Cancer cells secrete
matrix metalloproteinases (
MMP) that degrade the extracellular matrix and are responsible for some hallmarks of malignant
cancer. Many viruses, including a few currently used in
oncolytic virotherapy clinical trials, depend on intracellular
proteases to process their
proteins and activate their particles. We show here for measles virus (MV) that particle activation can be made dependent of
proteases secreted by
cancer cells. The MV depends on the intracellular
protease furin to process and activate its envelope fusion (F)
protein. To make F
protein activation
cancer cell specific, we introduced hexameric sequences recognized by an
MMP and identified the
mutant proteins most effective in fusing
MMP-expressing human
fibrosarcoma cells (HT1080). We showed that an
MMP inhibitor interferes with syncytia formation elicited by mutant F
proteins and confirmed
MMP-dependent cleavage by Edman degradation sequence analysis. We generated recombinant MVs expressing the modified F
proteins in place of
furin-activated F. These viruses spread only in cells secreting
MMP. In nude mice, an
MMP-activated MV retarded HT1080 xenograft growth as efficiently as the
furin-activated MV
vaccine strain. In MV-susceptible mice, the
furin-activated virus caused lethal
encephalitis upon intracerebral inoculation, whereas the
MMP-activated did not. Thus, MV particle activation can be made dependent of
proteases secreted by
cancer cells, enhancing safety. This study opens the perspective of combining targeting at the particle activation, receptor recognition, and selective replication levels to improve the therapeutic index of MV and other viruses in ongoing clinical trials of oncolysis.