Douglas Hanahan, Robert A. Weinberg. Hallmarks of cancer: the next generation. Cell, Volume 144, Issue 5, p646–674, 4 March 2011
In 2000, we presented a metaphor, in which the numerous signaling molecules affecting cancer cells operate as nodes and branches of elaborate integrated circuits that are reprogrammed derivatives of the circuits operating in normal cells. The ensuing decade has both solidified the original depiction of these circuits and expanded the catalog of signals and the interconnections of their signaling pathways. It is difficult if not impossible to graphically portray this circuit comprehensively and coherently, as was already the case in 2000.
We now suggest a portrayal of this circuitry that is aligned with individual hallmarks of cancer. Thus, the intracellular integrated circuit can be segmented into distinct subcircuits, each of which is specialized to support a discrete cell-biological property in normal cells and is reprogrammed in order to implement a hallmark capability in cancer cells (Figure 2). Only a subset of hallmark capabilities are addressed in this figure, either because their underlying control circuits remain poorly understood or because they overlap extensively with those portrayed here.
An additional dimension of complexity involves considerable interconnections and thus crosstalk between the individual subcircuits. For example, certain oncogenic events can affect multiple capabilities, as illustrated by the diverse effects that prominent oncogenes, such as mutant RAS and upregulated MYC, have on multiple hallmark capabilities (e.g., proliferative signaling, energy metabolism, angiogenesis, invasion, and survival). We anticipate that future renditions of this integrated circuit will encompass subcircuits and associated hallmark capabilities that are still not addressed here.