The Relationship Between Dormant Cancer Cells and Their Microenvironment

Abstract

The majority of cancer deaths are due to metastases that can occur years or decades after primary tumor diagnosis and treatment. Disseminated tumor cells (DTCs) surviving in a dormant state in target organs appear to explain the timing of this phenomenon. Knowledge on this process is important as it might provide a window of opportunity to prevent recurrences by eradicating dormant DTCs and/or by maintaining DTCs in a dormant state. Importantly, this research might offer markers of dormancy for early monitoring of metastatic relapse. However, our understanding of the mechanisms underlying the regulation of entry into and exit from dormancy is still limited and crippling any therapeutic opportunity. While cancer cell-intrinsic signaling pathways have been linked to dormancy regulation, it is likely that these pathways and the switch controlling reactivation from dormancy are regulated by microenvironmental cues. Here we review and discuss recent findings on how the microenvironment regulates cancer dormancy and raise new questions that may help advance the field.

Keywords: Cancer immunology; Cancer signaling; Dormancy; Dormancy models; Latency; Metastasis; Microenvironment; Minimal residual disease.

Fig. 1

Overview of dormancy-inducing signaling pathways. (A) Overview of dormancy marker expression in DTCs based on known dormancy-signaling pathways. (B) Microenvironment-derived atRA, TGFβ2, and BMP-4 and -7 cooperate to induce a dormant state in DTCs characterized by activating p38 and NR2F1 and inhibiting ERK1/2 signaling. p38 and NR2F1 induce the cell cycle inhibitors p27 and p21, which results in cell cycle arrest (Bragado et al., 2013; Kobayashi et al., 2011; Sosa et al., 2015).

Fig. 2

Extrinsic signals inducing dormancy in disseminated tumor cells (DTCs) in different microenvironments. (A) Dormancy induction in the bone microenvironment is in part mediated by osteoblasts through GAS6/AXL signaling (Shiozawa et al., 2010; Taichman et al., 2013). DTCs can escape osteoblast-induced dormancy through activation of TYRO or through activation of osteoclasts. Osteoclasts can be activated through RANKL (Lawson, McDonald, et al., 2015) or through recruitment of osteoclast progenitors via VCAM1/integrin α4β1 signaling (Lu et al., 2011). How these dormancy escape mechanisms occur spontaneously in patients and whether they resemble alternative dormancy pathways or cooperate remain to be established. (B) DTCs in the perivascular niche frequently enter dormancy due to thrombospondin (TSP-1) signaling (Ghajar et al., 2013). Activated endothelium on the other hand releases periostin (POSTN) and TGFβ1 that induce DTC proliferation and possibly escape from dormancy. (C) BMP-4, a TGFβ family member enriched in the lung microenvironment, induces dormancy (Gao et al., 2012). Overexpression of CoCo, a BMP inhibitor, allows DTCs to escape dormancy.

Fig. 3

Effects of macrophages and NK cells on dormancy. (A) Monocytes are recruited to DTCs by CCL2 and assist their extravasation in the lung through VEGF secretion (Qian et al., 2009, 2011). In the lung tissue, these monocytes differentiate into metastasis-associated macrophages that promote DTC proliferation (Kitamura et al., 2015; Qian et al., 2015). (B) The role of monocytes and macrophages in dormancy has not been established. If DTCs require monocytes to extravasate, why do some DTCs enter dormancy instead of entering a cycle of macrophage-assisted proliferation? Can niche-derived factors such as TSP-1 in the endothelial niche override the growth-promoting effect of macrophages? Are there macrophage subtypes that induce dormancy? Do some DTCs fail to retain growth-promoting macrophages? Can DTCs extravasate independent of monocytes and therefore enter dormancy? (C) Activation of WNT signaling allows DTCs to enter a proliferative state in which they are more susceptible to cytotoxic signals from NK cells. Once cells enter a dormant state through activation of DKK1 and subsequent WNT inhibition, they are able to escape NK cytotoxic signals (Malladi et al., 2016).

Fig. 4

Effects of T-cells on dormancy. (A) Some studies suggest that dormant DTCs survive by escaping adaptive immune responses (Matsuzawa et al., 1991; Saudemont & Quesnel, 2004; Weinhold et al., 1979). (B) Other studies indicate that T-cell-derived IFNγ and TNFR signaling induce dormancy (bottom) (Farrar et al., 1999; Muller-Hermelink et al., 2008). (C) Whether immune-mediated dormancy resembles cellular dormancy or population-based dormancy, where tumor cell killing and proliferation are in equilibrium, is not clear either.