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  • Review Article
  • Published:

Metastasis: from dissemination to organ-specific colonization

Nature Reviews Cancer volume 9, pages 274–284 (2009)Cite this article

Key Points

  • Metastasis progression can be viewed as a stepwise sequence of events, which is mediated by different classes of metastasis genes.

  • For each type of cancer, the clinical course of these events occurs with distinct temporal kinetics and in unique organ sites.

  • The long latency period of certain tumour types suggests the further evolution or 'speciation' of malignant cells in the microenvironments of a particular organ. The acquisition of pro-metastatic functions earlier during primary tumour formation might enable other cancer subtypes to relapse more quickly.

  • The organ specificity of metastatic cells is determined by unique infiltrative and colonization functions required after their dissemination from a primary tumour.

  • New insights into the importance of latency and organ-specific colonization should be considered in the design of optimized therapeutic strategies.

Abstract

Metastasis to distant organs is an ominous feature of most malignant tumours but the natural history of this process varies in different cancers. The cellular origin, intrinsic properties of the tumour, tissue affinities and circulation patterns determine not only the sites of tumour spread, but also the temporal course and severity of metastasis to vital organs. Striking disparities in the natural progression of different cancers raise important questions about the evolution of metastatic traits, the genetic determinants of these properties and the mechanisms that lead to the selection of metastatic cells.

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Figure 1: Basic steps of metastasis and hypothetical classes of metastasis genes.
Figure 2: Organ-specific barriers to metastatic infiltration.
Figure 3: Metastasis progression genes expressed in the primary tumour.
Figure 4: The temporal course of metastasis.
Figure 5: Metastatic speciation of latent disseminated tumour cells.

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Acknowledgements

We thank members of the Massagué lab for insightful discussions. The primary research for the topic of this review is supported by grants from the National Institutes of Health, the Hearst Foundation and the Kleberg Foundation. D.X.N was a postdoctoral fellow of the Damon Runyon Cancer Research Foundation. J.M. is an Investigator of the Howard Hughes Medical Institute.

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  1. Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Don X. Nguyen, Paula D. Bos & Joan Massagué

  2. Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Joan Massagué

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  1. Don X. Nguyen
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Correspondence to Joan Massagué.

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Glossary

Infiltration

The entry of cancer cells into distant organs through invasion and extravasation.

Colonization

The outgrowth of metastatic cells that have co-opted a distant organ microenvironment.

Latency

The time between primary tumour diagnosis and clinically detectable metastatic outgrowths.

Intravasation

The entry of tumour cells into the bloodstream.

Extravasation

The exit of tumour cells from capillary beds into the parenchyma of an organ.

Basal breast cancer

A more aggressive subtype of breast cancer with characteristics of mammary basal cells, and that typically lacks oestrogen and progesterone receptors.

Luminal breast cancer

A subtype of breast cancer with characteristics of cells that originate from the normal lumen or ducts of the mammary gland.

Dormancy

A state of cellular quiescence in the G0 phase of the cell cycle. When referring to a tumour cell mass, dormancy describes a balanced state of proliferation and apoptosis.

Angiogenic switch

The transition between a non-angiogenic state of the tumour cell mass and a neovascularized state that enables tumour oxygenation and growth.

Tumour-propagating phenotype

The ability of the infiltrated tumour cells to reinitiate growth at the secondary site. This is referred to by some investigators as the 'cancer stem cell phenotype'.

Metastatic speciation

An evolutionary process by which new metastatic populations arise, owing to the various selective pressures that act on the heterogeneous cancer cells escaping the primary tumour.

Gliosis

Stimulation of astrocytes in injured areas of the brain.

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Nguyen, D., Bos, P. & Massagué, J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9, 274–284 (2009). https://doi.org/10.1038/nrc2622

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