Hold on or Cut? Integrin- and MMP-Mediated Cell–Matrix Interactions in the Tumor Microenvironment

Abstract

The tumor microenvironment (TME) has become the focus of interest in cancer research and treatment. It includes the extracellular matrix (ECM) and ECM-modifying enzymes that are secreted by cancer and neighboring cells. The ECM serves both to anchor the tumor cells embedded in it and as a means of communication between the various cellular and non-cellular components of the TME. The cells of the TME modify their surrounding cancer-characteristic ECM. This in turn provides feedback to them via cellular receptors, thereby regulating, together with cytokines and exosomes, differentiation processes as well as tumor progression and spread. Matrix remodeling is accomplished by altering the repertoire of ECM components and by biophysical changes in stiffness and tension caused by ECM-crosslinking and ECM-degrading enzymes, in particular matrix metalloproteinases (MMPs). These can degrade ECM barriers or, by partial proteolysis, release soluble ECM fragments called matrikines, which influence cells inside and outside the TME. This review examines the changes in the ECM of the TME and the interaction between cells and the ECM, with a particular focus on MMPs.

Metalloproteinases 1 and 3 as Potential Biomarkers in Breast Cancer Development

“…MMPs are a subclass of ECM degradation proteins with concentration differences between healthy and cancer tissues. Changes in the ECM and the interactions between cells and the ECM, with a particular focus on MMPs, have been well documented [56]. Additionally, MMP expression alters the rigidity, porosity, and many other characteristics of the ECM, facilitating cell migration and invasion.…”

“…MMP-2 and MMP-9 are also involved in each stage of breast-cancer-to-bone metastasis [80]. For these reasons, MMP-2 and MMP-9 have been considered as reliable biomarkers for the prediction of BC prognosis [54] and for metastasis development [55,56].…”

Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment

“…Cancer cells and their neighboring stroma cells change the composition and physical properties of the ECM in the tumor mass remarkably (Eble and Niland, 2019;Henke et al, 2019). Distinct ECM proteins are abundantly deposited in the TME, such as collagen fibrils, fibronectin variants EDA and EDB, and tenascin-W (Acerbi et al, 2015;Naba et al, 2016Naba et al, , 2017Eble and Niland, 2019;Niland and Eble, 2020). They are deposited in gradients within the TME, with high concentrations of collagens and fibronectin in the periphery of the tumor mass, especially of desmoplastic tumors (Oudin and Weaver, 2016;Wang et al, 2016;Eble and Niland, 2019).…”

“…Also, infiltrating immune cells are influenced by tumor cells and thus attenuate their tumor-suppressive properties (Huber et al, 2020;Sadeghalvad et al, 2020;Yang et al, 2020). The noncellular ECM, mostly synthesized, secreted, and arranged by CAFs, consists of collagen-containing fibrils, water-resorbing proteoglycans and glycosaminoglycans and a plethora of other ECM-proteins (Eble and Niland, 2019;Niland and Eble, 2020). Together, they form the scaffold, which keeps the tissue in shape and provides a stiff collagenous capsule of desmoplastic tumors (Leight et al, 2017;Mohammadi and Sahai, 2018;Martins Cavaco et al, 2020).…”

The Yin and Yang of Discoidin Domain Receptors (DDRs): Implications in Tumor Growth and Metastasis Development

“…As a whole, the ECM forms an interconnected network. During tumor development, the ECM is continuously remodeled, with new synthesis and proteolytic degradation of the matrix components [5]. Collagens are the most abundant proteins in the ECM and, to date, 28 different collagens (I to XXVIII) have been found expressed in tissues and tumors.…”