Cathepsin D, a Marker for the Metastatic Potential of Breast Cancer, May Regulate the Mitogenic Activity of Fibroblast Growth Factor 1

摘要

Cathepsin D was initially thought to be an individual prognostic indictor for the disease state of human breast cancers. Over the years, the data substantiating such a role for cathepsin D has been quite conflicting However, there is strong evidence that cathepsin D plays a role in the degradation of the extracellular matrix (ECM) and basement membrane surrounding tumors. In doing so, cathepsin D is an active participant in releasing ECM-bound growth factors, one of which is FGF-1. FGF-1 is a potent mitogen and angiogenic factor found in both normal and malignant tissues. FGF-1 mediates its effects by binding to its cognate receptor. Evidence indicates that the act of ligand biding to the receptor is insufficient for transduction of the mitogenic signal. It is speculated that FGF-FGFR internalization and its subsequent processing may play an active role in completing the mitogenic signal. The reported studies indicate FGF-1 is internalized into clathrin-coated< vesicles by the classical, receptor- mediated endocytic pathway. Upon disruption of internalization and processing pharmacological inhibitors, FGF-1 mitogenic activity is hindered. Furthermore, pretreatment of FGF-1 stimulated cells with an inhibitor of the major lysosomal proteases, cathepsin D, results in a reduction in the mitogenic response. Therefore, a cathepsin-ID-like activity and possibly other cellular proteases may be participants in the FGF-1 signal transduction pathway A small, linear fragment of FGF-1 has been identified that mimics, in some instances, the mitogenic bioactivity of the intact growth factor, supporting the notion that a processed form of FGF may have an intracellular role in signaling. Breast carcinomas are characterized by the overexpression and secretion of various proteases, one of which is cathepsin D. Consequently, cathepsin D may play a coordinated role with FGF-1 in tumor progression and invasion.