IGF1 Receptor Signaling Regulates Adaptive Radioprotection in Glioma Stem Cells

Abstract

Cancer stem cells (CSCs) play an important role in disease recurrence after radiation treatment as a result of intrinsic properties such as high DNA repair capability and antioxidative capacity. It is unclear, however, how CSCs further adapt to escape the toxicity of the repeated irradiation regimens used in clinical practice. Here, we have exposed a population of murine glioma stem cells (GSCs) to fractionated radiation in order to investigate the associated adaptive changes, with the ultimate goal of identifying a targetable factor that regulates acquired radioresistance. We have shown that fractionated radiation induces an increase in IGF1 secretion and a gradual upregulation of the IGF type 1 receptor (IGF1R) in GSCs. Interestingly, IGF1R upregulation exerts a dual radioprotective effect. In the resting state, continuous IGF1 stimulation ultimately induces downregulation of Akt/ extracellular-signal-regulated kinases (ERK) and FoxO3a activation, which results in slower proliferation and enhanced self-renewal. In contrast, after acute radiation, the abundance of IGF1R and increased secretion of IGF1 promote a rapid shift from a latent state toward activation of Akt survival signaling, protecting GSCs from radiation toxicity. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity, suggesting that blockade of IGF1R signaling is an effective strategy to reverse radioresistance. Together, our results show that GSCs evade the damage of repeated radiation not only through innate properties but also through gradual inducement of resistance pathways and identify the dynamic regulation of GSCs by IGF1R signaling as a novel mechanism of adaptive radioprotection.

Overcoming therapeutic resistance in glioblastoma: the way forward

“…The molecular phenotype of each cell is further altered by its unique position relative to other cells and local environment. Hypoxia (52), vascular niche for maintaining stemness (53,54), and secreted factors produced by other tumoral or stromal cells all influence the molecular phenotypes of tumor cells (55)(56)(57)). Heterogeneity at the cellular level adds another layer of complexity ( Figure 1C).…”

“…GSCs can overcome the damage induced by chemotherapy and radiotherapy not only through innate properties (e.g., genetic heterogeneity), but also through adaptive resistance pathways (20,55,63). How well studies that are based on known cell surface markers represent GSC populations and behavior is being debated (58,59).…”

“…This subpopulation had low expression of cell cycle genes, suggesting slower growth than the remainder of tumor cells. There is emerging evidence that GSCs vary in different GBM subtypes (66)(67)(68), between treatment-naive and recurrent GBM (51,55,63,69), and even within alternate niches in the same tumor (i.e., perivascular and hypoxic) (54,66,70). Which subpopulations of GSCs can initiate tumor recurrence needs further clarification.…”

Growth factors and kinases in glioblastoma growth

“…Additionally, the IGF-IR pathway appears to be involved in glioma stem cells' ability to adapt to repeated radiation, leading to radio-resistant cells. However, radio-resistant tumors treated with IGF-IR inhibitors have resulted in a significant increase in radiosensitivity [83,84] . It has been reported that in an in vivo model, the invasion and proliferation of glioblastomas are significantly reduced by blocking IGF-IR, while showing an increase in apoptosis and a reduction in intratumoral vascularization at the same time [85,86] .…”

Targeting glioblastoma cancer stem cells: the next great hope?

“…By doing so, NVP-BEZ235 potentiates the damage caused by ionizing radiation in glioma cells. 42,144 Some of the other targets that reportedly increase the radiosensitivity of CSCs include polo-like kinase 1, 49 cyclin-dependent kinase 6, 147 insulin-like growth factor-1 receptor, 103 DNA binding protein-1, 47 and miR-210.…”