The current paradigm and challenges ahead for the dormancy of disseminated tumor cells

Abstract

Disseminated tumor cells (DTCs) are known to enter a state of dormancy that is achieved via growth arrest of DTCs and/or a form of population equilibrium state, strongly influenced by the organ microenvironment. During this time, expansion of residual disseminated cancer is paused and DTCs survive to fuel relapse, sometimes decades later. This notion has opened a new window of opportunity for intervening and preventing relapse. Here we review recent data that have further augmented the understanding of cancer dormancy and discuss how this is leading to new strategies for monitoring and targeting dormant cancer.

Fig. 1 ∣. Differences and commonalities among normal quiescent, senescent, differentiated cells and dormant cancer cells.

Cell-cycle arrest and survival programs are shared across all programs. Although differentiation and senescence are typically irreversible or highly stable stages, quiescence and dormancy are reversible. It would appear that normal quiescent cells and dormant cancer cells interpret the same microenvironmental factors in a similar manner, and this leads to the activation of survival and self-renewal programs. However, dormant DTCs also turn on diapause and pluripotency programs and an unfolded protein response (UPR) also observed in senescent cells. Normal quiescent, senescent and differentiated cells are green; the dormant cancer cell is blue. SASP, senescence-associated secretory phenotype.

Fig. 2 ∣. The various BM niches, cell types and cues that regulate the dormancy of DTCs and HSCs.

Both the osteoblastic niche and the perivascular niche in the BM are involved in DTC dormancy by producing a wide range of cues (cytokines, microRNA, extracellular vesicles, cell-cell contact signaling, etc.) that drive dormancy. Additionally, dormant cancer cells downregulate antigen presentation and upregulate immunosuppressive ligands in order to evade recognition by the immune system. Over time and reciprocally, cancer cells also remodel their surrounding microenvironment and hypothetically feed a proliferative positive loop. EVs, extracellular vesicles; ECs, endothelial cells; PD-1, receptor for PD-L1; MHCI, MHC class I; vWF, von Willebrand factor; MSC, mesenchymal stem cell.

Fig. 3 ∣. Cues, receptors and cell types involved in DTC reactivation and pro-dormancy niches.

In the BM, a pro-dormancy niche involves the action of several factors (such as LIF, TGFβ2, GAS6, BMPs; additional details, Table 1) that leads to the induction of quiescence in both DTCs and HSCs. In contrast, reactivation niches in the lung and liver awaken dormant DTCs in a manner that involves formation of NETs, extracellular matrix stiffness, TGFβ1 and inhibitors of BMP molecules. NE, neutrophil elastase.