Targeting CD44high/ID1+Patient Glioma Initiating Cells by TGF beta Receptor I Inhibitor Could Radiosensitize Glioblastoma

Purpose/Objective(s)
Cancer Initiating Cells (CICs), are a cellular subpopulation within the tumor that have stem cell characteristics, and with a high oncogenic capacity. CICs have the ability to generate secondary tumors that reproduce the characteristics and cellular diversity of the original tumor when implanted in mice. CICs are responsible for tumor initiation, propagation, recurrence and resistance to treatments. This indicates that CICs are critical therapeutic targets and that the understanding of the biology of CICs is crucial to improve anti-cancer treatments. The main goal of this project is to study the effect of radiation therapy on patient-derived Glioma Initiating Cells (GICs) and assess the combination of radiation therapy and anti-TGFβ therapies to target GICs.
Materials/Methods
Fresh glioma samples are obtained soon after resection and GICs are isolated and cultured. GICs generate tumors similar to the patient when inoculated orthotopically in the brain of mice. Patient-derived cells and tumors are irradiated (9 Gy) and/or treated with a specific TGFβ-Receptor I inhibitor. Markers of GICs and tumor growth are assessed by cytometry and MRI.
Results
TGFβ pathway is crucial for GICs, and the inhibition of TGF β signal using a specific TGFβ-Receptor I inhibitor results in a decrease in the GIC population within the tumor. We assess that the irradiation of patient-derived cells results in an increase of CD44 high/ID1+ GICs subpopulation both in vitro and in vivo. The increase in the GICs subpopulation is prevented by the treatment with the TGFβRI inhibitor which decreases the percentage of CD44 high subpopulation. We have analyzed the viability of cells after irradiation and in combination with the TGFβRI inhibitor and found that the TGFβRI inhibitors can radiosensitize patient-derived cells. We have validated our results in an in vivo mouse xenograft model.
Conclusions
CD44 high GICs are radioresistant and the irradiation of patient-derived cells or mouse xenograft tumors promote an enrichment of the CD44 high /ID1 + population. Blockage of the TGFβ pathway using an specific inhibitor causes a decrease in the CD44 high population of GICs and make the tumor more sensitive to radiation therapy. As GICs are responsible for tumor relapse, the concomitant treatment with radiation therapy and TGFβ-Receptor I inhibitor could prevent tumor recurrence in GBM patients.