Stromal metalloproteinases: Crucial contributors to the tumor microenvironment

Proteolytic balance is crucial for the maintenance of tissue homeostasis. In cancer, dysregulated proteolysis is involved in unregulated tissue remodeling and inflammation, leading to the promotion of tumor growth, local invasion, and metastasis. Metalloproteinases, which were first identified as collagen cleaving enzymes, have been shown to extensively degrade extracellular matrix proteins or selectively release cell surface-bound cytokines, growth factors, or their receptors, thereby impacting extracellular matrix integrity, immune cell recruitment and tissue turnover. Although tumor cells produce various metalloproteinases, the major source is thought to be stromal cells infiltrating the tumor. Different types of stromal cells express specific sets of metalloproteinases and their inhibitors, which specifically alter the milieu within the tumor. In this review, recent findings and knowledge regarding metalloproteinases derived from stromal cells during the creation of the tumor microenvironment are described and their contribution to the tumor progression and metastasis discussed.