Preclinical evaluation of destruxin B as a novel Wnt signaling target suppressing proliferation and metastasis of colorectal cancer using non-invasive bioluminescence imaging.

In continuation to our studies toward the identification of direct anti-cancer targets, here we showed that destruxin B (DB) from Metarhizium anisopliae suppressed the proliferation and induced cell cycle arrest in human colorectal cancer (CRC) HT29, SW480 and HCT116 cells. Additionally, DB induced apoptosis in HT29 cells by decreased expression level of anti-apoptotic proteins Bcl-2 and Bcl-xL while increased pro-apoptotic Bax. On the other hand, DB attenuated Wnt-signaling by downregulation of ß-catenin, Tcf4 and ß-catenin/Tcf4 transcriptional activity, concomitantly with decreased expression of ß-catenin target genes cyclin D1, c-myc and survivin. Furthermore, DB affected the migratory and invasive ability of HT29 cells through suppressed MMPs-2 and -9 enzymatic activities. We also found that DB targeted the MAPK and/or PI3K/Akt pathway by reduced expression of Akt, IKK-α, JNK, NF-κB, c-Jun and c-Fos while increased that of IκBα. Finally, we demonstrated that DB inhibited tumorigenesis in HT29 xenograft mice using non-invasive bioluminescence technique. Consistently, tumor samples from DB-treated mice demonstrated suppressed expression of ß-catenin, cyclin D1, survivin, and endothelial marker CD31 while increased caspase-3 expression. Collectively, our data supports DB as an inhibitor of Wnt/ß-catenin/Tcf signaling pathway that may be beneficial in the CRC management.

Pulmonary resection for colorectal cancer metastases: duration between cancer onset and lung metastasis as an important prognostic factor.

BACKGROUND: Pulmonary resection is the most effective treatment available for colorectal lung metastases. However, the characteristics of those patients most likely to benefit from surgical resection have not yet been adequately clarified. We have made a critical analysis for the potential prognostic factors and their clinical significance in lung metastasis from colorectal cancer. METHODS: We analyzed 63 consecutive patients who underwent curative pulmonary resection for colorectal lung metastases at National Taiwan University Hospital from January 1997 to December 2006. Median follow-up was 37.3 (range 12-122) months. Disease-free and overall survival rates were evaluated by Kaplan-Meier analysis, and multivariate analyses of various prognostic characteristics were performed. RESULTS: Overall 5-year survival and disease-free survival rates were 43.9% and 19.5%, respectively. Multivariate analysis showed that the interval for development of lung metastases from primary colorectal cancer and the mode of operation were the only two independent prognostic factors for survival. With regard to disease-free survival, the interval between initial resection of colorectal cancer and following lung metastases was the only significant independent prognostic factor. Besides, subset analysis showed that the 5-year survival rate in repeated resection group for recurrence of colorectal metastasis in residual lung was 85.7%. CONCLUSION: Pulmonary resection, initial or even repeated resection for metastatic tumor from colorectal cancer should be encouraged for selected patients as it can significantly improve survival. Patients who have lung metastases within 1 year after primary tumor resection and those who do not undergo anatomical resection for metastatic lung tumor should be followed more carefully due to poor prognosis.