Cellular Phenotype Plasticity in Cancer Dormancy and Metastasis

Abstract

Cancer dormancy is a period of cancer progression in which residual tumor cells exist, but clinically remain asymptomatic for a long time, as well as resistant to conventional chemo- and radiotherapies. Cellular phenotype plasticity represents that cellular phenotype could convert between epithelial cells and cells with mesenchymal traits. Recently, this process has been shown to closely associate with tumor cell proliferation, cancer dormancy and metastasis. In this review, we have described different scenarios of how the transition from epithelial to mesenchymal morphology (EMT) and backwards (MET) are connected with the initiation of dormancy and reactivation of proliferation. These processes are fundamental for cancer cells to invade tissues and metastasize. Recognizing the mechanisms underlying the cellular phenotype plasticity as well as dormancy and targeting them is likely to increase the efficiency of traditional tumor treatment inhibiting tumor metastasis.

Keywords: EMT; MET; cancer cell dormancy; cancer metastasis; cellular phenotype plasticity.

Figure 1

During tumor progression, epithelial tumor cells undergo partial EMT through their crosstalk with contextual signals, including growth factor signaling, inflammatory cytokines, immune environment and hypoxia. Concomitantly, these tumor cells within intermediate states gain the ability of motility while remaining cell-cell junction and expressing E-cadherin. After complete EMT, the intermediate tumor cells lose their epithelial junctions, their cytoskeleton reconstructed and vimentin filaments were generated instead of E-cadherin. After intravasation and extravasation through blood vessel, the EMT positive tumor cells arrive at their target organ, and they have to experience MET to accomplish colonization.

Figure 2

Snail, one of EMT transcription factors, could dramatically impair cell-cycle progression by repressing the transcription of cyclin D2. Moreover, Snail could suppress tumor cell proliferation through binding to flanking region of proliferating cell nuclear antigen (PCNA) gene to decrease its expression. When Snail suppresses the expression of PCNA, the PAF (PCNA-associated factor) then dissociates from PCNA complexes and combines with β-catenin, which then upregulates Wnt/β-catenin target gene expression via activating Wnt signaling pathway and represses E-cadherin expression. And Zeb1 and Snail induce G1 arrest by promoting hypophosphorylation of Rb protein, the suppressor protein of tumor progression, and decreasing the expression of cyclin D1.

Figure 3

During tumor progression, EMT positive tumor cells from primary tumor gain the ability of migration and invasion and their proliferation is inhibited which are thought to be dormant tumor cells. They are colored gray. After systemic dissemination, only a small portion of circulating tumor cells arrive at their target organ and they have to undergo MET to accomplish colonization. Until now, there are two different viewpoints concerning the following stages. (A) when EMT positive tumor cells arriving at target organ, the MET program induce their colonization and activation. The activated tumor cells then proliferate into macrometastasis. They are colored red. (B) when EMT positive tumor cells arriving at target organ, the MET program may just promote their colonization or formation of micrometastasis that stay in dormant stage. Then the secondary partial EMT is thought to induce their activation and turn the dormant micrometastasis into macrometastasis.

Figure 4

Once activated, TGF-β bound to its cell surface receptor forming tetrameric complexes to promote the formation of Smad family transcription factors, which then move into nucleus and combine as well as concomitantly up-regulate the expression of other transcription factors including Snail, Zeb, and Twist. Moreover, TGF-β/Smad involved in EMT program need the cooperation of some other pathways, including Wnt/β-catenin. TGF-β could up-regulate the expression of β-catenin and its nuclear accumulation.