Ecology and evolution of dormant metastasis.

Genetic studies suggest that sequential dissemination from a primary metastasis, usually at the bone, is a major route of metastatic progression in early, radically resected cancer. Disseminated tumor cells (DTCs) can likely infiltrate but not grow, and may remain dormant once disseminated for extended intervals (from months to decades). The stationary nature of DTCs prevents them from being successfully treated as an asymptomatic residual disease in the adjuvant setting; critically, they can eventually relapse, adapt, and develop therapy resistance, causing incurable overt metastasis. Metastatic lesions usually first appear in one tissue, which invigorates metastatic cells for further dissemination to other organs, with a fatal outcome. Clinical and genetic data now indicate that metastatic lesions in one organ can seed secondary metastases in other organs: in other words, metastasis arising from metastasis. Herein we discuss recent insight into metastasis cell dormancy mechanisms, survival, communication with the local microenvironment, and eventual changes that endow DTCs with the capacity to expand and colonize to other metastatic sites.