Insulin-like growth factor 2 and its receptors (IGF 1R and IGF 2R/mannose 6-phosphate) in endometrial adenocarcinoma.

OBJECTIVE To investigate the consequences of IGF proteins dysfunction in development of endometrial adenocarcinomas. METHODS The expression of IGF 2 and IGF 1R was correlated with the expression of IGF 2R and apoptosis rate in 59 human endometrial adenocarcinomas, 10 endometrial hyperplasias and 7 normal tissues. The presence of mutations in the IGF 2R gene was followed in 46 adenocarcinomas. We also examined the effect of IGF 1 receptor blockage on cancer cell proliferation. In groups of either IGF 2-positive or IGF 2-negative tumors (stages III and IV) the expression of IGF 1 and IGF 1R was correlated with cell proliferation index and telomerase activity. RESULTS The expression of IGF 2 and IGF 1R was much higher in malignant tissue of stages III and IV than in tumors of stages I and II and normal or hyperplastic endometrium. This correlated with a decreased apoptosis rate and IGF 2R expression. Eight adenocarcinomas expressed biallelic mutation of the IGF 2R gene. The specific inhibition of IGF 1R and IGF 2 decreased tumor cell proliferation in IGF 2/IGF 1R-positive tumors. Furthermore, the positive correlation between increased expression of IGF 1 and IGF 1R proteins and increased telomerase activity and cell proliferation index was found in both IGF 2-negative and IGF 2-positive tumors. CONCLUSION Our data suggest that IGF 1, IGF 2 and their receptors are involved in the progression of endometrial adenocarcinomas. As cancer cell proliferation can be abrogated by blocking mRNA or protein products of these genes, tumors with extensive involvement of the IGF 2 pathway would be candidates for the therapeutics strategies aimed at interference with this pathway.