The extracellular matrix (ECM) is known as a molecular network of macromolecules present in all solid tissues (Figure 1), which plays an important role in the growth, migration and differentiation of cells. This ECM is part of a complex and plastic microenvironment in health and disease: its composition and physical properties are under homoeostatic control during embryonic development, while gross alterations of its properties have been demonstrated in the microenvironment adjacent to tumour cells (the tumour stroma). The loss of tissue ECM homeostasis and integrity is now seen as one of the hallmarks of cancer, being involved in progression and metastasis processes.

Figure 1: Overview of the basic building blocks of the extracellular matrix that come together to form the highly ordered supramolecular structures, which contribute to the various interstitial matrix, microfibrils and the basal laminae within tissues. (Source: Filipe et al., 2018)

This also holds true in the frame of breast cancer. There is increasing evidence that the complexity of the tumour microenvironment – consisting of several cell types and the surrounding ECM – plays a crucial role in development, progression, and response to therapies against breast cancer. In addition to the morphological and molecular classification of breast cancer subtypes, it has been proposed to categorize invasive breast carcinomas by the means of ECM characterization (Figure 2) (Bergamaschi et al., 2008).

Figure 2: Schematic illustration of histological, molecular and ECM classification of breast cancer subtypes. Dotted lines indicate lower degree of association. (Source: Heldin et al., 2013; https://doi.org/10.1093/jb/mvt085)

Four ECM subtypes, exhibiting differential upregulation of ECM-related genes, were associated with different clinical outcomes (Heldin et al., 2013; Bergamaschi et al., 2008):

  • ECM1 subclass is characterized by a dense stroma expressing integrins, collagens and adhesion molecules. It is overrepresented in ER-/PR-basal-like tumours. ECM1 signature was linked to a poorer prognosis compared to other subclasses.
  • ECM2 subclass represents a clinically aggressive phenotype: it is characterized by a mixed-type stroma and by increased levels of hyaluronan and ERþ/PRþ luminal B tumours carrying HER2 amplification. ECM2 represents the second clinically aggressive phenotype.
  • ECM3 and ECM4 subclasses are low grade ERþ/PRþ and express genes involved in the maintenance of stroma, such as SPARC and laminins, respectively. These signatures are linked to a more favourable outcome.

This ECM signature correlated with differences in the biology of the tumour that are reflected in clinical outcome. The review by Claire Roberston (2016) gave an overview of the different elements of the ECM which have been linked to prognosis of breast cancers, including changes in ECM protein composition, splicing, and microstructure. The diverse mechanisms by which cells interact with the surrounding ECM represent an attractive target for new therapeutics for cancers. However, the dramatic failure in clinical trials of one such class of treatment – namely matrix metalloproteinase (MMP) inhibitors – highlights the need for improved preclinical models and better understanding of cell-ECM interactions.

In this context, we are convinced that relevant 3D in vitro models will help to fill the gap between cancer preclinical R&D and clinical efficiency, if they properly reproduce the tumoral ECM features. Given the role of hyaluronan and other ECM components in breast cancer biology (and prognosis), BIOMIMESYS® provides an interesting tool for cultivating cancer cells in a relevant 3D microenvironment. Why not trying it in your research?

We would like to thank Dr Samuel Meignan and Dr Karine Hannebicque, for helpful discussions about this topic! We are looking forward to collaborating with you in this frame…


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