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Assessment of Endostatin Gene Therapy for Familial Adenomatous Polyposis–Related Desmoid Tumors

¹ Institute of Cancer and Cancer Research UK Clinical Centre, Barts and The London Queen Mary's School of Medicine and Dentistry; ² Polyposis Registry, Cancer Research UK Colorectal Cancer Unit, St. Mark's Hospital, London, United Kingdom; and ³ Center for Human Genetics, Laboratorium voor Moleculaire Diagnostiek, Leuven, Belgium

Requests for reprints: Georges Vassaux, Centre for Molecular Oncology, Institute of Cancer and Cancer Research UK Clinical Centre, Barts and The London Queen Mary's School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom. Phone: 44-20-7014-0321; Fax: 44-20-7014-0431; E-mail: georges.vassaux{at}cancer.org.uk.

Constitutive activation of the Wnt signaling pathway is a hallmark of many cancers, including familial adenomatous polyposis (FAP)–related desmoid tumors. Endostatin is a well-known antiangiogenic protein that has been described recently as a potential inhibitor of this signaling pathway. Here, we show that endostatin directly induces apoptosis and inhibits the Wnt signaling pathway in colorectal cancer cell lines bearing mutations on the adenomatous polyposis coli (APC) gene as a model of FAP-related malignant cells. We then explore the relationship between apoptosis and inhibition of this pathway and show that they are not correlated. These results seem to contradict a well-recognized study, showing that reintroduction of the APC cDNA in APC-deficient cells leads to apoptosis. To reconcile our conclusions with the literature, we further show that a truncated fragment of APC capable of inhibiting the Wnt signaling pathway in SW480 cells is incapable of inducing apoptosis in these cells, confirming that APC-mediated apoptosis is uncoupled to the inhibition of the Wnt signaling pathway. Finally, we show that endostatin directly induces cell death on primary FAP-related desmoid tumor cells in culture. This phenomenon is also independent of the inhibition of the Wnt signaling pathway. Considering the current lack of effective treatment against desmoid tumors, we advocate that endostatin gene therapy represents an attractive new therapeutic approach for this disease. (Cancer Res 2006; 66(16): 8233-40)

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