CYR61 and αVβ5 Integrin Cooperate to Promote Invasion and Metastasis of Tumors Growing in Preirradiated Stroma

Abstract

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 AVB5 integrin as proteins cooperating to mediate these effects. The anti-AV integrin monoclonal antibody 17E6 and the small molecular AVB3/ AVB5 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 AVB5 integrin as proteins that cooperate to mediate metastasis. They also identify AV integrin inhibition as a potential therapeutic approach for preventing metastasis in patients at risk for postradiation recurrences. [Cancer Res 2008;68(18):7323-31]

The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

“…Integrins are known to regulate TGF-b1 signaling through trans-activation of TGF-b1 receptors and downstream signaling (43)(44)(45). CCN1 binds to integrin a avb3 and avb5, which are known to enhance TGF-b signaling by physical association with TGF-bRII (46)(47)(48)(49). We speculate that CCN1 binding to these integrins may be necessary for enhanced TGF-b1/SMAD3 signaling.…”

Tenascin-C: Exploitation and collateral damage in cancer management

“…This effect was abrogated with Cilengitide, a peptide antagonist of the av integrin subunit. 85 Yet it is not clear which cells had expressed Cyr61 and how the local Cyr61 rich microenvironment impacts on distant metastasis formation. Whether an increased risk of developing metastasis upon local recurrences after radiotherapy holds also true in human cancer patients is supported by some but not all studies (reviewed in 81 ), nor is it known whether a similar mechanism involving Cyr61 as seen in the murine model also applies to the human disease.…”

Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells

“…In vitro migration and invasion assay Assays were performed as described previously by Monnier et al (2008).…”

“…Cell lysis, sodium dodecyl sulfate-PAGE and blotting were performed as described previously by (Monnier et al (2008).…”

“…For immunohistochemical detection of micro-vessels, tissue was stained with biotinylated rat anti-mouse CD31 as described earlier by Monnier et al (2008).…”