Insulin-like Growth Factor System: functional role and regulation in carcinomas

Sammanfattning: The insulin-like growth factor (IGF) system demonstrates numerous actions during neoplastic growth and is therefore an interesting target with potential clinical implications. While numerous studies have established important roles of the IGF system in regulating cellular growth and survival of several tumor forms, very limited reports exist regarding its role in renal cell carcinoma (RCC). The aim of this thesis was to improve the understanding of the role of the IGF system in RCC tumorigenesis and relate it to the knowledge around its functions in e.g. breast cancer. RCC express IGF-I receptors and overexpress IGFBP-3, but prior to this thesis their roles were uncharacterized. As a first step, two model systems for human RCC were established. IGFs promoted RCC growth in particular in cells derived from a primary tumor. Although metastasis derived cells were responsive to IGF-I stimulation in vitro, the proliferative response was much lower. This correlates to the findings in vivo where IGF-I stimulated growth of early, but not established, xenograft RCC. In both these systems, IGFBP-3 has an important growth regulatory function and potentially roles that are IGF-IR independent. In accordance with studies in breast cancer, IGF-I enhances TGF-? signaling and TGF-? promotes IGFBP-3 production which influences the biological activity of IGF. The highly IGF responsive RCC from the primary tumor, was insensitive to TGF-? growth inhibition and stimulated by IGFBP-3. In contrast, the metastasis derived RCC retained sensitivity to TGF-? growth constraints, which was further enhanced in the presence of IGFBP-3. Moreover, IGFBP-2 was identified as a novel regulator of tumor suppressor PTEN that block the feedback increase in PTEN that protects from overstimulation by IGF-II. Previous observations together with these new findings suggest additional mechanisms by which the IGF system can regulate growth inhibitory circuits to circumvent the normal anticancer defense system, which could then contribute to tumor progression. This improved understanding of the growth factor pathways involved in promoting breast cancer or RCC growth as well as obstructing normal anticancer defense mechanisms is of clinical importance. It could aid in the development of next generation drugs as well as be a tool in the identification of patients likely to respond to treatments.