The functionalized human serine protease granzyme B/VEGF₁₂₁ targets tumor vasculature and ablates tumor growth.

The Functionalized Human Serine Protease Granzyme B/VEGF121 Targets Tumor Vasculature and Ablates Tumor Growth Running title: Granzyme B/VEGF121 blocks growth of solid tumors

The Functionalized Human Serine Protease Granzyme B/VEGF121 Targets Tumor Vasculature and Ablates Tumor Growth

The serineprotease granzymeB (GrB) induces apoptosis throughboth caspase-dependent and -independent multiple-cascade mechanisms. VEGF121 binds to both VEGF receptor (VEGFR)-1 and VEGFR-2 receptors. We engineered a unique GrB/VEGF121 fusion protein and characterized its properties in vitro and in vivo. Endothelial and tumor cell lines showed varying levels of sensitivity to GrB/VEGF121 that corr...

Granzyme M expressed by tumor cells promotes chemoresistance and EMT in vitro and metastasis in vivo associated with STAT3 activation

Granzyme M is a serine protease known to be often expressed by natural killer cells and induce target cells apoptosis in combination with perforin. However, we detected granzyme M expression in murine and human cancer cell lines and human tumor samples in our study. Granzyme M increased chemoresistance, colony-formation, cytokine secretion and invasiveness in vitro. Most importantly, granzyme M...

Targeting of Tumor Neovasculature with GrB/VEGF121, a Novel Cytotoxic Fusion Protein

Angiogenesis is a critical process in numerous diseases, and intervention in neovascularization has therapeutic value in several disease settings, including ocular diseases, arthritis, and in tumor progression and metastatic spread. Various vascular targeting agents have been developed, including those that inhibit growth factor receptor tyrosine kinases, blocking antibodies that interfere with...

Mechanistic studies of a novel human fusion toxin composed of vascular endothelial growth factor (VEGF)121 and the serine protease granzyme B: directed apoptotic events in vascular endothelial cells.

The serine protease granzyme B (GrB; 25 kDa) is capable of inducing apoptosis through both caspase-dependent and caspase-independent mechanisms. We designed a novel vascular-targeting fusion construct designated as GrB/vascular endothelial growth factor (VEGF)121, which is composed of a non-heparin-binding isoform of VEGF and the proapoptotic pathway enzyme GrB fused via a short, flexible tethe...