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. 2022 Sep 16;66(4):319–331. doi: 10.1042/EBC20220016

Figure 2. Simplified view of proliferation/dormancy plasticity.

Figure 2

Tumor cells exist in a spectrum of cell cycle states: cells with fast cycling (proliferative), slow cycling (shallow quiescence), reversible growth arrest (deep quiescence) and irreversible growth arrest (senescence). These conditions are dynamically controlled based on the balance between cell cycle activators and inhibitors. Canonical WNT signaling induces proliferation of cancer stem cells (CSCs) through direct up-regulation of CCND1 and MYC and secondary up-regulation of CCNA2, CCNB1, CCND2, CCND3, CCNE2 and CDK4. In contrast, TGFβ (transforming growth factor-β) signaling induces CSC dormancy through up-regulation of CDKN1A, CDKN1B, CDKN1C and CNKN2B. TGFβ and YAP signaling converge to up-regulate WNT5A transcription and then WNT5A potentiates TGFβ and YAP signaling to constitute a TGFβ-WNT5A-YAP signaling loop. Noncanonical WNT signaling induces CSC dormancy through canonical WNT signaling inhibition and cross-talk with TGFβ signaling. Proliferation/dormancy plasticity is controlled by the canonical and noncanonical WNT signaling networks via cell cycle control.