Proton irradiation suppresses angiogenic genes and impairs cell invasion and tumor growth.
The energy deposition characteristics of proton radiation have attracted considerable attention in light of its implications for carcinogenesis risk in space travel, as well for application to cancer treatment. In space, it is the principle component of the galactic cosmic radiation to which astronauts will be exposed. For treatment, an increasing number of proton facilities are being established to exploit the physical advantages of this radiation type. However, the possibility that there may also be biologically based advantages to proton exposure has not been considered in either context. We demonstrate here that high-energy proton irradiation can inhibit expression of major pro-angiogenic factors and multiple angiogenesis-associated processes, including invasion and endothelial cell proliferation, which is prominent in cancer progression. Dose-dependent suppression of angiogenic signaling was demonstrated for both cancer and nontransformed cells. Pan-genomic microarray analysis and RT-PCR revealed that post-irradiation (0.5, 1.0 and 2.0 Gy), critical pro-angiogenic signaling factors including: vascular endothelial growth factor (VEGF), interleukin 6 and 8 (IL-6, IL-8) and hypoxia-inducible factor-1 alpha (HIF-1A), were significantly downregulated. Co-culture studies demonstrated that endothelial cell proliferation and invasion were inhibited by culturing with irradiated cancer or fibroblast cells, which suggests that proton irradiation may, in addition to direct action, contribute to angiogenesis suppression through modulation of paracrine signalings from targeted cells. Addition of recombinant IL-8 or VEGF partially restored these functions in vitro, while in vivo, an attenuated tumor growth rate was demonstrated for proton-irradiated human lung cancer cells. Taken together, these findings provide novel pre-clinical evidence that proton irradiation may, in addition to its physical targeting advantages, have important biological ramifications that should be a consideration in the optimization of proton therapy.
Center of Cancer Systems Biology, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
Swati
S
Girdhani
Clare
C
Lamont
Philip
P
Hahnfeldt
Amir
A
Abdollahi
Lynn
L
Hlatky
D002465:Cell Movement / Q000528:radiation effects*; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D015870:Gene Expression / Q000528:radiation effects; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology / Q000532:radiotherapy*; D009389:Neovascularization, Pathologic / Q000235:genetics; D018919:Neovascularization, Physiologic; D061766:Proton Therapy; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A