Expression of a suicidal gene under control of the human secreted protein acidic and rich in cysteine (SPARC) promoter in tumor or stromal cells led to the inhibition of tumor cell growth.
The successful use of transcriptional targeting for cancer therapy depends on the activity of a given promoter inside the malignant cell. Because solid human tumors evolve as a "cross-talk" between the different cell types within the tumor, we hypothesized that targeting the entire tumor mass might have better therapeutic effect. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein overexpressed in different human cancers malignant melanomas both in the malignant cells compartment as in the stromal one (fibroblasts and endothelial cells). We have shown that expression of the herpes simplex virus-thymidine kinase (TK) gene driven by the SPARC promoter in combination with ganciclovir inhibited human melanoma cell growth in monolayer as well as in multicellular spheroids. This inhibitory effect was observed both in homotypic spheroids composed of melanoma cells alone as well as in spheroids made of melanoma cells and stromal cells. Expression of the TK gene was also efficient to inhibit the in vivo tumor growth of established melanomas when TK was expressed either by the malignant cells themselves or by coadministered endothelial cells. Our data suggest that the use of therapeutic genes driven by SPARC promoter could be a valuable strategy for cancer therapy aiming to target all the cellular components of the tumor mass.
Lopez
María V
MV
Gene Therapy Laboratory, Leloir Institute-Consejo Nacional de Investigaciones Científicas y Técnicas, Faculty of Exact and Natural Sciences, University of Buenos Aires, Argentina.
Blanco
Patricia
P
Viale
Diego L
DL
Cafferata
Eduardo G
EG
Carbone
Cecilia
C
Gould
David
D
Chernajovsky
Yuti
Y
Podhajcer
Osvaldo L
OL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D015774:Ganciclovir / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide; D005822:Genetic Vectors; D006801:Humans; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015676:Osteonectin / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D018139:Simplexvirus / Q000235:genetics; D018874:Spheroids, Cellular / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology*; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D015676:Osteonectin; D011505:Protein-Tyrosine Kinases; D015774:Ganciclovir