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Calcium in tumour metastasis: new roles for known actors

Key Points

  • The ubiquitous second messenger Ca2+ is a crucial regulator of cell migration. Although increases in intracellular Ca2+ concentration ([Ca2+]i) organized in space, time and amplitude have been known to be important in cell migration for some time, the sources of Ca2+ and the mechanism by which it modulates this process in cancer cells are only now beginning to be understood.

  • In general, Ca2+-dependent mechanisms of malignant migration do not seem to be very different from those that are evident in normal physiological migration, and thus searching for potential differences is quite a challenging task. The major differences seem to arise on a quantitative level owing to aberrant expression of Ca2+-handling proteins and/or Ca2+-dependent effectors, leading to the increased turnover of focal adhesions and more effective proteolysis of extracellular matrix components.

  • Recently, a number of known molecular players in cellular Ca2+ homeostasis, such as the Ca2+-permeable members of the transient receptor potential (TRP) channel family and the constituents of store-operated Ca2+ entry, calcium release-activated calcium channel protein 1 (ORAI1) and stromal interaction molecule 1 (STIM1), have been implicated in the development of the metastatic cell phenotype and tumour cell migration. The data linking specific TRP channels to cancer cell migration, invasion and metastasis are still largely phenomenological.

  • Ca2+-permeable ion channels might also be of use in determining prognosis, as the expression pattern of such channels, and the degree of their functionality, change with cancer progression.

  • Ca2+ signalling still constitutes a novel area of research in oncology. As this field is still rather young, not all the potential players have yet been investigated, and for those that have been studied, the specific roles in migration, invasion and metastasis of different types of cancers are only just beginning to be understood.

Abstract

In most cases, metastasis, not the primary tumour per se, is the main cause of mortality in cancer patients. In order to effectively escape the tumour, enter the circulation and establish secondary growth in distant organs cancer cells must develop an enhanced propensity to migrate. The ubiquitous second messenger Ca2+ is a crucial regulator of cell migration. Recently, a number of known molecular players in cellular Ca2+ homeostasis, including calcium release-activated calcium channel protein 1 (ORAI1), stromal interaction molecule 1 (STIM1) and transient receptor potential (TRP) channels, have been implicated in tumour cell migration and the metastatic cell phenotype. We discuss how these developments have increased our understanding of the Ca2+ dependence of pro-metastatic behaviours.

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Figure 1: Molecular organization of focal adhesion complexes and their regulation by Ca2+.
Figure 2: Major Ca2+ entry and Ca2+ release systems involved in migration, invasion and metastasis.

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Acknowledgements

The research of N.P. and R.S. is supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), Ligue Nationale Contre le Cancer, Fondation de Recherche Medicale (FRM), Association pour la Recherche sur le Cancer (ARC) and Région Nord/Pas-de-Calais. Y.S. was supported in part by a visiting scientist program of the Universite de Lille 1.

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Correspondence to Natalia Prevarskaya.

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Glossary

Depolarizing membrane potentials

All types of resting cells are characterized by the negative potential on their plasma membrane, thus the interior of the cell is negatively charged with respect to the extracellular space. The shift of the membrane potential to less negative values relative to the resting potential is called depolarization and the shift to more negative values is called hyperpolarization.

Gating

The process of opening and closing ion channels by various stimuli.

m-calpain

Isoform of Ca2+-dependent cystein protease that is activated by millimolar [Ca2+]i. It differs from another isoform, calpain, which is activated by micromolar [Ca2+]i.

Auxiliary (regulatory) subunits

A protein complex of ion channels can sometimes include additional subunits which do not participate in pore formation, but which modulate functional properties of the channel.

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Prevarskaya, N., Skryma, R. & Shuba, Y. Calcium in tumour metastasis: new roles for known actors. Nat Rev Cancer 11, 609–618 (2011). https://doi.org/10.1038/nrc3105

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