabolism necessary for unrestricted growth. Moreover, the very signals that enable unrestricted cell proliferation inhibit autophagy, which normally sustains cells during nutrient limitation. In tumors, inactivation of the autophagy pathway may enhance necrosis and inflammation and promote genomic instability, which can further enhance tumor growth. Thus, tumor cells cannot adapt efficiently to metabolic stress and could be induced to die by metabolic catastrophe, in which high energy demand is contrasted by insufficient energy production. Efforts to exploit this unique metabolic state clinically previously focused mainly on detecting tissue displaying increased glycolytic metabolism. The challenge now is to induce metabolic catastrophe therapeutically as an approach to killing the unkillable cells. Below we discuss recent work that has shed light on the interplay between these processes and the ongoing challenge to translate this knowledge for therapeutic benefit. (Cancer Prev Res 13, 75-80, 2008)

Keywords: Autophagy, Apoptosis, Necrosis, AKT