Assessment of endostatin gene therapy for familial adenomatous polyposis-related desmoid tumors

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 16; pp. 8233 - 8240
• Main Authors: MARTINICO, Sandra C. M, JEZZARD, Sarah, STURT, N. Julian H, MICHILS, Genevieve, TEJPAR, Sabine, PHILLIPS, Robin K, VASSAUX, Georges
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.2006
• Subjects: Adenomatous Polyposis Coli - genetics; Adenomatous Polyposis Coli - therapy; Antineoplastic agents; Axin Protein; Biological and medical sciences; Cell Line; Cell Line, Tumor; Colorectal Neoplasms - genetics; Colorectal Neoplasms - therapy; Dermatology; Endostatins - genetics; Fibromatosis, Aggressive - genetics; Fibromatosis, Aggressive - therapy; Gastroenterology. Liver. Pancreas. Abdomen; Genes, APC; Genetic Therapy; Humans; Kidney; Medical sciences; Pharmacology. Drug treatments; Repressor Proteins - genetics; RNA, Neoplasm - genetics; RNA, Small Interfering - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumor Cells, Cultured; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Evaluation; Treatment; Endostatin; Digestive diseases; Intestinal disease; Benign neoplasm; Familial adenomatous polyposis coli; Gene therapy; Soft tissue benign tumor; Desmoid tumor; Genetic disease
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-06-1209

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.