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Metastasis: a question of life or death

Key Points

  • Metastasis occurs through a series of sequential steps in which tumour cells first migrate from the primary tumour, penetrate blood vessels and then colonize distant sites. It is a highly inefficient process. Indeed, very few of the tumour cells that gain access to the vasculature give rise to metastastic foci in a secondary organ.

  • Recent data indicate that the mechanisms controlling metastasis can be regulated independently from primary tumour development.

  • In vitro and in vivo, the metastatic potential of tumours is associated with an increased resistance to apoptosis. Furthermore, the experimental modulation of apoptotic or anti-apoptotic factors influences metastatic efficiency.

  • Anoikis and amorphosis are important barriers to metastasis. Anoikis is cell death induced by the disruption of cell attachment and cell–matrix interactions, whereas amorphosis is cell death stimulated by the loss of cytoskeletal architecture.

  • Early survival of tumour cells after attachment to the secondary site and the development of micrometastases are crucial steps of the metastatic process.

  • Metastasis is the most common cause of cancer death. Most patients with metastatic disease respond transiently to conventional treatments. Further elucidation of the relationship between resistance to apoptosis of metastatic cancer cells and their chemoresistance should provide important clues to improve systemic therapies.

Abstract

The metastatic process is highly inefficient — very few of the many cells that migrate from the primary tumour successfully colonize distant sites. One proposed mechanism to explain this inefficiency is provided by the cancer stem cell model, which hypothesizes that micrometastases can only be established by tumour stem cells, which are few in number. However, recent in vitro and in vivo observations indicate that apoptosis is an important process regulating metastasis. Here we stress that the inhibition of cell death, apart from its extensively described function in primary tumour development, is a crucial characteristic of metastatic cancer cells.

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Figure 1: Apoptosis as a safeguard system preventing metastasis at three crucial steps.
Figure 2: Resistance to anoikis and amorphosis is a crucial event during metastatic spread.
Figure 3: Tumour immune surveillance.
Figure 4: Role of the microenvironment in the development of micrometastases.
Figure 5: The dependence receptor model and metastasis.

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Acknowledgements

We thank H. Bilak for text correction, C. Caux for critical reading of the manuscript and B. Bouchet for the development of figures. Work in Mehlen's and Puisieux's laboratories are supported by institutional funds from the Centre National de la Recherche Scientifique (P.M.), Agence Nationale de la Recherche (ANR) (P.M.), Institut national de la santé et de la recherche médicale (A.P.), and Institut National du Cancer (INCA) (P.M. and A.P.), and by grants from the Ligue Nationale Contre le Cancer (P.M. and A.P.), the Association pour la Recherche contre le Cancer (P.M. and A.P.), the Comité Départemental de l'Ain (A.P.) and the National Institute of Health (P.M.).

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Glossary

Natural killer cells

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Mehlen, P., Puisieux, A. Metastasis: a question of life or death. Nat Rev Cancer 6, 449–458 (2006). https://doi.org/10.1038/nrc1886

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