Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells
Menée in vitro et in vivo, cette étude met en évidence le rôle essentiel joué par une enzyme, la synthase HAS2, dans le développement d'un micro-environnement tumoral favorable au processus métastatique d'un cancer du sein
The molecular mechanisms that operate within the organ microenvironment to support metastatic progression remain unclear. Here we report that upregulation of the hyaluronan synthase HAS2 occurs in highly metastatic breast stem-like cancer cells (CSCs) defined by CD44+/CD24-/ESA+ phenotype, where it plays a critical role in the generation of a pro-metastatic microenvironment in breast cancer. HAS2 was critical for interaction of CSCs with tumor associated macrophages (TAMs), leading to enhanced secretion of PDGF-BB from TAMs which then activated stromal cells and enhanced CSC self-renewal. Loss of HAS2 in CSCs or treatment with 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan synthases which blocks hyaluronan production, drastically reduced the incidence and growth of metastatic lesions in vitro or in vivo, respectively. Taken together, our findings demonstrate a critical role for HAS2 in the development of a pro-metastatic microenvironment and suggest that HAS2 inhibitors can act as anti-metastatic agents that disrupt a paracrine growth factor loop within this microenvironment.
Cancer Research 2011