Do all roads lead to Rome? Routes to metastasis development

Metastasis, the life-threatening aspect of cancer, is a systemic disease process. Considerable progress has been made in recent years regarding how tumor cells circulating in the blood and lymphatic systems interact with and extravasate into secondary sites, and what determines whether these disseminated tumors cells survive, remain dormant or go on to form macrometastases. New insights into the routes that tumor cells take once leaving the primary tumor have emerged. Novel concepts regarding early seeding of metastases coupled to parallel progression, self-seeding of primary tumors by circulating tumor cells and the induction of premetastatic niches in distant organs by primary tumors have come to the fore. The perceived role of the lymphatic system in determining patterns of metastasis formation in distant organs has been reassessed. Together these new insights have the potential to offer new therapeutic options. In particular, the regulation of tumor cell dormancy emerges as a key event in metastasis formation, and therapeutic control of dormancy holds the promise of rendering cancer a chronic rather than life-threatening disease.