Is cancer a disease of abnormal cellular metabolism? New angles on an old idea

In the 1920s, Otto Warburg observed that tumor cells consumed a large amount of glucose, much more than normal cells, and converted most of it to lactic acid. This phenomenon, now known as the "Warburg effect," is the foundation of one of the earliest general concepts of cancer: that a fundamental disturbance of cellular metabolic activity is at the root of tumor formation and growth. In the ensuing decades, as it became apparent that abnormalities in chromosomes and eventually individual genes caused cancer, the "metabolic" model of cancer lost a good deal of its appeal, even as emerging technologies were exploiting the Warburg effect clinically to detect tumors in vivo. We now know that tumor suppressors and proto-oncogenes influence metabolism, and that mutations in these genes can promote a metabolic phenotype supporting cell growth and proliferation. Thus, these advances have unified aspects of the metabolic and genetic models of cancer, and have stimulated a renewed interest in the role of cellular metabolism in tumorigenesis. This review reappraises the notion that dysregulated cellular metabolism is a key feature of cancer, and discusses some metabolic issues that have escaped scrutiny over the years and now deserve closer attention. Genet Med 2008:10(11):767-777.