Low doses of ionizing radiation promote tumor growth and metastasis by enhancing angiogenesis.
Low doses of ionizing radiation promote tumor growth and metastasis by enhancing angiogenesis.
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DOI：
10.1371/journal.pone.0011222
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发表时间：
2010-06-21
期刊：
影响因子：
3.7
通讯作者：
Santos SC
中科院分区：
文献类型：
--
作者：
Sofia Vala I;Martins LR;Imaizumi N;Nunes RJ;Rino J;Kuonen F;Carvalho LM;Rüegg C;Grillo IM;Barata JT;Mareel M;Santos SC
放射治疗是癌症中广泛使用的治疗选择。然而，最近的证据表明，在分割放射治疗期间，在肿瘤靶体积内递送的电离辐射（IR）剂量可促进肿瘤侵袭和转移。此外，肿瘤区域周围的组织也暴露于低剂量的IR，其低于在肿瘤块内部递送的IR，因为外部放射治疗通过多个辐射束递送到肿瘤，以防止对处于危险中的器官的损伤。这些低剂量的IR对肿瘤区域周围的健康组织，特别是对脉管系统的生物学效应仍然很大程度上有待确定。我们发现，低于或等于0.8戈伊的IR剂量增强内皮细胞迁移，而不影响细胞增殖或存活。此外，我们表明，低剂量IR诱导几种内皮细胞蛋白的快速磷酸化，包括血管内皮生长因子（VEGF）受体-2，并在缺氧模拟条件下诱导VEGF的产生。通过激活VEGF受体-2，低剂量IR增强内皮细胞迁移并防止抗血管生成药物贝伐单抗促进的内皮细胞死亡。此外，我们观察到，低剂量IR加速胚胎血管生成的萌芽在斑马鱼发育过程中，并促进成人血管生成在斑马鱼鳍再生和小鼠基质胶测定。使用小鼠白血病和原位乳腺癌的实验模型，我们表明，低剂量IR促进肿瘤生长和转移，这些影响被阻止的VEGF受体酪氨酸激酶抑制剂的管理之前立即IR曝光。这些发现为了解IR潜在的促转移作用提供了新的机制，并可能为改进当前的放射治疗方案提供新的理论基础。
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.
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影响因子：
64.8
作者：
Downs, JA;Lowndes, NF;Jackson, SP
通讯作者：
Jackson, SP
影响因子：
6.2
作者：
Vicini, FA;Kestin, L;Martinez, A
通讯作者：
Martinez, A
影响因子：
64.8
作者：
Mauceri, HJ;Hanna, NN;Weichselbaum, RR
通讯作者：
Weichselbaum, RR
影响因子：
8
作者：
Constantino, S;Santos, R;Gouilleux, F
通讯作者：
Gouilleux, F
影响因子：
3.4
作者：
McBride, WH;Chiang, CS;Liao, YP
通讯作者：
Liao, YP