Models, mechanisms and clinical evidence for cancer dormancy

• Published in: Nature reviews. Cancer Vol. 7; no. 11; pp. 834 - 846
• Main Author: Aguirre-Ghiso, Julio A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2007; Nature Publishing Group
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer cells; Cancer Research; Cell proliferation; Development and progression; Disease Progression; Drug Resistance, Neoplasm; Epigenesis, Genetic; Genetic aspects; Humans; Mice; Mice, Inbred Strains; Mice, Transgenic; Models, Biological; Neoplasm Invasiveness - physiopathology; Neoplasm Metastasis - physiopathology; Neoplasm Proteins - physiology; Neoplasm Recurrence, Local - physiopathology; Neoplasm, Residual; Neoplasms - blood supply; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - pathology; Neovascularization, Pathologic - physiopathology; Physiological aspects; review-article; Time Factors; Tumor Burden; Tumor Escape
• ISSN: 1474-175X; 1474-1768; 1474-1768
• DOI: 10.1038/nrc2256

Key Points 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. Cancer dormancy is a very important yet poorly understood phenomenon in cancer progression. What do we know about the mechanisms of cancer dormancy and can it be targeted therapeutically? Patients with cancer can develop recurrent metastatic disease with latency periods that range from years even to decades. This pause can be explained by cancer dormancy, a stage in cancer progression in which residual disease is present but remains asymptomatic. Cancer dormancy is poorly understood, resulting in major shortcomings in our understanding of the full complexity of the disease. Here, I review experimental and clinical evidence that supports the existence of various mechanisms of cancer dormancy including angiogenic dormancy, cellular dormancy (G0–G1 arrest) and immunosurveillance. The advances in this field provide an emerging picture of how cancer dormancy can ensue and how it could be therapeutically targeted.