RAT GLIOBLASTOMA CELLS EXPRESSING AN ANTISENSE RNA TO THE INSULIN-LIKE GROWTH-FACTOR-I (IGF-1) RECEPTOR ARE NONTUMORIGENIC AND INDUCE REGRESSION OF WILD-TYPE TUMORS

Insulin-like growth factor-1 (TGF-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 th e role of the IGF-1R in the growth and tumorigenicity of rat C6 gliobl astoma cells. For this purpose, antisense RNA to IGF-1R RNA was introd uced into cells by either the addition of oligodeoxynucleotides or by transfection with plasmids that express antisense RNA to IGF-1R RNA. A t low cell density, C6 cells grew slowly in serum-free medium and prol iferated with the sole addition of IGF-1 or IGF-2. Both antisense IGF- 1R oligodeoxynucleotides and stable transfection with a plasmid expres sing an antisense IGF-1R RNA inhibited IGF-1-mediated growth in monola yers and clonogenicity in soft agar. Sense oligodeoxynucleotides and s ense-expressing plasmid had no effect on either parameter. In stable a ntisense transfectants, tyrosine-phosphorylated IGF-1 receptors were n ot detectable, although they were easily detected in wild-type cells. When wild-type C6 cells were injected s.c. into syngeneic immunocompet ent rats, tumors developed within 1 week In contrast, stably transfect ed C6 cells overexpressing antisense IGF-1R RNA were nontumorigenic. M oreover, when C6 IGF-1R antisense cells mere injected, subsequent tumo r formation by wild-type C6 cells was completely prevented. Finally, i njection of C6 IGF-1R antisense cells into rats carrying an establishe d wild-type C6 tumor caused complete regression of the tumors. The res ults demonstrate the critical importance of the IGF-1R in glioblastoma cell growth, clonogenicity, and tumorigenicity. Although the mechanis m is presently unknown, the fact that the injection of C6 cells expres sing an antisense RNA to IGF-1R RNA leads to regression of already est ablished wild-type C6 tumors suggests the possibility of practical app lications.