Figure 2. Manifestation of cancer dormancy.

a Tumour cells that have accumulated genetic and epigenetic changes that provide a growth advantage (solid blue line) form a primary tumour. After a treatment that results in tumour regression, residual disease can be detectable for long periods thereafter (dashed blue line). After this time, the tumour mass can increase again, but now in distant secondary organs (dashed red lines). b During the dormancy stage, sub-clinical disease might be due to dormant cells that have entered a G0–G1 arrest (cellular dormancy) and these cells might develop mechanisms to evade immune system recognition and eradication. c Angiogenic dormancy results from the balance between pro- and anti-angiogenic factors (such as vascular endothelial growth factor (VEGF) and thrombospondin (TSP), respectively). Genetic alterations in the pathways that maintain angiogenic dormancy or an exogenous angiogenic ‘spike’ might restore tumour growth. Oncogenic Ras can induce VEGF and repress TSP. By contrast, the stress-activated kinase p38 and the tumour suppressor p53 can induce TSP or repress VEGF. Loss of function of p53 and/or p38 might tip the balance towards enhanced angiogenesis. d Immunosurveillance. Proliferating tumour cells are kept at low numbers (sub-clinical) by an active immune system. This can be due to cytotoxic CD8+ T lymphocytes or anti-idiotypic antibodies against the B-cell receptor that arrest the tumour cells. An interruption of this state of dormancy might be due to tumour cell escape from immune system control by downregulation of specific tumour-associated antigens or by expression of co-stimulatory molecules that induce apoptosis of cytotoxic CD8⁺ T lymphocytes. It is unclear whether these forms of dormancy are mutually exclusive, although they are probably not, how long they last or whether they occur at different times. It is possible that cellular dormancy most frequently precedes the immunosurveillance or the angiogenic dormancy phase.