Metastasis ‘systems’ biology: how are macro-environmental signals transmitted into microenvironmental cues for disseminated tumor cells?

•DTC dormancy is maintained through tissue (particularly endothelial) homeostasis.•Chronic lifestyle exposures (e.g., alcohol) alter organ physiology.•Lifestyle exposures increase site-specific relapse by disrupting the dormant niche.•We advocate for metastasis prevention strategies that incorporate lifestyle changes or lifestyle change-inspired therapies. Disseminated breast tumor cells reside on or near stable microvascular endothelium. Currently, the cues that disrupt DTC dormancy and facilitate outgrowth are largely unknown. This article explores the hypothesis that specific patient lifestyle exposures (e.g., alcohol abuse) may disrupt the microenvironments that maintain disseminated tumor cell (DTC) dormancy in a tissue-specific fashion. We suggest that such exposures are ‘transmitted’ to the dormant niche in the form of injury. Thus, we discuss the relationship between wound healing and metastasis using liver as an example to illustrate how injury steers the phenotype of liver endothelium and perivascular hepatic stellate cells to a potentially pro-metastatic one. We posit further that non-steroidal anti-inflammatory drugs (NSAIDs) — recently shown to prevent metastatic relapse — may act by preserving the dormant niche. We conclude by suggesting that maintenance of the dormant niche – either through patient lifestyle or via development of therapeutics that mimic local molecular cues/responses that coincide with a healthy lifestyle – is a means to prevent metastatic relapse, and should be the subject of far greater research.