Abstract
BACKGROUND: Insulin-like growth factor receptor I (IGF-IR) signaling can contribute to the formation, maintenance, and/or progression of many diverse tumor types, including glioblastomas. We investigated the effect of an IGF-IR blocking antibody (IMC-A12) on tumors derived either from U87 cells or from glioblastoma stem-like (GS) cells in vitro and in vivo. METHODS: Two different xenograft models were established in nude mice. U87 cells were used to generate solid tumors, and the glioblastoma stem-like cell line GS-12 was used to generate diffusely invasive tumors. In both models, IMC-A12 was administered intratumorally via osmotic mini-pumps with catheters for 3-4 weeks. Tumor size, proliferation, apoptosis and angiogenesis were evaluated histologically and immunohistochemically. Receptor expression and activation were analyzed by flow cytometry and immunoprecipitation. Proliferation, apoptosis and migration were studied in vitro. RESULTS: Growth of U87 and of GS-12 tumors was inhibited by 75% and by 50%, respectively. In the solid, non-invasively growing U87 tumors, the intratumoral blood vessel density was reduced significantly, whereas the tumor cell proliferation and apoptosis rates did not differ from controls. In contrast, in the highly invasive GS-12 model, IMC-A12 treatment had no effect on tumor neovascularization, while the proportion of proliferating cells was decreased by 30% compared to controls. We therefore hypothesized that IMC-A12 interfered directly with the stem-like GS-12 glioblastoma cells but not with U87 cells. FACS analyses revealed that only 6% of U87 cells expressed IGF-IR, whereas 87% of GS-12 cells expressed the receptor. IGF-I and IGF-II-induced receptor activation was blocked by IMC-A12 in vitro, and the antibody reduced proliferation of GS-12 cells by 40% and migration by 27%. In contrast, IMC-A12 had no effect on the proliferation or migration of U87 cells. CONCLUSIONS: IGF-IR blockade can inhibit glioblastoma growth in vivo by different mechanisms. In the highly invasive GS-12 model it inhibits proliferation and migration directly. In contrast, in highly angiogenic tumors derived from U87 cells, which barely express IGF-IR, it acts by blocking neovascularization. These findings suggest that the IGF-IR signaling pathway might be useful to target both the highly proliferative angiogenesis-dependent solid tumor component as well as the non-angiogenic infiltrative tumors cells at the invasive edge in glioblastomas. SECONDARY CATEGORY: Tumor Biology.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.