Abstract
Dynamic remodeling of the extracellular matrix (ECM) is essential for development, wound healing and normal organ homeostasis. Life-threatening pathological conditions arise when ECM remodeling becomes excessive or uncontrolled. In this Perspective, we focus on how ECM remodeling contributes to fibrotic diseases and cancer, which both present challenging obstacles with respect to clinical treatment, to illustrate the importance and complexity of cell-ECM interactions in the pathogenesis of these conditions. Fibrotic diseases, which include pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease, account for over 45% of deaths in the developed world. ECM remodeling is also crucial for tumor malignancy and metastatic progression, which ultimately cause over 90% of deaths from cancer. Here, we discuss current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression, and how improving our understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies. This can only be achieved through the use of appropriate in vitro and in vivo models to mimic disease, and with technologies that enable accurate monitoring, imaging and quantification of the ECM.
Highlights
The extracellular matrix (ECM) is one of the most important regulators of cellular and tissue function in the body
In this Perspective, we focus on how ECM composition and remodeling is thought to be crucial for tumorigenesis and metastatic progression in cancer, as well as how disruption of normal ECM homeostasis leads to fibrotic diseases such as pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease
We showed that tumor-driven ECM remodeling and matrix stiffening at sites distant from the primary tumor is lysyl oxidase (LOX) dependent and acts to recruit bone-marrow-derived cells (BMDCs), and to facilitate tumor cell colonization and growth
Summary
The extracellular matrix (ECM) is one of the most important regulators of cellular and tissue function in the body. Is probably associated with a disproportionate increase in inappropriate post-translational cross-linking and modification of ECM proteins, such as by glycation (discussed earlier) In fibrotic diseases such as pulmonary fibrosis, liver cirrhosis, cardiovascular disease and systemic sclerosis, evidence suggests that the constitutive activation of collagensecreting myofibroblast-like cells is responsible for increasing both collagen amount and concentration. In such cases, these cells can synthesize and secrete excessive ECM components, collagens, leading to increased tissue stiffness and progressive organ dysfunction. A detailed discussion of integrins in cancer is beyond the
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