Models, mechanisms and clinical evidence for cancer dormancy

Abstract

In the clinic, tumour dormancy is observed in local recurrences or metastases. It usually refers to the time after treatment that a patient is asymptomatic but still carries local remnant or disseminated tumour cells that do not grow into overt lesions. Tumour dormancy ensues when cancer cell proliferation is counteracted by other mechanisms such as apoptosis because of impaired vascularization or immunosurveillance, and cellular dormancy ensues when the cancer cells enter a growth arrest. Cancer dormancy is a relevant problem because the majority of solid tumours and haematological malignancies undergo a period of dormancy that is characterized by years to decades of minimal residual disease. Because metastases always arise from disseminated tumour cells it is of importance to understand the biology of dormant tumour cells. Several mechanisms can explain cancer dormancy. These include the disruption of crosstalk between growth factor and adhesion signalling, which prevents tumour cells from interpreting their microenvironment, leading to cellular tumour dormancy through a G0–G1 arrest or 'differentiation'; the inability of a tumour cell population to recruit blood vessels despite active proliferation; and immunosurveillance, which can prevent residual tumour cell expansion. The expression of genes that selectively suppress metastases might function by inducing dormancy. In addition, quiescent tumour 'stem' cells might be dormant tumour cells. Finally, dormant tumour cells seem to have active drug resistance mechanisms that might protect them from therapy. The therapeutic opportunities that emerge from understanding dormancy include the possibility of inducing and/or maintaining the dormancy of tumour cells and inducing cell death in residual dormant cells by targeting their survival and drug-resistance mechanisms. Studies of cancer dormancy might help determine whether a patient has dormant disease and what type of mechanism is active. These studies will be instrumental in identifying biomarkers of dormant cancer.