Ionizing Radiation in Glioblastoma Initiating Cells

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a median survival of 12–15 months with treatment consisting of surgical resection followed by ionizing radiation (IR) and chemotherapy. Even aggressive treatment is often palliative due to near universal recurrence. Therapeutic resistance has been linked to a subpopulation of GBM cells with stem cell-like properties termed GBM initiating cells (GICs). Recent efforts have focused on elucidating resistance mechanisms activated in GICs in response to IR. Among these, GICs preferentially activate the DNA damage response (DDR) to result in a faster rate of double-strand break (DSB) repair induced by IR as compared to the bulk tumor cells. IR also activates NOTCH and the hepatic growth factor (HGF) receptor, c-MET, signaling cascades that play critical roles in promoting proliferation, invasion, and resistance to apoptosis. These pathways are preferentially activated in GICs and represent targets for pharmacologic intervention. While IR provides the benefit of improved survival, it paradoxically promotes selection of more malignant cellular phenotypes of GBM. As reviewed here, finding effective combinations of radiation and molecular inhibitors to target GICs and non-GICs is essential for the development of more effective therapies.

Cancer-driven dynamics of immune cells in a microfluidic environment

“…In parallel, the development of methods aimed at considering the system as a whole, hence with all its constituents mutually interacting, have become a major topic, involved as a necessary step beyond reductionism limitations6111213. For example, cancer progression involves multiple events and is the result of the interactions with cells of the immune system within the tumor micro-environment1415161718192021.…”

PARP inhibitors and IR join forces to strike glioblastoma-initiating cells

“…GICs express stem cell markers, notably PROM1 (CD133), FUT4 (SSEA-1), L1CAM and CD44, and they can also express markers of neurons, astrocytes and oligodendrocytes, suggesting that they can differentiate into all major cell types present in the adult brain. [2][3][4] Consistent with the hypothesis that poor patient survival is linked to the presence of a therapy-resistant cell population in glioblastoma, GICs are resistant to ionizing radiation (IR) 5,6 and to the chemotherapeutic agent temozolomide, 7 both of which are widely used in the clinic as first-line therapy. 1 The resistance has been attributed to enhanced DNA damage checkpoint responses, enhanced repair of damaged DNA and enhanced export of toxic compounds from the cells.…”

“…1 The resistance has been attributed to enhanced DNA damage checkpoint responses, enhanced repair of damaged DNA and enhanced export of toxic compounds from the cells. [5][6][7] In an article in this issue, Venere et al 8 identified new properties of GICs that can be exploited for more efficient therapies. Specifically, they report that GICs isolated from xenografted human glioblastomas contain high levels of reactive oxygen species (ROS), at least as compared with non-GICs.…”

Malignant Tumours of the Central Nervous System in Kazakhstan - Incidence Trends from 2004-2011

“…It is proved that ionizing radiation causes brain tumors in humans. Radiation therapy for ringworm in children has led to a significant and statistically significant increased risk of gliomas, meningiomas and nerve sheath tumors (Rivera et al, 2013). The results of epidemiological studies that have investigated the risk of brain tumors in relation to the X-ray examination of skull and teeth, are contradictory.…”