Disseminated tumor cells (DTCs) are recognized as the seeds of metastasis. However, metastatic lesions can become symptomatic years or decades after primary tumor removal. This clinical finding suggests that DTCs are not immediately competent to initiate growth and can persist in a dormant state. Here we review recent data for three potential scenarios that could result in DTC dormancy: () The target organ microenvironment instructs DTCs to enter dormancy; () primary tumors pre-encode a dormancy signature that only becomes evident when DTCs enter target organs that produce dormancy-inducing cues; and () early dissemination spawns DTCs that, by virtue of being closely related to normal cells, would retain the capacity to respond to dormancy-instructing signals and enter dormancy in target organs. The literature supports the existence of these scenarios and provides insight into how to prevent metastasis. Importantly, cotargeting dormant and proliferative DTCs in stage IV cancer may also improve outcomes in this clinical setting.


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