Fig. 1

Normal vs. cancer bifurcations in differentiation pathways. Pluripotent stem cells differentiate to form either normal or cancer stem cells (SC or CSC, respectively). By default, normal stem cell differentiation is active, while cancer differentiation is blocked by several tissue-specific barriers. As the barriers are removed by mutations or some environmental cues, cancer stem cells become gradually activated and the cryptic program is brought into action in a step-by-step manner. As a result, “differentiated” tumor cells are formed. a Carcinogenic program is blocked. b, c Gene mutations sequentially remove the barriers and make “differentiation leaps” possible. The numbers denote rate-limiting events (mutations) that are required to pass the differentiation stages. The gradual darkening of cells represents their acquisition of a cancer phenotype. Lightning arrows, mutations; arrows, passage possible; ⊥, block of cancer differentiation. (Reprinted from A.V. Lichtenstein (2008) Cancer: shift of the paradigm, Med Hypotheses, 71(6):839–850, with permission from Elsevier)