Effects of irradiation on tumor cell survival, invasion and angiogenesis

Abstract

Ionizing irradiation is a widely applied therapeutic method for the majority of solid malignant neoplasms, including brain tumors where, depending on localization, this might often be the only feasible primary intervention.Without doubt, it has been proved to be a fundamental tool available in the battlefield against cancer, offering a clear survival benefit in most cases. However, numerous studies have associated tumor irradiation with enhanced aggressive phenotype of the remaining cancer cells. A cell population manages to survive after the exposure, either because it receives sublethal doses and/or because it successfully utilizes the repair mechanisms. The biology of irradiated cells is altered leading to up-regulation of genes that favor cell survival, invasion and angiogenesis. In addition, hypoxia within the tumor mass limits the cytotoxicity of irradiation, whereas irradiation itself may worsen hypoxic conditions, which also contribute to the generation of resistant cells. Activation of cell surface receptors, such as the epidermal growth factor receptor, utilization of signaling pathways, and over-expression of cytokines, proteases and growth factors, for example the matrix metalloproteinases and vascular endothelial growth factor, protect tumor and non-tumor cells from apoptosis, increase their ability to invade to adjacent or distant areas, and trigger angiogenesis. This review will try to unfold the various molecular events and interactions that control tumor cell survival, invasion and angiogenesis and which are elicited or influenced by irradiation of the tumor mass, and to emphasize the importance of combining irradiation therapy with molecular targeting.

Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

“…Radiation consistently increases motility and invasion in GBM cells (5,6,19). Four cell lines were exposed to radiation after treatment with control adenovirus, Ad.5/3-shcon, or Ad.5/3-shmda-9.…”

“…However, inevitable recurrence occurs near resection margins and within the high-dose radiation field, implying that intrinsic invasiveness and radioresistance contribute significantly to relapse (3,4). Sublethal radiation has repeatedly been shown to induce invasion and migration in surviving tumor cells, enhancing the very property that makes curative treatment so difficult (5,6). A contributing factor to tumor relapse and recurrence is the ability of tumor cells to escape from the primary tumor mass (7), which underscores the importance of developing antiinvasive therapies that complement, and ideally enhance, conventional therapeutic approaches (8).…”

Irradiation affects cellular properties and Eph receptor expression in human melanoma cells

“…Although there is evidence that irradiation can lead to radioresistant tumor cell subpopulations with enhanced proliferation and invasion, and that irradiation-induced cytotoxic effects impair also surrounding healthy tissue, 1 it is broadly accepted that ionizing radiation like X-ray lead to biochemical changes in the cellular metabolism resulting in death of tumor cells. The irradiation-induced impairment of cellular viability, proliferation and clonal survival was analyzed in many different tumor entities, among them were glioblastoma, non-small-cell lung cancer, colon carcinoma and melanoma.…”

Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer?

“…Radiation damage to tumor cell mitochondria will hasten a dependence on glucose and glutamine for growth and survival (Warburg, 1956a;Seyfried and Shelton, 2010). Indeed, radiation therapy is known to upregulate the PI3K/Akt signaling pathway, which drives glioma glycolysis and chemotherapeutic drug resistance (Elstrom et al, 2004;Zhuang et al, 2009;Kargiotis et al, 2010;Seyfried and Shelton, 2010). Brain cancer energy metabolism and the standard of care: role of glucose High-dose glucocorticoids (dexamethasone) are generally prescribed to reduce radiation-associated brain swelling and tumor edema.…”