Dormancy of metastatic melanoma

Abstract

Metastatic dormancy of melanoma has not received sufficient attention, most likely because once detectable, metastasis is almost invariably fatal and, understandably, the focus has been on finding ways to prolong life of patients with overt recurrences. Nevertheless, analysis of the published clinical and experimental data on melanoma indicates that some aspect of melanoma biology imitate traits recently associated with dormancy in other solid cancers. Among them the ability of some melanomas to disseminate early during primary tumor progression and once disseminated, to remain undetected (dormant) for years. Comparison of cutaneous and uveal melanoma indicates that, in spite of being of the same origin, they differ profoundly in their clinical progression. Importantly for this discussion, between 40 and 50% of uveal melanoma remain undetected for longer than a decade, while less than 5% of cutaneous melanoma show this behavior. Both types of melanoma have activating oncogene mutations that provide autonomous pro-proliferative signals, yet the consensus is that those are not sufficient for tumor progression. If that is the case, it is possible to envision that signals from outside the tumor cell, (microenvironment) shape the fate of an individual disseminated cell, regardless of an oncogene mutation, to progress or to pause in a state of dormancy. To stimulate further debate and inquiry we describe here a few examples of potential signals that might modify the fate of disseminated cell and provide brief description of the current knowledge on dormancy in other cancers. Our hope is to convince the reader that disseminated melanoma cells do enter periods of prolonged dormancy and that finding ways to induce it, or to prolong it, might mean an extension of symptoms-free life for melanoma patients. Ultimately, understanding the biology of dormancy and the mechanisms of dormant cell survival, might allow for their specific targeting and elimination.

Figure 1

Microenvironment and dormancy in melanoma. Mutations in B-Raf or N-Ras in cooperation with PTEN silencing or deletion help melanoma cells activate pro-survival and proliferation signals. Possibly, a similar proliferative signal is relayed by the mutant Gq protein. Survival signals activating PI3K and Akt might come also from integrin interaction with extracellular matrix. Conditions of reduced ERK mediated mitogenic and survival signals, with other survival signals intact, might allow melanoma cells to persist in a quiescent state. Because senescence is thought to be an early barrier to tumor development that is no longer functional in established melanoma, it is likely that quiescence (reversible) is the cell fate that better explains the cellular dormancy of melanoma cells. Microenvironment-derived signals that limit growth might be dependent on TGFβ signaling or on fibrillar collagen-I and DDR2 signaling. These can promote the upregulation of cell cycle inhibitors that might enforce quiescence. How these signals antagonize or uncouple the proliferative signals derived from the oncogenes is unknown. Liver, the main target of uveal melanoma metastasis, remains clinically free of disease for longer than 10 yr in close to half of the patients examined. This remarkable finding suggests that in some patients the microenvironment somehow causes yet unidentified mediators to induce anti-proliferative, most likely, epigenetic changes and establish melanoma cell dormancy.