Figure 4. An integrated view of cancer metastasis dormancy.

Tumour cells that survive dissemination lodge in the target organ parenchyma. This new microenvironment most probably determines the fate of the disseminated tumour cells and could account for most of the dormancy time (Time #1). If the cells are not genetically progressed it is possible that they are unable to grow autonomously or transduce growth signals from the microenvironment, instead entering a quiescence-like phenotype. Stress from dissemination might contribute to activating growth arrest programmes. Even with genetic alterations, stress and/or microenvironment signals might impose a growth-suppressive programme. For tumour stem cells, a quiescent state might be a natural response to a microenvironment that lacks recruitment signals. Normal differentiated cells can remain growth arrested for years and solitary cells are found years after surgery, suggesting that a prolonged tumour cell arrest might be plausible. Upon exit from quiescence, tumour cells can fully progress into overt lesions. It is possible that before becoming overt lesions, dormancy might continue (Time #2) owing to the immune system preventing tumour expansion. The immune system can control pathogens during a lifetime. Therefore, it might prevent tumour mass expansion for long periods. After exit from quiescence or evasion of the immune system a tumour cell mass can enter angiogenic dormancy. Differentiated tissues such as the retinal pigment epithelium, which produces angiogenesis inhibitors (pigment epithelium-derived factor 126), can maintain the vasculature from expanding for long periods and therefore prevent diseases such as macular degeneration. However, it is still unclear how long (Time #3) this mechanism can be maintained in a genetically unstable proliferative tumour cell population, which probabilistically should be prone to accumulating new genetic alterations that activate the angiogenic switch.