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Vascular remodeling during radiotherapy

Stephane Supiot
(Université de Nantes)
JPG - 14.4 ko

An increasing number of studies suggest that the microenvironment, and especially the vasculature, plays a major role in radiosensitivity. Due to excessive production of angiogenic molecules, blood vessels in solid tumors display an incomplete maturation that causes hypoxia and impacts the efficacy of irradiation. During radiotherapy, the proportion of hypoxic cells rapidly increases following the treatment fraction since normoxic cells are preferentially killed by irradiation. In the next hours, hypoxic tumor cells may gain an easier access to oxygenation, and therefore become more sensitive to the subsequent fraction of irradiation [1]. However, blood vessels are also largely affected by radiotherapy and thereby it is necessary to explore the vascular modifications during radiotherapy that may also impact tumor reoxygenation [2].

Recently, different studies explored the importance of vascular modifications during radiotherapy and their consequences on tumor reoxygenation. During and after ablative hypofractionated radiotherapy, Lan et al. showed that tumor microvessel density (MVD) and hypoxia decreased, while perfusion increased [3]. These vascular modifications were accompanied by an increase in the number of pericytes and their coverage of vessels. Similarly, using conventionally fractionated radiotherapy, we showed that hypoxia regressed rapidly during radiotherapy while tumor vessels perfusion and the diffusion of small molecules increased without any detectable changes in blood vessel density, size or network morphology [4]. However, a tumor vascular maturation defined by perivascular coverage was clearly observed along with an increase in endothelial intercellular junctions. Both in normal brain [5] and in tumor tissues [6], the specific recruitment to the site of irradiation of perivascular bone marrow derived cells (BMDCs) was noted concurrently with an increased vessel diameter, MVD and leakiness. Interestingly, EGFR inhibition altered vessel morphology by dissociating pericytes and decreased hypoxia, but did not radiosensitized tumor cells [6]. At the opposite, SDF-1/CXCR4 inhibition prevented vascular maturation, decreased vascular perfusion and MVD and radiosensitized tumors cells while increasing tumor hypoxia.

Altogether, these observations indicate that vascular remodeling plays an important role during radiotherapy and contributes to the radioresistance of blood vessels. Moreover, these results show that, in addition to tumor cell killing, vascular remodeling plays an uncovered role in tumor reoxygenation and sensitivity during radiotherapy. Radio-induced vascular remodeling somehow differs from the concept of vascular normalization, with similar features (increased perfusion, decreased hypoxia, increased perivascular coverage) but also different characteristics depending on tumor models and irradiation protocol. Therefore, the complex role of angiogenesis or vasculogenesis during radiotherapy deserves further studies to better understand the influence of vascular maturation on the radiosensitivity of tumor cells.

[1] L. M. Van Putten & R. F. Kallman, Oxygenation status of a transplantable tumor during fractionated radiation therapy. J Natl Cancer Inst 40 : 441-451, 1968.

[2] H. J. Park, R. J. Griffin, S. Hui, S. H. Levitt & C. W. Song, Radiation-induced vascular damage in tumors : implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS), Radiat Res 177, 311-327, 2012.

[3] J. Lan, X. L. Wan, L. Deng, J. X. Xue, L. S. Wang, et al., Ablative hypofractionated radiotherapy normalizes tumor vasculature in lewis lung carcinoma mice model, Radiat Res, 179 : 458-464, 2013.

[4] V. Potiron, R. Abderrahmani, K. Clément-Colmou, S. Marionneau-Lambot, T. Oullier, et al., Improved functionality of the vasculature during conventionally fractionated radiation therapy of prostate cancer, PLoS One, 8 (12), e84076, 2013.

[5] K. Burrell, R. P. Hill, G. Zadeh, High-resolution in-vivo analysis of normal brain response to cranial irradiation, PLoS One, 7, e38366, 2012.

[6] F. H. Chen, S. Y. Fu, Y. C. Yang, C. C. Wang, C. S. Chiang, et al., Combination of vessel-targeting agents and fractionated radiation therapy : the role of the SDF-1/CXCR4 pathway, Int J Radiat Oncol Biol Phys, 86, 777-784, 2013.

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