Current Insight Into the Metastatic Process and Melanoma Cell Dissemination

Tumour metastasis is the primary cause of death in cancer patients, and cutaneous melanoma is one of the most highly metastatic cancers. While early stage melanomas are almost always curable, despite new and promising treatments (Flaherty et al., 2010; Hodi et al., 2010), advanced unresectable melanomas (Stage III and IV) have a much worse prognosis (Shivers et al., 1998). Similarly, once uveal melanomas have metastasized, they are irremediably lethal (Kivela et al., 2006). Until recently, tumour cell dissemination was thought to be a late event in cancer progression (Fearon and Vogelstein, 1990). But the advent of sensitive and reliable techniques for detecting circulating tumour cells has revealed that tumour cells can disseminate long before the primary tumour reaches a clinically detectable size. A growing body of convergent studies, including those from our laboratory, confirms this finding in both mice and humans. If some cancer cells disseminate before diagnosis and if metastases develop from these disseminated cancer cells, how can the treatment of the primary tumour impact disease progression? Or might it be more efficient to focus therapeutic intervention on the control of the disseminated cancer cells? This new paradigm of early dissemination implies that disseminated cancer cells remain dormant or under control for prolonged periods of time, often for decades, before developing into overt metastases. It is not yet clear why only some disseminated cancer cells develop into metastases and why not all patients with disseminated cancer cells develop metastatic disease. Tumour-initiating cells may only represent a small fraction of disseminated cancer cells, as proposed by the cancer stem cell hypothesis. Alternatively, disseminated cancer cells may require additional adaptation to their new environment or specific signals delivered by their new environment to exit from dormancy (the metastatic niche model). It is certain that the immune system plays a crucial role in controlling the dormancy of disseminated cancer cells, since both acquired and iatrogenic immune