Key Points
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The motility of both tumour and normal host cells contributes to tumour metastasis at several steps, including breaching of basement membrane, escape from the primary tumour, migration to blood and lymphatic vessels, intravasation and extravasation and movement into distant organs. The ability to migrate towards favourable environments is a fundamental and evolutionarily conserved cellular behaviour from unicellular organisms to humans.
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Both normal and cancer cells migrate using diverse modes including amoeboid, mesenchymal, epithelial, collective and individual. Simple model organisms also exhibit these diverse modes of motility and offer experimental advantages such as low cost, amenability to large-scale genetic and pharmacological screening and live imaging of cells interacting within their native environments.
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Studies of the social amoeba Dictyostelium discoideum have unravelled the complex signalling networks that mediate chemokine-directed cell migration, which is also observed with human immune and tumour cells.
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The combination of high-resolution live imaging and genetic screening in the nematode has revealed that cells can breach a basement membrane by pushing the matrix aside and also by degrading it. This potentially offers a new mechanism to target cancer invasion therapeutically.
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Cooperative, collective cell motility appears to contribute to tumour metastasis. Border cells in the Drosophila melanogaster ovary serve as a simple model that is genetically tractable and amenable to live imaging. This model has revealed that some mechanisms of cooperative, collective cell migration, such as the requirement for E-cadherin, differ from those of single-cell motility.
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Direct modelling of metastasis can be carried out in both flies and fish. Work in flies has resulted in the identification and optimization of kinase inhibitors for metastatic thyroid cancer. The fish offers the lowest-cost vertebrate model for intravasation and extravasation studies and is amenable to live imaging as well as genetic and pharmacological manipulation.
Abstract
Metastasis remains the greatest challenge in the clinical management of cancer. Cell motility is a fundamental and ancient cellular behaviour that contributes to metastasis and is conserved in simple organisms. In this Review, we evaluate insights relevant to human cancer that are derived from the study of cell motility in non-mammalian model organisms. Dictyostelium discoideum, Caenorhabditis elegans, Drosophila melanogaster and Danio rerio permit direct observation of cells moving in complex native environments and lend themselves to large-scale genetic and pharmacological screening. We highlight insights derived from each of these organisms, including the detailed signalling network that governs chemotaxis towards chemokines; a novel mechanism of basement membrane invasion; the positive role of E-cadherin in collective direction-sensing; the identification and optimization of kinase inhibitors for metastatic thyroid cancer on the basis of work in flies; and the value of zebrafish for live imaging, especially of vascular remodelling and interactions between tumour cells and host tissues. While the motility of tumour cells and certain host cells promotes metastatic spread, the motility of tumour-reactive T cells likely increases their antitumour effects. Therefore, it is important to elucidate the mechanisms underlying all types of cell motility, with the ultimate goal of identifying combination therapies that will increase the motility of beneficial cells and block the spread of harmful cells.
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Acknowledgements
The authors thank their anonymous reviewers for helpful suggestions and careful reading of the manuscript. This work was funded by the Intramural Research Program, National Cancer Institute, National Institutes of Health, by internal funding from the University of Michigan to C.A.P and by NIH grants R01GM73164 and R01GM46425 to D.J.M.
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D.J.M. wrote the sections on Caenorhabditis elegans and Drosophila melanogaster. C.A.P and C.H.S. wrote the sections on Dictyostelium discoideum and zebrafish. All authors contributed equally to writing the other parts of the article and reviewing and/or editing the manuscript before submission.
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Glossary
- Lamellipodium
-
A quasi-two-dimensional structure localized at the leading edge of motile cells that contains a highly dynamic actin network.
- Lamellum
-
A structure containing stable actin filaments and mature adhesion sites localized just behind the lamellipodium.
- Basement membrane
-
A thin, fibrous membrane that separates epithelium, mesothelium or endothelium from the underlying stroma.
- Chemokines
-
A family of low molecular mass proteins that are secreted by various cells and regulate a variety of responses, including cell migration, morphogenesis and proliferation as well as angiogenesis by binding to G protein-coupled receptors.
- Matrix metalloproteinase
-
(MMP). Calcium-dependent, zinc-containing endopeptidases that degrade matrix proteins.
- Mesendoderm
-
An embryonic tissue layer that differentiates into mesoderm and endoderm.
- Directional persistence
-
A measure commonly defined as the ratio of displacement to trajectory length.
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Stuelten, C., Parent, C. & Montell, D. Cell motility in cancer invasion and metastasis: insights from simple model organisms. Nat Rev Cancer 18, 296–312 (2018). https://doi.org/10.1038/nrc.2018.15
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DOI: https://doi.org/10.1038/nrc.2018.15
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