title: Radiation-induced modifications of the tumor microenvironment promote metastasis.
abstract: Radiotherapy is successfully used to treat cancer. Emerging evidence, however, indicates that recurrences after radiotherapy are associated with increased local invasion, metastatic spreading and poor prognosis. Radiation-induced modifications of the tumor microenvironment have been proposed to contribute to increased aggressive tumor behavior, an effect also referred to as tumor bed effect, but the putative mechanisms involved have remained largely elusive. We have recently demonstrated that irradiation of the prospective tumor stroma impairs de novo angiogenesis through sustained inhibition of proliferation, migration and sprouting of endothelial cells. Experimental tumors growing within a pre-irradiated field have reduced tumor angiogenesis and tumor growth, increased hypoxia, necrosis, local invasion and distant metastasis. Mechanisms of progression involve adaptation of tumor cells to local hypoxic conditions as well as selection of cells with invasive and metastatic capacities. The matricellular protein CYR61 and integrin αVβ5 emerged as molecules that cooperate to mediate lung metastasis. Cilengitide, a small molecular inhibitor of αV integrins prevented lung metastasis formation. These results represent a conceptual advance to the understanding of the tumor bed effect and indicate that αV integrin inhibition might be a potential therapeutic approach for preventing metastasis in patients at risk for post-radiation recurrences.
authors.affiliation: Division of Experimental Oncology, Multidisciplinary Oncology Center (CePO), University Medical Center (CHUV), University of Lausanne (UNIL), Switzerland. curzio.ruegg@unifr.ch
authors.forename: Curzio
authors.initials: C
authors.lastname: Rüegg
authors.forename: Yan
authors.initials: Y
authors.lastname: Monnier
authors.forename: François
authors.initials: F
authors.lastname: Kuonen
authors.forename: Natsuko
authors.initials: N
authors.lastname: Imaizumi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D015687:Cell Hypoxia / Q000502:physiology; D002465:Cell Movement / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D055515:Cysteine-Rich Protein 61 / Q000502:physiology; D018450:Disease Progression; D042783:Endothelial Cells / Q000528:radiation effects; D006801:Humans; D055806:Microvessels / Q000528:radiation effects; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D009369:Neoplasms / Q000098:blood supply / Q000503:physiopathology / Q000532:radiotherapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000532:radiotherapy; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000502:physiology; D012910:Snake Venoms / Q000627:therapeutic use; D059016:Tumor Microenvironment / Q000502:physiology / Q000528:radiation effects*
chemical_list: D020533:Angiogenesis Inhibitors; C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D009363:Neoplasm Proteins; D019030:Receptors, Vitronectin; D012910:Snake Venoms; C064660:integrin alphaVbeta5; C422910:Cilengitide