gms | German Medical Science

Objective: This study aimed to investigate the role of the insulin-like growth factor-1 receptor (IGF-1R) in glioblastoma. We used an IGF-1R antibody (IMC-A12) to inhibit the growth of glioblastoma (stem-like) cell lines in vitro and in vivo.

Method: Two different xenograft tumor models were established in nude mice. We used U87 cells to generate solid tumors and GS-12 glioblastoma stem-like (GS) cells to produce diffusely invasive tumors. IMC-A12 was administered intratumorally via brain catheters connected to osmotic mini-pumps. Tumor size, proliferation, apoptosis and angiogenesis were determined histologically and by immunohistochemistry. IGF-1R expression was quantified by flow cytometry. Proliferation, migration and apoptosis were analyzed in vitro.

Results: Histological analyses revealed that tumor growth was inhibited by 73.7% and 50.2% compared to control tumors in U87 and GS-12 tumor models, respectively. In solid U87 tumors, intratumoral blood vessel density was reduced by 25.4%, whereas rates of proliferation and apoptosis did not differ from control tumors. In contrast, in the invasive stem cell model, IMC-A12 treatment had no effect on tumor neovascularization, however the proportion of proliferating cells decreased by 27.2% compared to controls. We therefore hypothesized that IMC-A12 interfered directly with stem-like cells. Indeed, in vitro analyses revealed that IMC-A12 significantly reduced proliferation of GS-12 cells by 39.9% but not that of U87 cells. Furthermore, various GS cell lines displayed a strikingly higher expression of IGF-1R (> 87%) than conventional lines, such as U87 (< 6%). In vitro apoptosis assays showed that IMC-A12 had no pro-apoptotic effect on either cell type.

Conclusions: IGF-1R blockade inhibits tumor growth in vivo by reducing proliferation of GS-12 directly, in contrast to U87-induced tumors, where reduction is caused by inhibition of tumor angiogenesis. These findings suggest that the IGF-1R signaling pathway might be useful to target both the proliferative angiogenesis-dependent solid tumor component as well as the non-angiogenic infiltrative tumor cells at the invasive edge in human glioblastomas.