INVESTIGADORES
PODHAJCER Osvaldo Luis
artículos
Título:
Tumor associated stromal cells play a critical role on the outcome of the oncolytic efficacy of conditionally replicative adenoviruses.
Autor/es:
LOPEZ MV; VIALE DL; CAFFERATA EG; BRAVO AI; CARBONE C; GOULD DJ; CHERNAJOVSKY Y; PODHAJCER OL
Revista:
PLOS ONE
Editorial:
PUBLIC LIBRARY SCIENCE
Referencias:
Año: 2009 vol. 4 p. 5119 - 5134
ISSN:
1932-6203
Resumen:
The clinical efficacy of conditionally replicative oncolytic adenoviruses (CRAd)
is still limited by the inefficient infection of the tumor mass. Since tumor
growth is essentially the result of a continuous cross-talk between malignant
and tumor-associated stromal cells, targeting both cell compartments may
profoundly influence viral efficacy. Therefore, we developed SPARC
promoter-based CRAds since the SPARC gene is expressed both in malignant cells
and in tumor-associated stromal cells. These CRAds, expressing or not the Herpes
Simplex thymidine kinase gene (Ad-F512 and Ad(I)-F512-TK, respectively) exerted
a lytic effect on a panel of human melanoma cells expressing SPARC; but they
were completely attenuated in normal cells of different origins, including fresh
melanocytes, regardless of whether cells expressed or not SPARC. Interestingly,
both CRAds displayed cytotoxic activity on SPARC positive-transformed human
microendothelial HMEC-1 cells and WI-38 fetal fibroblasts. Both CRAds were
therapeutically effective on SPARC positive-human melanoma tumors growing in
nude mice but exhibited restricted efficacy in the presence of co-administered
HMEC-1 or WI-38 cells. Conversely, co-administration of HMEC-1 cells enhanced
the oncolytic efficacy of Ad(I)-F512-TK on SPARC-negative MIA PaCa-2 pancreatic
cancer cells in vivo. Moreover, conditioned media produced by stromal cells
pre-infected with the CRAds enhanced the in vitro viral oncolytic activity on
pancreatic cancer cells, but not on melanoma cells. The whole data indicate that
stromal cells might play an important role on the outcome of the oncolytic
efficacy of conditionally replicative adenoviruses