Kinetic Model Characterization of Protease Activity in Tumor Microenvironments

Series: 
Applied and Computational Mathematics Seminar
Monday, February 1, 2010 - 13:00
1 hour (actually 50 minutes)
Location: 
Skiles 255
,  
Biomedical Engineering (BME), Georgia Tech
  Tissue remodeling involves the activation of proteases, enzymes capable of degrading the structural proteins of tissue and organs. The implications of the activation of these enzymes span all organ systems and therefore, many different disease pathologies, including cancer metastasis. This occurs when local proteolysis of the structural extracellular matrix allows for malignant cells to break free from the primary tumor and spread to other tissues. Mathematical models add value to this experimental system by explaining phenomena difficult to test at the wet lab bench and to make sense of complex interactions among the proteases or the intracellular signaling changes leading to their expression. The papain family of cysteine proteases, the cathepsins, is an understudied class of powerful collagenases and elastases implicated in extracellular matrix degradation that are secreted by macrophages and cancer cells and shown to be active in the slightly acidic tumor microenvironment. Due to the tight regulatory mechanisms of cathepsin activity and their instability outside of those defined spaces, detection of the active enzyme is difficult to precisely quantify, and therefore challenging to target therapeutically. Using valid assumptions that consider these complex interactions we are developing and validating a system of ordinary differential equations to calculate the concentrations of mature, active cathepsins in biological spaces. The system of reactions considers four enzymes (cathepsins B, K, L, and S, the most studied cathepsins with reaction rates available), three substrates (collagen IV, collagen I, and elastin) and one inhibitor (cystatin C) and comprise more than 30 differential equations with over 50 specified rate constants. Along with the mathematical model development, we have been developing new ways to quantify proteolytic activity to provide further inputs. This predictive model will be a useful tool in identifying the time scale and culprits of proteolytic breakdown leading to cancer metastasis and angiogenesis in malignant tumors.