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Cancer cells possess a nearly universal set of characteristics termed thehallmarks of cancer, including replicative immortality and resisting celldeath. Dysregulated differentiation is present in virtually all cancers yet hasnot yet been described as a cancer hallmark. Like other hallmarks, dysregulateddifferentiation involves a breakdown of the cellular cooperation that typicallymakes multicellularity possible - in this case disrupting the division of laboramong the cells of a body. At the time that the original hallmarks of cancerwere described, it was not known that dysregulated differentiation wasmechanistically distinct from growth inhibition, but now that this is known, itis a further reason to consider dysregulated differentiation a hallmark ofcancer. Dysregulated differentiation also has clinical utility, as it forms thebasis of pathological grading, predicts clinical outcomes, and is a viabletarget for therapies aimed at inducing differentiation. Here we argue thathallmarks of cancer should be near universal, mechanistically distinct, andhave clinical utility for prognosis and/or therapy. Dysregulateddifferentiation meets all of these criteria.

A Missing Hallmark of Cancer: Dysregulation of Differentiation