Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26+ cancer stem cells in colorectal carcinoma

Molecular Cancer

Research

Sunny KM Wong¹  Jensen TC Poon¹  Roberta WC Pang¹  Thomas CC Yau¹  Wai-Lun Law¹  Alvin HK Cheung¹  Colin SC Lam¹  Ariel KM Chow¹  Johnny HW Man¹  Nathan SM Cheng¹  Lui Ng¹  Timothy MH Wan¹ 

[1] Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, Hong Kong;

关键词: Colorectal cancer;    Cancer stem cells;    Raf265;    Raf/MEK/ERK signaling pathway;    Metastasis;   

DOI  :  10.1186/s12943-015-0352-y

 received in 2014-09-18, accepted in 2015-03-25,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundIn colorectal carcinoma (CRC), activation of the Raf/MEK/ERK signaling pathway is commonly observed. In addition, the commonly used 5FU-based chemotherapy in patients with metastatic CRC was found to enrich a subpopulation of CD26+ cancer stem cells (CSCs). As activation of the Raf/MEK/ERK signaling pathway was also found in the CD26+ CSCs and therefore, we hypothesized that an ATP-competitive pan-Raf inhibitor, Raf265, is effective in eliminating the cancer cells and the CD26+ CSCs in CRC patients.MethodsHT29 and HCT116 cells were treated with various concentrations of Raf265 to study the anti-proliferative and apoptotic effects of Raf265. Anti-tumor effect was also demonstrated using a xenograft model. Cells were also treated with Raf265 in combination with 5FU to demonstrate the anti-migratory and invasive effects by targeting on the CD26+ CSCs and the anti-metastatic effect of the combined treatment was shown in an orthotopic CRC model.ResultsRaf265 was found to be highly effective in inhibiting cell proliferation and tumor growth through the inhibition of the RAF/MEK/ERK signaling pathway. In addition, anti-migratory and invasive effect was found with Raf265 treatment in combination with 5FU by targeting on the CD26+ cells. Finally, the anti-tumor and anti-metastatic effect of Raf265 in combination with 5FU was also demonstrated.ConclusionsThis preclinical study demonstrates the anti-tumor and anti-metastatic activity of Raf265 in CRC, providing the basis for exploiting its potential use and combination therapy with 5FU in the clinical treatment of CRC.

【 授权许可】

Unknown   
© Chow et al. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.