title: Low doses of ionizing radiation promote tumor growth and metastasis by enhancing angiogenesis.
abstract: 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.
authors.affiliation: Angiogenesis Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Sofia Vala
authors.forename: Leila R
authors.initials: LR
authors.lastname: Martins
authors.forename: Natsuko
authors.initials: N
authors.lastname: Imaizumi
authors.forename: Raquel J
authors.initials: RJ
authors.lastname: Nunes
authors.forename: José
authors.initials: J
authors.lastname: Rino
authors.forename: François
authors.initials: F
authors.lastname: Kuonen
authors.forename: Lara M
authors.initials: LM
authors.lastname: Carvalho
authors.forename: Curzio
authors.initials: C
authors.lastname: Rüegg
authors.forename: Isabel Monteiro
authors.initials: IM
authors.lastname: Grillo
authors.forename: João Taborda
authors.initials: JT
authors.lastname: Barata
authors.forename: Marc
authors.initials: M
authors.lastname: Mareel
authors.forename: Susana Constantino Rosa
authors.initials: SC
authors.lastname: Santos
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D000068258:Bevacizumab; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000528:radiation effects; D003094:Collagen / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D004338:Drug Combinations; D042783:Endothelial Cells / Q000473:pathology / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D007797:Laminin / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000528:radiation effects; D051379:Mice; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D009362:Neoplasm Metastasis / Q000473:pathology*; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy; D009389:Neovascularization, Pathologic / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011879:Radiotherapy Dosage; D012038:Regeneration / Q000528:radiation effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D000068258:Bevacizumab; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt