Assessment of endostatin gene therapy for familial adenomatous polyposis-related desmoid tumors.
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.
Martinico
Sandra C M
SC
Institute of Cancer and Cancer Research UK Clinical Centre, Barts and The London Queen Mary's School of Medicine and Dentistry, London, UK.
Jezzard
Sarah
S
Sturt
N Julian H
NJ
Michils
Genevieve
G
Tejpar
Sabine
S
Phillips
Robin K
RK
Vassaux
Georges
G
D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000628:therapy*; D060466:Axin Protein; D002460:Cell Line; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000628:therapy; D043169:Endostatins / Q000235:genetics*; D018222:Desmoid Tumors / Q000235:genetics* / Q000628:therapy*; D017491:Genes, APC; D015316:Genetic Therapy; D006801:Humans; D007668:Kidney; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured
D060466:Axin Protein; D043169:Endostatins; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D012097:Repressor Proteins