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  • Review Article
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Models, mechanisms and clinical evidence for cancer dormancy

Nature Reviews Cancer volume 7, pages 834–846 (2007)Cite this article

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.

Abstract

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.

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Figure 1: Tumour dormancy as a component of cancer progression.
Figure 2: Manifestation of cancer dormancy.
Figure 3: Signals that regulate cellular tumour dormancy.
Figure 4: An integrated view of cancer metastasis dormancy.

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Acknowledgements

I apologize to those authors whose work I could not cite directly because of space constraints. I would like to thank the members of my laboratory and L. Ossowski (Mount Sinai School of Medicine) for stimulating discussions and critical reading of the manuscript. I also thank D. Schewe for discussions and help with the figures. This work is supported by a grant from the Samuel Waxman Cancer Research Foundation Tumour Dormancy Program and the NIH/National Cancer Institute grant CA109182 to J.A.A.G.

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  1. Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, University at Albany, State University of New York, One Discovery Drive, Rensselaer, 12144-3456, New York, USA

    Julio A. Aguirre-Ghiso

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colon cancer

gastric cancer

head and neck carcinoma

oral cavity

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Glossary

Disseminated tumour cells

Tumour cells that have physically separated from the primary tumour and spread to other anatomical locations through circulation. In this Review these tumour cells are not yet considered micrometastases as they have not yet expanded to form a small population of cells.

Minimal residual disease

Remnant tumour cells that are left after treatment and that cannot be detected by conventional clinical testing. These cells can persist in the primary site or as disseminated tumour cells in proliferative and/or dormant phases.

Dormant

Applies to cells in a non-dividing state whose physiological functions become paused or quiescent. In several organisms, such as Caenorhabditis elegans, dormant is a synonym for diapause (pause in development). Plant seeds are also dormant during the latency phase before germination.

Tumour mass dormancy

Cancer cell proliferation that is counterbalanced by apoptosis owing to poor vascularization (see angiogenic dormancy) or by an immune response. In this case the cancer cells are never truly inactive, but rather are incapable of expanding beyond a certain number.

Cellular dormancy

When normal cells enter the G0 phase of the cell cycle and have low metabolism. This might apply to cancer cells that enter a G0–G1 arrest. This form of dormancy is clinically asymptomatic, and the tumour cells are truly inactive.

Angiogenic dormancy

Occurs when cancer cell proliferation is counterbalanced by apoptosis owing to poor vascularization. In this case, the cancer cells are incapable of expanding beyond a certain number and although clinically asymptomatic the tumour cells are not truly inactive.

Genetically fit

The concept of evolutionary genetic fitness. Having the appropriate traits and properties to survive and grow in a particular environment.

Immortalization

Cells with genetic alterations that become insensitive to the Hayflick limit (the number of times a normal cell can divide in vitro before dying or entering senescence). Immortalized cells evade senescence and proliferate limitlessly in culture but are unable to form tumours.

Transformation

Cells that have been immortalized but now acquire additional genetic and epigenetic alterations that allow them to form primary tumours.

Micrometastasis

A small group of tumour cells, derived from a disseminated tumour cell, that has grown in secondary organs but is too small to be seen or detected by available methods. These lesions might also be clinically asymptomatic.

Orthotopic

The growth of transplanted cells or tissues in the normal anatomical position and tissue of origin.

Niche

A term borrowed from ecology, it refers to a unique and optimal tissue microenvironment with defined nurturing and positional cues in a given anatomical location that allows a cell or group of cells to survive and function.

Reconstituted basement membrane assays

Assays that take advantage of extracellular matrix gels that are derived from a cancer cell line, or collagen-I gels. Cells embedded in these matrices can recapitulate the tissue organization that is observed in the tissue of origin.

Acinar structures

Sac-like structures that are formed by secretory epithelial cells that have defined apico-basal polarity.

Fibronectin

An extracellular matrix molecule that is a main constituent of normal tissues but is also present in serum. The α5β1 integrin is its most specific receptor (other integrins can also bind it) and it can serve as a survival or mitogenic factor.

CD8+ T lymphocytes

Immune cells from the T-cell lineage specialized in killing target cells (that is, virus-infected cells). These responses are usually mediated by class-I major histocompatibility complexes and cytotoxicity is delivered by a repertoire of molecules that are contained in secretory vesicles.

Neovascularization

The formation of new blood vessels that create new pathways for blood flow during normal tissue development or remodelling, or during pathological conditions such as tumour growth or retinopathy.

Angiogenic switch

When a small tumour mass senses the lack of appropriate blood supply and activates a series of transcriptional programmes that allows them to produce signals that will recruit new blood vessels.

Adaptation

Mechanisms that allow normal or tumour cells to respond to a determined stress with a programme that allows them to correct and survive the imposed stress signals.

Dauer stage

German for 'enduring'. It is an alternative larval stage in which development is arrested in response to environmental or hormonal cues in nematodes such as Caenorhabditis elegans. It allows larvae to survive harsh conditions for long periods until the environment is propitious to resume development.

Unfolded protein response

A cellular response to stress that is unique to the endoplasmic reticulum (ER), and which senses the misfolding of proteins in the ER. It activates a series of pathways that help the cells survive proteotoxicity that is caused by unfolded proteins or activate mechanisms of cell death.

Humoral response

The component of the immure response that is mediated by secreted antibodies.

Anti-idiotypic antibodies

Antibodies that are directed towards the hypervariable regions of an antibody.

Oestrogen starvation

Occurs when cells that are usually dependent on oestrogen for normal cellular functions are deprived of this hormone. This is usually done in cell culture by leaving oestrogen out of the tissue culture medium.

ABC transporters

ATP-dependent protein pumps that extrude numerous compounds from the cell cytoplasm. These can be exogenous molecules such as drugs, or physiological membrane constituents such as cholesterol.

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Aguirre-Ghiso, J. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7, 834–846 (2007). https://doi.org/10.1038/nrc2256

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