Hipertermi beyin tümörü kök hücrelerinin radyoterapiye duyarlılığını arttırıyor
Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling.
Cancer Res. 2015 Apr 15;75(8):1760-9. doi: 10.1158/0008-5472.CAN-14-3621. Epub 2015 Feb 20.
Man J1, Shoemake JD1, Ma T1, Rizzo AE2, Godley AR3, Wu Q1, Mohammadi AM4, Bao S1, Rich JN1, Yu JS5.
Author information
• 1Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio.
• 2Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio.
• 3Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio.
• 4Department of Neurosurgery, Cleveland Clinic, Cleveland, Ohio.
• 5Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio. Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio. yuj2@ccf.org.
Abstract
Glioma stem-like cells (GSC) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells, and it is reemerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth, and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment.
