Extracellular matrix degradation

Several stages during the process of tumour invasion and metastases require increased degradation or breakdown of extracellular matrix or connective tissue surrounding tumour cells. The extracellular matrix is a complex mixture of proteins including different types of collagen, elastin, fibronectin, and laminin. Digestion of extracellular matrix is carried out by several groups of proteolytic enzymes. Major groups of enzymes implicated in tumour invasion and metastases are:

Matrix metalloproteinases (MMPs)

A family of zinc-containing enzymes involved in the degradation of the extracellular matrix; considerable evidence indicates that individual MMPs have an important role in tumour invasion and tumour spread while expression of individual MMPs in tumours may be associated with prognosis2. MMPs are broadly classified into collagenases, gelatinases, stromelysins, and the recently-identified membrane-type MMPs.

MMPs are secreted proteins, produced as pro-enzymes and activated by cleavage of a N-terminal propeptide. Gelatinases, particularly MMP-2, appear to be important in initial stages of tumour invasion as they degrade components of the basement membrane, while other MMPs contribute to later stages of tumour invasion. Membrane-type MMPs that are membrane-bound appear to be involved in activation of MMP-2, which is capable of activating other MMPs.

Activity of MMPs is regulated by interaction with naturally occurring inhibitors, tissue inhibitors of metalloproteinases. Clinical interest in MMPs is considerable since the use of synthetic, low-molecular-weight, broad-spectrum inhibitors of MMPs can prevent tumour spread in human tumour xenografts. Several MMP inhibitors are being developed for clinical use.

Plasmin system

Urokinase-type plasminogen activator (uPA) is a serine protease that catalyzes the activation of plasminogen to plasmin—a broad-spectrum protease that in turn can break down a variety of extracellular matrix components. Plasmin can also promote the activation of MMP-2, thus linking plasmin system and MMPs in tumour invasion.

Cathepsins

A group of lysosomal proteolytic enzymes that also degrade many components of the extracellular matrix. Widely expressed in tumour cells, stromal cells, and endothelial cells. Cathepsins can be activated by uPA.

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