Research Project
7234757
DESCRIPTION (provided by applicant): The high molecular weight form of FGF-2 (24kDa FGF-2) is produced by alternative translational start sites and consists of the more commonly studied 18kDa FGF-2 with an additional 55 amino acids at the amino terminal end. Treatment of endothelial or breast carcinoma cells with 24kDa FGF-2 results in an 80% decrease in migration rate although it continues to promote cell proliferation. We have performed deletion mutagenesis and developed a truncated form of 24kD FGF-2 which is highly effective in inhibiting migration in vitro while having no effect on cell growth. This peptide consists of the amino terminal 86 amino acids of 24kD FGF-2 and is referred to as ATE+31. Studies in animals have shown that ATE+31 is highly effective in suppressing mammary carcinoma and lung carcinoma tumor growth by two mechanisms, suppressing the angiogenic response and inhibiting tumor cell migration away from the tumor core. Studies of the mechanism by which ATE+31 inhibits migration have revealed that growth factor-induced increases in focal adhesion kinase (FAK) phosphorylation are abrogated by ATE+31. The decrease in phosphorylation occurred at tyr397 ,tyr407, and tyr861. Concomitantly, exposure to ATE+31 inhibited the reorganization of micro filaments and loss of focal adhesions that accompany growth factor treatment making enhanced motility difficult to attain. The hypothesis that this project will address states that ATE+31 inhibits cell migration through a mechanism involving the suppression of FAK function through inhibition of enhanced phosphorylation. The project will examine the mechanism by which ATE-31 inhibits cell migration and employ animal models to test the in vitro results in vivo. Specifically the project will define the mechanisms by which ATE+31 suppresses FAK phosphorylation and how it subsequently inhibits focal adhesion/rnicrofi lament dynamics and employ mouse models of angiogenesis and tumor development to test the experimental results in vivo. In addition, the therapeutic potential of ATE+31 will be evaluated in animal models of tumor development, regression, and metastasis will be evaluated.
