Proteolytic-antiproteolytic balance and its regulation in carcinogenesis.
Cancer development is essentially a tissue remodeling process in which normal tissue is substituted with cancer tissue. A crucial role in this process is attributed to proteolytic degradation of the extracellular matrix (ECM). Degradation of ECM is initiated by proteases, secreted by different cell types, participating in tumor cell invasion and increased expression or activity of every known class of proteases (metallo-, serine-, aspartyl-, and cysteine) has been linked to malignancy and invasion of tumor cells. Proteolytic enzymes can act directly by degrading ECM or indirectly by activating other proteases, which then degrade the ECM. They act in a determined order, resulting from the order of their activation. When proteases exert their action on other proteases, the end result is a cascade leading to proteolysis. Presumable order of events in this complicated cascade is that aspartyl protease (cathepsin D) activates cysteine proteases (e.g. cathepsin B) that can activate pro-uPA. Then active uPA can convert plasminogen into plasmin. Cathepsin B as well as plasmin are capable of degrading several components of tumor stroma and may activate zymogens of matrix metalloproteinases, the main family of ECM degrading proteases. The activities of these proteases are regulated by a complex array of activators, inhibitors and cellular receptors. In physiological conditions the balance exists between proteases and their inhibitors. Proteolytic-antiproteolytic balance may be of major significance in the cancer development. One of the reasons for such a situation is enhanced generation of free radicals observed in many pathological states. Free radicals react with main cellular components like proteins and lipids and in this way modify proteolytic-antiproteolytic balance and enable penetration damaging cellular membrane. All these lead to enhancement of proteolysis and destruction of ECM proteins and in consequence to invasion and metastasis.
Skrzydlewska
Elzbieta
E
Department of Analytical Chemistry, Medical University of Bialystok, Mickiewicza 2, 15-230 Bialystok, Poland. skrzydle@amb.edu.pl
Sulkowska
Mariola
M
Koda
Mariusz
M
Sulkowski
Stanislaw
S
D005109:Extracellular Matrix / Q000201:enzymology*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D009369:Neoplasms / Q000209:etiology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010447:Peptide Hydrolases / Q000378:metabolism*
D010447:Peptide Hydrolases