Antitumor effects of cilengitide are restricted to integrin-αvβ3–positive tumors. A, Representative images of the BLI signal intensity 49 days (DAOY_control, left), 89 days (DAOY-KO#22, middle), and 36 days (HD-MB03_WT, right) after implantation, corresponding to the time of first death. Three mice are shown per condition. B, Tumor growth of DAOY_control (left), DAOY-KO#22 (middle), and HD-MB03_WT (right) as assessed by luciferase activity. Photon flux was quantified and analyzed using the IVIS imaging system. C, Survival curves of mice orthotopically implanted with DAOY_control (left), DAOY KO_#22 (middle), and HD-MB03 (right) cells in the cerebellum and treated with cilengitide. Day 0 corresponds to tumor implantation, and the black arrow indicates the start of treatment. Mice were treated with 300 µg cilengitide three times a week. The median survival (from the start of treatment) is shown at the bottom of the graphs. The P value is indicated in the graph (log-rank test). D, Ki67 labeling of DAOY_control (left), DAOY-KO_#22 (center), and HD-MB03_WT (right) tumor sections. Representative images of Ki67 immunolabeling (green) and Hoechst33342 nuclear DNA counterstaining (blue) are shown at the top of the graphs. E, Vasculature labeling of DAOY_control (left), DAOY-KO_#22 (middle), and HD-MB03_WT (right) tumor sections. Vessels were identified by CD31 and αSMA immunofluorescent staining (green and magenta, respectively). The number of vessels (CD31+ and αSMA+) was determined, and results are expressed as the percentage of control conditions. Key: *, P < 0.05; **, P < 0.01 versus control.
ARTICLE ABSTRACT
Medulloblastoma is one of the most prevalent solid tumors found in children, occurring in the brain's posterior fossa. The standard treatment protocol involves maximal resection surgery followed by craniospinal irradiation and chemotherapy. Despite a long-term survival rate of 70%, wide disparities among patients have been observed. The identification of pertinent targets for both initial and recurrent medulloblastoma cases is imperative. Both primary and recurrent medulloblastoma are marked by their aggressive infiltration into surrounding brain tissue, robust angiogenesis, and resistance to radiotherapy. While the significant role of integrin-αvβ3 in driving these characteristics has been extensively documented in glioblastoma, its impact in the context of medulloblastoma remains largely unexplored. Integrin-αvβ3 was found to be expressed in a subset of patients with medulloblastoma. We investigated the role of integrin-αvβ3 using medulloblastoma-derived cell lines with β3-subunit depletion or overexpression both in vitro and in vivo settings. By generating radioresistant medulloblastoma cell lines, we uncovered an increased integrin-αvβ3 expression, which correlated with increased susceptibility to pharmacologic integrin-αvβ3 inhibition with cilengitide, a competitive ligand mimetic. Finally, we conducted single-photon emission computed tomography (SPECT)/MRI studies on orthotopic models using a radiolabeled integrin-αvβ3 ligand (99mTc-RAFT-RGD). This innovative approach presents the potential for a novel predictive imaging technique in the realm of medulloblastoma. Altogether, our findings lay the foundation for employing SPECT/MRI to identify a specific subset of patients with medulloblastoma eligible for integrin-αvβ3–directed therapies. This breakthrough offers a pathway toward more targeted and effective interventions in the treatment of medulloblastoma.
This study demonstrates integrin-αvβ3’s fundamental role in medulloblastoma tumorigenicity and radioresistance and the effect of its expression on cilengitide functional activity.
