Molecular Initiation
The Snowflake that triggers the Avalanche
Heparanase stands as cancer's primary molecular bulldozer - the only mammalian endoglycosidase capable of cleaving heparan sulfate proteoglycans within the extracellular matrix. This seemingly simple enzymatic action initiates a series of biological events with profound consequences for tumor behavior.
The process begins when pro-heparanase (65 kDa) undergoes proteolytic processing by cathepsin L to form the active enzyme (50 kDa). This activation requires specific microenvironmental conditions, a slightly acidic pH (5.8-6.4) precisely matching the acidic tumor microenvironment. Once activated, a single heparanase molecule can cleave multiple heparan sulfate chains, creating an amplification effect where minimal enzyme produces maximal impact.
Like the initial fracture in a snowpack that precedes an avalanche, heparanase's cleavage of heparan sulfate chains represents the critical triggering event. The first cuts disrupt structural integrity and release sequestered growth factors, which in turn activate receptors, stimulate cellular responses, and progressively recruit downstream mediators in an expanding cascade of molecular events.