A tankyrase inhibitor impairs tumor growth and angiogenesis through the Wnt/β-catenin attenuation

Abstract

Aberrant regulation of Wnt signaling pathway is a prevalent theme in cancer biology. While it has been demonstrated to be involved in many types of tumours it has been poorly studied in ovarian cancer. We analyzed the effect of inhibiting Wnt/β-catenin in a xenograft model of human ovarian cancer. A human ovarian adenocarcinoma cell line (IGROV-1) was subcutaneously injected in 6-8 weeksold female nude mice. Once the tumour was palpable, we injected a tankyrase inhibitor, which attenuates Wnt/β-catenin signalling (XAV939: 2.5 and 5 mg/kg) every two days three times. Mice were euthanized 3 days after the last injection. The involvement of Wnt/β-catenin pathway in tumour growth, morphology and angiogenesis was evaluated. Our results showed a significant decrease in tumour size when mice were treated with XAV939, which strikingly, was higher at the 2.5 mg/kg dose than the 5 mg/kg dose (day 7: no treated animals vs. 2.5 mg/kg group, p<0.001; no treated animals vs. 5 mg/ kg group: p< 0.05). No significant differences were appreciated in mice weight between groups. There was also a significant decrease in β-Catenin and Cyclin D1 levels measured by western blot at both doses used. On the other hand, we observed a decrease in the endothelial cell area stained with CD31 marker. Additionally, we detected a decrease in the periendothelial cell area, measured using α-Smooth-muscle-actin, compared with tumours from animals with no treatment. In hematoxilin-eosin stained sections of tumours we distinguished that the morphology notably changed after treatment with XAV939. A tumour loss of integrity and accumulation of interstitial fluid was evident and dose dependent. In conclusion, we demonstrate a clear involvement of Wnt/β-catenin in ovarian tumour growth and we suggest and implication of this pathway in tumour angiogenesis.