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Review
. 2021 Jul;125(2):164-175.
doi: 10.1038/s41416-021-01328-7. Epub 2021 Apr 6.

Breast cancer as an example of tumour heterogeneity and tumour cell plasticity during malignant progression

Fabiana Lüönd #  1 , Stefanie Tiede #  1 , Gerhard Christofori  2
Affiliations
Review

Breast cancer as an example of tumour heterogeneity and tumour cell plasticity during malignant progression

Fabiana Lüönd et al. Br J Cancer. 2021 Jul.

Abstract

Heterogeneity within a tumour increases its ability to adapt to constantly changing constraints, but adversely affects a patient's prognosis, therapy response and clinical outcome. Intratumoural heterogeneity results from a combination of extrinsic factors from the tumour microenvironment and intrinsic parameters from the cancer cells themselves, including their genetic, epigenetic and transcriptomic traits, their ability to proliferate, migrate and invade, and their stemness and plasticity attributes. Cell plasticity constitutes the ability of cancer cells to rapidly reprogramme their gene expression repertoire, to change their behaviour and identities, and to adapt to microenvironmental cues. These features also directly contribute to tumour heterogeneity and are critical for malignant tumour progression. In this article, we use breast cancer as an example of the origins of tumour heterogeneity (in particular, the mutational spectrum and clonal evolution of progressing tumours) and of tumour cell plasticity (in particular, that shown by tumour cells undergoing epithelial-to-mesenchymal transition), as well as considering interclonal cooperativity and cell plasticity as sources of cancer cell heterogeneity. We review current knowledge on the functional contribution of cell plasticity and tumour heterogeneity to malignant tumour progression, metastasis formation and therapy resistance.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Intratumoural heterogeneity as a consequence of cancer-cell-intrinsic and cancer-cell-extrinsic factors.
Individual cancer cells can differ with respect to a large number of capabilities, which are regulated at different levels by cell-intrinsic cues, including genetic, epigenetic and proteomic changes. The major intrinsic causes of intratumoural heterogeneity include cancer cell migration and invasion, genetic instability, epigenomic/transcriptomic and proteomic regulation, the degree of epithelial-to-mesenchymal transition (EMT) and cell plasticity, and the extent of stemness. Extrinsic factors in the tumour microenvironment (TME), such as the tumour vasculature and residing and infiltrating cells of the immune system, also contribute to intratumoural heterogeneity through cell–cell interactions and paracrine signalling. Intratumoural heterogeneity evolves in time and space, changes in response to therapy and the development of resistance, and varies between different patients (adapted from ref. ).
Fig. 2
Fig. 2. Epithelial-to-mesenchymal plasticity during the metastatic process.
Cancer cells can invade the surrounding tissue as single cells by epithelial-to-mesenchymal transition (EMT) followed by protease-independent amoeboid migration, or by EMT and protease-dependent mesenchymal migration. Cells in a hybrid EMT state can migrate as cohesive groups that are often led by a mesenchymal cell (a cancer cell or fibroblast), while mesenchymal cancer cells migrate as single cells or as multicellular streams. Cancer cells can actively intravasate or be passively shed into the circulation. Perivascular macrophages can aid cancer cells in the intravasation process. Circulating tumour cells (CTCs) are found in various stages of EMT as single cells or in clusters with epithelial, hybrid EMT and mesenchymal cancer cells as well as stromal cells, such as neutrophils. Successful metastatic outgrowth requires an epithelial phenotype, which most likely arises from invasive mesenchymal cancer cells undergoing mesenchymal-to-epithelial transition (MET), while tumour dormancy might be associated with a mesenchymal phenotype. Note that the molecular details of the differential regulation of the distinct modes of cancer cell migration and invasion, the intravasation process, the decision to circulate either as single cancer cell or to form CTC clusters, and CTC extravasation, tumour dormancy and metastatic outgrowth, are still widely unknown and remain to be explored.
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