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Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance?

Nature Reviews Cancer volume 13, pages 365–376 (2013)Cite this article

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Abstract

Immunotherapies, signal transduction inhibitors and chemotherapies can successfully achieve remissions in advanced stage cancer patients, but durable responses are rare. Using malignant melanoma as a paradigm, we propose that therapy-induced injury to tumour tissue and the resultant inflammation can activate protective and regenerative responses that represent a shared resistance mechanism to different treatments. Inflammation-driven phenotypic plasticity alters the antigenic landscape of tumour cells, rewires oncogenic signalling networks, protects against cell death and reprogrammes immune cell functions. We propose that the successful combination of cancer treatments to tackle resistance requires an interdisciplinary understanding of these resistance mechanisms, supported by mathematical models.

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Figure 1: Tumour evolution, therapy-induced tumour tissue damage and development of therapy resistance.
Figure 2: Interdisciplinary treatment approaches in melanoma.
Figure 3: Inflammation-induced phenotypic plasticity of tumour cells and immune cells.
Figure 4: Reconciling plasticity and clonal selection using ecology models.
Figure 5: Mouse and human co-clinical trials to facilitate the establishment of effective combination therapy protocols.

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Acknowledgements

This work was supported by the following grants: German Research Foundation SP A12 in the SFB832 and SP22 in the SFB704 to T.T.; German Cancer Aid SP9 in the German Melanoma Research Network to T.T.; German Research Foundation SPP 1590 “Probabilistic structures in evolution” to A.B.. M.H., A.B. and T.T. are members of the Excellence Cluster ImmunoSensation at the University of Bonn, Germany. The authors thank all members of the Hölzel, Tüting and Bovier groups for helpful discussions and critical reading.

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Authors and Affiliations

  1. Department of Clinical Chemistry and Clinical Pharmacology, Michael Hlzel is at the Unit for RNA Biology, University of Bonn, 53105 Bonn, Germany.,

    Michael Hölzel

  2. Anton Bovier is at the Institute for Applied Mathematics, University of Bonn, 53115 Bonn, Germany.,

    Anton Bovier

  3. Department of Dermatology and Allergy, Thomas Tüting is at the Laboratory of Experimental Dermatology, University of Bonn, 53105 Bonn, Germany.,

    Thomas Tüting

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  1. Michael Hölzel
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Glossary

Cancer stem cell (CSC) model

Rare quiescent and self-renewing cancer stem cells cause relapse after cytoreductive therapies, thus rebuilding a hierarchical tumour organization.

Darwinian clonal selection

Tumour cell variants with pre-existing or acquired hardwired genetic aberrations that confer therapy resistance are selected in a Darwinian evolutionary process. Typically, genomic instability and genetic heterogeneity by branched tumour evolution are a source of such resistant cell variants.

Epithelial-to-mesenchymal transition

(EMT). A reversible developmental programme that describes the acquisition of mesenchymal traits by epithelial cells. EMT programmes are reactivated in invasive cancers and believed to be a prerequisite for metastatic spread.

Phenotypic plasticity

In contrast to genomic instability or hardwired mutations, phenotypic plasticity is a source of tumour heterogeneity by, in principle, reversible phenotype switches. Altered epigenetic states are prominent examples.

Quiescent state models

Non-cycling cells are insensitive to DNA-damaging agents and any quiescent cell that can switch back into the proliferative state can cause a relapse, irrespectively of properties such as stemness or its degree of differentiation.

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Hölzel, M., Bovier, A. & Tüting, T. Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance?. Nat Rev Cancer 13, 365–376 (2013). https://doi.org/10.1038/nrc3498

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