Endogenous expression of proteases in colon cancer cells facilitate influenza A viruses mediated oncolysis.
Previously we have developed a prototype for conditionally replicating oncolytic influenza A virus which is based on deletions in the non-structural (NS1) protein. Multi-cycle replication of influenza A virus in malignant tissue is critically dependent on a protease which cleaves the viral entry protein. Here we demonstrate that the malignant colon cancer cell lines Caco-2, HT-29 and SW-620 can endogenously provide a virus-activating protease, which allows lytic multi-cycle replication of NS1 deletion viruses in those cancer cells in vitro. The oncolytic potency of an influenza NS1 deletion virus (NS1-80) was further tested in SCID mice bearing HT-29 derived tumors. The intra-tumoral injection of live, but not of heat inactivated NS1-80 virus significantly inhibited progression of established tumors. We conclude that a selected set of human cancer expressing virus activating- proteases will be a preferred target for oncolytic tumor therapy using influenza A virus mutants.
Sturlan
Sanda
S
Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria.
Stremitzer
Stefan
S
Bauman
Suzann
S
Sachet
Monika
M
Wolschek
Markus
M
Ruthsatz
Tanja
T
Egorov
Andrej
A
Bergmann
Michael
M
D000818:Animals; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology / Q000821:virology; D050504:Oncolytic Viruses / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D009976:Orthomyxoviridae Infections / Q000201:enzymology / Q000473:pathology / Q000821:virology; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*
C085820:INS1 protein, influenza virus; D017361:Viral Nonstructural Proteins; D010447:Peptide Hydrolases