Matrix stiffening and acquired resistance to chemotherapy: concepts and clinical significance

Extracellular matrix (ECM) refers to the non-cellular components of the tumour microenvironment, fundamentally providing a supportive scaffold for cellular anchorage and transducing signaling cues that orchestrate cellular behaviour and function. The ECM integrity is abrogated in several cases of cancer, ending in aberrant activation of a number of mechanotransduction pathways and induction of multiple tumorigenic events such as extended proliferation, cell death resistance, epithelial-mesenchymal transition and most importantly the development of chemoresistance. In this regard, the present study mainly aims to elucidate how the ECM-stiffening process may contribute to the development of chemoresistance during cancer progression and what pharmacological approaches are required for tackling this issue. Hence, the first section of this review explains the process of ECM stiffening and the ways it may affect biochemical pathways to induce chemoresistance in a clinic. In addition, the second part focuses on describing some of the most important pharmacological agents capable of targeting ECM components and underlying pathways for overcoming ECM-induced chemoresistance. Finally, the third part discusses the obtained results from the application of these agents in the clinic for overcoming chemoresistance.