Etiology and Pathogenesis > Insulin-like Growth Factors

Abstract

Rat glioblastoma cells expressing an antisense RNA to the insulin-like growth factor-1 (IGF-1) receptor are nontumorigenic and induce regression of wild-type tumors

Resnicoff M, Sell C, Rubini M, Coppola D, Ambrose D, Baserga R, Rubin R

Department of Pathology and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107

Insulin-like growth factor-1 (IGF-1) and IGF-2 are critical regulators of cell proliferation. 
The growth-promoting action of both ligands is mediated by the type 1 IGF receptor (IGF-1R). 
We have investigated the role of the IGF-1R in the growth and tumorigenicity of rat C6 glioblastoma cells. 
For this purpose, antisense RNA to IGF-1R RNA was introduced into cells by either the addition of oligodeoxynucleotides or by transfection with plasmids that express antisense RNA to IGF-1R RNA. 
At low cell density, C6 cells grew slowly in serum-free medium and proliferated with the sole addition of IGF-1 or IGF-2. 
Both antisense IGF-1R oligodeoxynucleotides and stable transfection with a plasmid expressing an antisense IGF-1R RNA inhibited IGF-1-mediated growth in monolayers and clonogenicity in soft agar. 
Sense oligodeoxynucleotides and sense-expressing plasmid had no effect on either parameter. 
In stable antisense transfectants, tyrosine-phosphorylated IGF-1 receptors were not detectable, although they were easily detected in wild-type cells. 
When wild-type C6 cells were injected s.c. into syngeneic immunocompetent rats, tumors developed within 1 week. 
In contrast, stably transfected C6 cells overexpressing antisense IGF-1R RNA were nontumorigenic. 
Moreover, when C6 IGF-1R antisense cells were injected, subsequent tumor formation by wild-type C6 cells was completely prevented. 
Finally, injection of C6 IGF-1R antisense cells into rats carrying an established wild-type C6 tumor caused complete regression of the tumors. 
The results demonstrate the critical importance of the IGF-1R in glioblastoma cell growth, clonogenicity, and tumorigenicity. 
Although the mechanism is presently unknown, the fact that the injection of C6 cells expressing an antisense RNA to IGF-1R RNA leads to regression of already established wild-type C6 tumors suggests the possibility of practical applications.

PMID: 8174129 [PubMed - indexed for MEDLINE]