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CYR61 and Vβ5 Integrin Cooperate to Promote Invasion and Metastasis of Tumors Growing in Preirradiated Stroma

¹ Division of Experimental Oncology, Centre Pluridisciplinaire d'Oncologie, Faculty of Biology and Medicine, University of Lausanne, ² Swiss Institute for Experimental Cancer Research, National Centre for Competence in Research Molecular Oncology, and ³ Swiss Institute of Bioinformatics, Epalinges Office, Epalinges, Switzerland; ⁴ Institute of Pathology, Faculty of Biology and Medicine, ⁵ Institute of Applied Radiophysics, and ⁶ Department of Radio-Oncology, Centre Hospitalier Universitaire Vaudois and Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland; and ⁷ Merck KGaA, Department of Preclinical Oncology Research, Darmstadt, Germany

Requests for reprints: Curzio Rüegg, Division of Experimental Oncology, Centre Pluridisciplinaire d'Oncologe, 155 Chemin des Boveresses, CH1066 Epalinges, Switzerland. Phone: 41-21-692-5853; Fax: 41-21-692-5872; E-mail: curzio.ruegg{at}unil.ch.

Key Words: hypoxia • therapy • radiotherapy • tumor escape • metastasis • integrin • CYR61

Radiotherapy is widely used to treat human cancer. Patients locally recurring after radiotherapy, however, have increased risk of metastatic progression and poor prognosis. The clinical management of postradiation recurrences remains an unresolved issue. Tumors growing in preirradiated tissues have an increased fraction of hypoxic cells and are more metastatic, a condition known as tumor bed effect. The transcription factor hypoxia inducible factor (HIF)-1 promotes invasion and metastasis of hypoxic tumors, but its role in the tumor bed effect has not been reported. Here, we show that tumor cells derived from SCCVII and HCT116 tumors growing in a preirradiated bed, or selected in vitro through repeated cycles of severe hypoxia, retain invasive and metastatic capacities when returned to normoxia. HIF activity, although facilitating metastatic spreading of tumors growing in a preirradiated bed, is not essential. Through gene expression profiling and gain- and loss-of-function experiments, we identified the matricellular protein CYR61 and Vβ5 integrin as proteins cooperating to mediate these effects. The anti-V integrin monoclonal antibody 17E6 and the small molecular Vβ3/Vβ5 integrin inhibitor EMD121974 suppressed invasion and metastasis induced by CYR61 and attenuated metastasis of tumors growing within a preirradiated field. These results represent a conceptual advance to the understanding of the tumor bed effect and identify CYR61 and Vβ5 integrin as proteins that cooperate to mediate metastasis. They also identify V integrin inhibition as a potential therapeutic approach for preventing metastasis in patients at risk for postradiation recurrences. [Cancer Res 2008;68(18):7323–31]

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