IGF-1 Induces proliferation in Human Pituitary Tumors - Functional Blockade of IGF-1 Receptor as a Novel Therapeutic Approach in Non-functioning Tumors

Context: The growth hormone/insulin-like growth factor (IGF-1) axis plays a fundamental role in growth and development. IGF-1 and its receptor display potent proliferative and antiapoptotic activities and are considered key players in malignancy. Objective: The objective of the study was to explore the role of IGF-1 and its downstream pathways in the tumorigenesis of non-functioning pituitary tumors and to develop a targeted therapeutic approach for the treatment of these tumors. Design: Cultures of human non-functioning pituitary adenomas and MtT/E cells were incubated with IGF-1, IGF-1 receptor inhibitor or both and cell viability, proliferation and signaling were examined. Results: Our results show that IGF-1 elevated the number of viable cells and cell proliferation of human non-functioning pituitary tumor cells and of a non-secreting immortalized pituitary tumor cell line, MtT/E, respectively. IGF-1 induced the phosphorylation of ERK, Akt and p70S6K and the expression of cyclins D1 and 3. Our results also demonstrate the abrogation of IGF-1- induced cell viability as well as of IGF-1 receptor phosphorylation and downstream signaling by the selective IGF-1R inhibitor, NVP-AEW541. Conclusions: Our results suggest that IGF-1 controls cell proliferation and may contribute to pituitary tumor development and progression. Our results also indicate that blockade of IGF-1-induced proliferation and signaling by the selective IGF-1R inhibitor NVP-AEW541 may constitute an attractive novel strategy for the treatment of these invasive tumors that, as yet, do not respond to any known medical treatment