Metastasis prevention by targeting the dormant niche

Abstract

Despite considerable advancements that shattered previously held dogmas about the metastatic cascade, the evolution of therapies to treat metastatic disease has not kept up. In this Opinion article, I argue that, rather than waiting for metastases to emerge before initiating treatment, it would be more effective to target metastatic seeds before they sprout. Specifically, I advocate directing therapies towards the niches that harbour dormant disseminated tumour cells to sensitize them to cytotoxic agents. Treatment sensitization, achieved by disrupting reservoirs of leukaemic stem cells and latent HIV, argues that this approach, although unconventional, could succeed in improving patient survival by delaying or even preventing metastasis.

Figure 1. Properties of dormant disseminated tumor cells (DTCs) are conferred by tissue-specific perivascular niches

Three properties that define dormant DTCs: survival, temporary growth arrest, and therapeutic resistance (a). Summaries of known and hypothesized mediators of these properties— survival (purple), quiescence (blue) and drug resistance (green) are shown for different tissue types. Lung (b), bone marrow (c) and brain (d) perivasculature exhibit tissue-specificity, and are a rich source of factors that confer dormancy properties. Whereas chemokine (C-X-C motif) ligand 12 (CXCL12)–chemokine (C-X-C motif) receptor 4 (CXCR4) signaling may mediate homing to and engraftment of each site, quiescence in lung is mediated by thrombospondin 1 (TSP-1) and bone morphogenetic protein 4 (BMP-4). Angiocrine tumor necrosis factor α (TNFα) drives chemoresistance of DTCs and may do the same for dormant DTCs. Conversely, TSP-1, BMP-7, transforming growth factor β2 (TGF-β2) and growth arrest-specific 6 (GAS-6) mediate DTC quiescence in bone marrow. Factors known to drive and maintain hematopoietic stem cell (HSC) quiescence (CXCL4, stem cell factor (SCF) and angiopoietin-1 (Ang-1)) may also act on DTCs in the bone marrow. Additionally, osteopontin may drive chemoresistance of solid tumor cells, as it does for leukemic cells. Finally, in the brain, osteopontin, laminins (primarily laminin-α2) and NOTCH ligands are niche constituents of stem-like glioblastoma cells, whereas ephrin-B2 is a known inducer of neural stem cell quiescence. These factors may also act on DTCs in brain, which require initial adhesion to the perivasculature to survive. Osteopontin and nitric oxide drive therapeutic resistance of glioblastoma cells, and these perivascular cues may function also to confer resistance to dormant DTCs. CAR, CXCL12-abundant reticular

Figure 2. Parallels between stem cell- and dormant disseminated tumor cell (DTC)-regulation by the perivascular niche

Stem cell survival and growth-arrest are maintained in a number of tissues by the perivascular niche. Upon activation of the niche (e.g., by wounding), growth-arrest cues are lost and/or overcome by proliferation-inducing signals, some of which are derived from endothelium. Stem cells give rise to rapidly dividing tissue-specific progenitors, which are ultimately steered towards differentiated cell types found in that tissue. DTCs are regulated in a similar fashion. Stable microvasculature maintains DTCs in a quiescent state; upon disruption of tissue homeostasis, activation cues (e.g., those derived from nascent, sprouting endothelium) spark DTC proliferation. Here, however, proliferating DTCs ignore differentiation cues and secrete a number of factors that lure resident- and circulating-cells to aid metastatic progression. Whether the parallels between tissue-specific stem cells and dormant DTCs end here, or whether dormant DTCs are indeed regulated by native stem cell niches within each tissue they occupy, remains to be seen.

Figure 3. Two strategies to treat disseminated tumor cells

A. Primary tumors are typically treated by neoadjuvant or adjuvant therapy (black arrows) around the time of surgery, and exhibit variable and unpredictable relapse dynamics. Two types of treatment strategies meant to address latent disseminated disease could be employed peri-operatively; chronic dormancy maintenance therapy (blue) or niche-targeted agents meant to sensitize dormant DTCs to cytotoxic treatment (green). Either strategy could result in metastasis prevention (green and blue dashed lines, respectively) B. Examples of chronic dormancy maintenance include: inducing expression of a global regulator of tumor dormancy (e.g., p38) (left panel) or using small molecules to induce expression of key dormant niche constituents, such as those that mediate DTC quiescence (e.g., thrombospondin 1 (TSP-1)) (blue circles, right panel). C. Alternatively, niche-targeted chemo-sensitization could be achieved by targeting either molecules that tether DTCs to the niche in order to induce DTC mobilization (purple circle, top panel) or cues that confer therapeutic resistance to dormant DTCs within the niche (green circle, bottom panel).