The Study of the Extracellular Matrix in Chronic Inflammation: A Way to Prevent Cancer Initiation?

Abstract

Bidirectional communication between cells and their microenvironment has a key function in normal tissue homeostasis, and in disease initiation, progression and a patient's prognosis, at the very least. The extracellular matrix (ECM), as an element of all tissues and cellular microenvironment, is a frequently overlooked component implicated in the pathogenesis and progression of several diseases. In the inflammatory microenvironment (IME), different alterations resulting from remodeling processes can affect ECM, progressively inducing cancer initiation and the passage toward a tumor microenvironment (TME). Indeed, it has been demonstrated that altered ECM components interact with a variety of surface receptors triggering intracellular signaling that affect cellular pathways in turn. This review aims to support the notion that the ECM and its alterations actively participate in the promotion of chronic inflammation and cancer initiation. In conclusion, some data obtained in cancer research with the employment of decellularized ECM (dECM) models are described. The reported results encourage the application of dECM models to investigate the short circuits contributing to the creation of distinct IME, thus representing a potential tool to avoid the progression toward a malignant lesion.

Keywords: 3D culture model; cancer; chronic inflammation; decellularization; extracellular matrix.

Figure 1

The ECM contribution in IME to TME progression. In the course of inflammation, in IME, immune cells induce the release of TNF-α, IFN-γ,TGF-β, influencing ECM turnover and protease activity. In turn, aberrant expression of ECM components and bioactive fragments resulting from ECM degradation activate TLRs on immune cells. The activation of TLRs induces pro-inflammatory cytokines’ and chemokines’ release, which fosters the inflammatory response. The perpetuation and the relapsing inflammatory response induce its chronicization and the passage from IME to TME. In TME, CAFs orchestrate ECM remodeling. CAFs originate from fibroblasts and mesenchymal cells or other cells in the EMT, induced by immune cells producing TNF-α, IFN-γ and TGF-β. CAFs exert several tumor-promoting functions, such as the release of growth factors and chemokines. In so doing, CAFs recruit endothelial and immune cells to join the TME, promoting tumor progression, while orchestrating the tumorigenic ECM deposition. Furthermore, altered ECM deposition provokes aberrant expression of some ECM components provoking hypoxia, desmoplasia and stiffness. Hypoxia induces the increase of oncogene activity, the inhibition of tumor suppressor genes and TME acidification. The acidification and metabolic changes in TME increase the MMPs’ activity and thus ECM degradation. The result of ECM degradation is the release of bioactive fragments and ECM-bound growth factors which induce the tumor progression. (Created with Biorender.com, accessed on 25 July 2022).