Heparanase Mechanisms in Melanoma Brain Metastasis.

摘要

Heparanase (HPSE) is the dominant endoglycosidase (endo- -D-glucuronidase) in mammals and is an important tumorigenic, angiogenic, and pro-metastatic enzyme. Highest levels of HPSE activity have been consistently detected in cells with highest propensities to colonize the brain. This emphasizes the potential for therapeutically targeting this enzyme in brain metastasis in general, brain-metastatic melanoma (BMM) in particular. Of interest, SST0001 is a small-molecule, non-anticoagulant heparin with potent anti-HPSE activities. Objective of the work was to assess the abilities of SST0001 to interfere with HPSE-mediated cell signaling and actions, and ultimately affecting the modulation of BMM. Accordingly, this, by employing the pINDUCER lentiviral system, and performing heparanase gain-/loss-of-function investigations in melanoma cell clones highly metastatic to brain (high BMM cell lines); and translated findings in xenografts. This was done in the presence or absence of SST0001 treatment, employing the pINDUCER lentiviral system. We found that HPSE plays important roles in mechanisms modulating BMM onset. A new molecular mechanism was also identified by which HPSE mediates an alternative survival pathway in BMM cells, being modulated by SST0001 in vitro and in vivo. These investigations can contribute to the development of novel therapeutic strategies for BMM to improve patient outcomes.