Self-renewal as a therapeutic target in human colorectal cancer. (Nature Medicine, 2014, 20:29-36.)

報告日期: 2014/05/02
報告時間: 4:00/5:00
報告學生: 董家豪(以英文報告)
講評老師: 吳佳慶
附件下載: 下載[1404-1396958472-1.pdf] 

Self-renewal asa therapeutic targetinhumancolorectalcancer

Nat Med. 2014, 20:29-36.

AntonijaKreso,PetervanGalen,…,John EDick&CatherineAO’Brien

 

Speaker:Chia-HaoTung(董家豪)                                                                Time: 2014/5/2 17:10-18:00

Commentator:Chia-ChingWu, PhD(吳佳慶老師)                                       Place: Room 602

Abstract:

Tumor recurrence remains the major problem in treatment of metastatic colorectal cancer1. Previous evidences indicate that small proportion of cells in a colorectal tumor has high tumor-initiating potential2. These cells can be functionally defined as cancer-initiating cells (CICs), which can divide to make more CICs (self-renewal) and differentiate into non-CICs. Since surviving CICs post cancer treatments play a central role in tumor recurrence3, drug development for targeting CICs becomes urgent. Expression of BMI-1 is associated with maintenance of CICs in hepatocellular carcinoma and glioblastoma4,5. However, its role in colorectal CICs has not been investigated. In this issue, the authors  report  that  knockdown  of  BMI-1  suppresses  tumor  growth  and  CIC  frequency  in  both well-characterized LS174T human colon cancer cell lines and primary patient-derived colon cancer cells. Next, analysis of BrdU staining, Ki67 expression and cleaved caspase-3 suggest that knockdown of BMI-1 diminishes the cell proliferation and increases the apoptosis. Furthermore, by gene expression modulation by small molecules (GEMS) technology and BMI-1 untranslated region-mediated reporter, a small molecule inhibitor PTC-209, which can suppress the reporter activity, is identified. Then PTC-209 can irreversibly impair the self-renewal and tumor-initiating potential of CICs and tumor growth in vitro and in vivo. Taken together, this study suggests that targeting the BMI-1 provide a new way to treat colorectal cancer.

 

References:

1.     Howlader,Net al (2012). SEERCancer StatisticsReview.NationalCancerInstitute.

2.     O'Brien CAet al  (2007).  Ahuman colon cancer cell capable of  initiating  tumour  growth inimmunodeficientmice.Nature. 445: 106-10.

3.     Todaro  M  et  al  (2007) Colon  cancerstem  cells  dictatetumorgrowth and  resist  cell  death  byproduction of interleukin-4.CellStemCell. 1: 389-402.

4.     Chiba  T  et al  (2008) The polycomb gene product  BMI1 contributes to  the  maintenance oftumor-initiatingside populationcells in hepatocellular carcinoma.CancerRes. 68: 7742-9.

5.     AbdouhMetal(2009)BMI1sustainshumanglioblastomamultiformestemcellrenewal.JNeurosci.29: 8884-96.