Role of Mast Cell Tryptase in Tobacco-Induced Carcinogenesis
Initial Award Abstract
The evolution of lung cancer appears ' to involve the influence of local growth stimuli for lung airway cells, in addition to exposure to specific carcinogens. On the basis of prior research establishing growth factor activity for tryptase, an enzyme released from inflammatory mast cells in the airways walls, it is proposed that tryptase may play an important role in the evolution of tobacco-related lung cancers.
The goals proposed for this research project are: a) to examine interactions of tryptase with tobacco-derived carcinogens in inducing cancerous conversion of airways cells; b) to examine activation by tryptase of cellular responses responsible for promoting cancer formation; and c) to investigate aspects of signaling used by tryptase to activate cells.
Our work has shown that the mast cell product tryptase can act as a growth factor for normal lung airway lining cells, a common source of lung cancers. We have also learned that tryptase is a growth factor for muscle cells found in the walls of airways. We are continuing with work to determine whether tryptase acts with carcinogens found in tobacco to accelerate cancerous growth of airway lining cells. Investigation of the intracellular signaling mechanisms utilized by tryptase to activate cells has shown that tryptase is capable of initiating events within cells which result in the activation of multiple steps in the mitogen-activated protein kinase cascade. The magnitude and specific components of the kinase cascade activated by tryptase is of great interest, as it can provide clues to the identification of the growth factor receptor type activated by tryptase, and the specific mechanisms used by tryptase to activate cells, including for cancer growth. |