Activation and biologic actions of HGF in the DLBCL microenvironment. HGF is produced by macrophages (M∅) and/or stromal cells. Expression and secretion of HGFA by DLBCL cells regulates the bioavailability of active HGF in the DLBCL microenvironment. Catalyzation of HGF activation by DLBCL cells can directly stimulate HGF/MET signaling (bottom panel), promoting DLBCL adhesion, growth, and survival. In addition, HGF can directly or indirectly stimulate angiogenesis. Bottom panel: schematic representation of the HGF-induced signaling events in DLBCL cells. HGF-induced activation of MAPK and PKB is mediated by Grb2/SOS coupling to RAS and GAB-1 coupling to PI3K, respectively.73 Activation of RAS/MAPK may lead to proliferation of DLBCL cells. Activation of PI3K/PKB leads to phosphorylation of FOXO3a and GSK3, which may control proliferation and survival (see “Discussion” for further details). Furthermore, PI3K mediates HGF-induced adhesion of DLBCL cells. Pre-HGF indicates inactive precursor of HGF.
