Noninvasive optoacoustic microangiography reveals dose and size dependency of radiation-induced deep tumor vasculature remodeling

HIF-1α Inhibition Improves Anti-Tumor Immunity and Promotes the Efficacy of Stereotactic Ablative Radiotherapy (SABR)

“…A recent study using the noninvasive optoacoustic microangiography method demonstrated that 12-18 Gy irradiation of murine tumors in a single dose induced numerous vascular fragmentations and pronounced reductions in the functional vascular density in 1-10 days [30]. Such radiation-induced vascular injuries would inevitably lead to a decline in the supply of oxygen to tumor cells [19,22,30,31], and the resultant hypoxic environment increases the expression of HIFs [2,3,42] (Figure 1).…”

“…It has been shown that structurally immature tumor microvasculatures are extremely sensitive to ionizing radiation [19]. Irradiation of tumors with doses higher than 8-10 Gy causes dose-dependent vascular damage, resulting in a decline in functional vascularity and blood perfusion [2,[19][20][21][22][23][24][25][26][27][28][29][30][31]. For example, in a rat tumor model, functional vascularity declined immediately after irradiation with 2.5 or 5.0 Gy but recovered within 1-2 days, while irradiation with doses greater than 10 Gy caused a severe and long-lasting shutdown of blood perfusion [28].…”

“…For example, in a rat tumor model, functional vascularity declined immediately after irradiation with 2.5 or 5.0 Gy but recovered within 1-2 days, while irradiation with doses greater than 10 Gy caused a severe and long-lasting shutdown of blood perfusion [28]. A recent study using the noninvasive optoacoustic microangiography method demonstrated that 12-18 Gy irradiation of murine tumors in a single dose induced numerous vascular fragmentations and pronounced reductions in the functional vascular density in 1-10 days [30]. Such radiation-induced vascular injuries would inevitably lead to a decline in the supply of oxygen to tumor cells [19,22,30,31], and the resultant hypoxic environment increases the expression of HIFs [2,3,42] (Figure 1).…”

“…It is becoming more and more apparent that the elevated anti-tumor immunity by high-dose irradiation is often counterbalanced or negated by the overwhelming immunosuppressive TME enriched with HIF-1α [11,17,[32][33][34][35]. The TME is intrinsically hypoxic due to insufficient blood supply, and it becomes further hypoxic when tumors are exposed to high-dose hypofractionated irradiation and blood vessels are occluded [3,19,30,31]. As addressed before and shown in Figure 2, the increase in hypoxia because of vascular occlusions leads to the accumulation of HIF-1α in the TME [2,3,12,42].…”

“…Cell death due to DNA damage is the major cell death mechanism when the delivered radiation dose per fraction is small, e.g., <5-8 Gy [7,8]. When the radiation dose exceeds 8-10 Gy per fraction, significant indirect cell death secondary to the vascular damage would occur [3,[19][20][21][22][23][24][25][26][27][28][29][30][31]. SABR is highly effective because it indirectly kills many radioresistant hypoxic tumor cells by causing vascular occlusion [2][3][4][5][6].…”