Ablative Hypofractionated Radiotherapy Normalizes Tumor Vasculature in Lewis Lung Carcinoma Mice Model

Abstract

Ablative hypofractionated radiotherapy (HFRT) significantly improves the overall survival of inoperable non-small cell lung cancer (NSCLC) patients compared with conventional radiation therapy. However, the radiobiological mechanisms of ablative HFRT remain largely unknown. The purpose of this study was to investigate the dynamic changes of tumor vessels and perfusion during and after ablative hypofractionated radiotherapy. Lewis lung carcinoma-bearing mice were treated with sham (control) and ablative hypofractionated radiotherapy of 12 Gy in 1 fraction (12 Gy/1F) and 36 Gy in 3 fractions (36 Gy/3F). Tumor microvessel density (MVD), morphology and function were examined at different times after irradiation. The results showed that, compared to the controls the MVD and hypoxia in ablative HFRT groups decreased, which were accompanied by an increase in the number of pericytes and their coverage of vessels. Functional tests revealed that tumor hypoxia and perfusion were improved, especially in the 36 Gy/3F group. Our results revealed that ablative hypofractionated radiotherapy not only repressed MVD and hypoxia, but also increased the vascular perfusion and the number of pericyte-covered vessels, suggesting that ablative HFRT normalized the tumor vasculature.

Improved Functionality of the Vasculature during Conventionally Fractionated Radiation Therapy of Prostate Cancer

“…Our data indicate a reduction of the hypoxic fraction after two weeks of treatment and are in agreement with recent data in subcutaneous tumors [9], [10], [34]. Tumor reoxygenation was defined as the concept that chronically hypoxic tumor cells gain a better access to oxygen during fractionated radiation therapy because aerobic tumor cells are eliminated by previous fractions [35].…”

“…Indeed, PC3-derived tumors grown subcutaneously have substantially greater vessel size and density (≈ x3, data not shown). Most importantly, recent studies using higher fraction doses are in agreement with our work for a decrease in tumor hypoxia and increased perfusion together with pericyte coverage [9], [10], except one report using very high (30 Gy) single dose irradiation [27]. Collectively, these studies suggest that increased perivascular coverage might play an essential role in vessel perfusion and reoxygenation after fractionated irradiation.…”

“…These results are contrasting with previous studies using higher dose irradiation, where endothelial cell death and decline in vessel density were reported, although at earlier time points [2], [4]. Particularly, fractions of 4 and 12 Gy for 2–3 weeks led to increased endothelial cell death and decreased MVD in subcutaneous tumors [8], [9], [10]. This is surprising since endothelial apoptosis is thought to occur only at single doses ≥ 10–15 Gy [2], [4].…”

“…Single high-dose irradiation can induce rapid apoptosis of the vasculature [6], [7]. In addition, both single high-dose and hypofractionated irradiation induce endothelial cell apoptosis, thereby decreasing vascular density [8], with surviving vessels more dilated [9], [10]. However, the importance of vascular damage in tumors receiving conventionally fractionated radiation therapy (CFRT: 1.8-2 Gy per fraction) is more controversial [11], [12].…”

Influence of Radiotherapy Fractionation Schedule on the Tumor Vascular Microenvironment in Prostate and Lung Cancer Models

“…Increased pericyte coverage has been shown after fractionated RT, with some evidence for contribution of bone-marrow-derived cells [6][7][8][9]11]. However, observations after high dose RT were more heterogeneous [10,13,14,19].…”