Low Doses of Ionizing Radiation Promote Tumor Growth and Metastasis by Enhancing Angiogenesis

Abstract

Radiotherapy is a widely used treatment option in cancer. However, recent evidence suggests that doses of ionizing radiation (IR) delivered inside the tumor target volume, during fractionated radiotherapy, can promote tumor invasion and metastasis. Furthermore, the tissues that surround the tumor area are also exposed to low doses of IR that are lower than those delivered inside the tumor mass, because external radiotherapy is delivered to the tumor through multiple radiation beams, in order to prevent damage of organs at risk. The biological effects of these low doses of IR on the healthy tissue surrounding the tumor area, and in particular on the vasculature remain largely to be determined. We found that doses of IR lower or equal to 0.8 Gy enhance endothelial cell migration without impinging on cell proliferation or survival. Moreover, we show that low-dose IR induces a rapid phosphorylation of several endothelial cell proteins, including the Vascular Endothelial Growth Factor (VEGF) Receptor-2 and induces VEGF production in hypoxia mimicking conditions. By activating the VEGF Receptor-2, low-dose IR enhances endothelial cell migration and prevents endothelial cell death promoted by an anti-angiogenic drug, bevacizumab. In addition, we observed that low-dose IR accelerates embryonic angiogenic sprouting during zebrafish development and promotes adult angiogenesis during zebrafish fin regeneration and in the murine Matrigel assay. Using murine experimental models of leukemia and orthotopic breast cancer, we show that low-dose IR promotes tumor growth and metastasis and that these effects were prevented by the administration of a VEGF receptor-tyrosine kinase inhibitor immediately before IR exposure. These findings demonstrate a new mechanism to the understanding of the potential pro-metastatic effect of IR and may provide a new rationale basis to the improvement of current radiotherapy protocols.

Ionizing radiation, ion transports, and radioresistance of cancer cells

“…Radiation-induced up-regulation of integrin- (Wild-Bode et al, 2001; Nalla et al, 2010; Canazza et al, 2011; Rieken et al, 2011), VEGF- (Sofia Vala et al, 2010; Badiga et al, 2011; Kil et al, 2012), EGF- (Kargiotis et al, 2008; Pickhard et al, 2011) or/and TGFbeta signaling (Canazza et al, 2011; Zhou et al, 2011) has been proposed to promote tumor cell migration. Downstream ion transport processes have been reported for glioblastoma cells (Steinle et al, 2011).…”

Distinct Luminal-Type Mammary Carcinomas Arise from Orthotopic Trp53-Null Mammary Transplantation of Juvenile versus Adult Mice

“…Indeed breast cancer molecular subtypes defined by transcriptomic profiling can also be characterized by methylome profiling (52), suggesting that the two may go hand-in-hand. Identical hypermethylated genes occur in histologically normal ducts that are adjacent to pre-invasive and invasive lesions, suggesting a common loco-regional etiology mediated by methylation (9,53,54). …”

The emerging quest for the optimal angiostatic combination therapy

“…It is generally realized that the effects of high-and low-dose radiotherapy vary. Sofia Vala et al [38] found that low doses of radiotherapy (0.5 Gy) induced rapid phosphorylation of several endothelial cell proteins, including VEGF receptor (VEGFR)-2 and induced VEGF production in hypoxia mimicking conditions. This effect may explain why they found that low-dose irradiation actually enhanced angiogenesis and endothelial cell migration.…”