Apc Restoration Promotes Cellular Differentiation and Reestablishes Crypt Homeostasis in Colorectal Cancer
作者： Lukas E Dow , Kevin P O’Rourke , Janelle Simon , Darjus F Tschaharganeh , Johan H van Es
DOI: 10.1016/J.CELL.2015.05.033
关键词: Cellular differentiation 、 KRAS 、 Colorectal cancer 、 Small hairpin RNA 、 Cancer research 、 Suppressor 、 Biology 、 Wnt signaling pathway 、 Adenomatous polyposis coli 、 Immunology 、 RNA interference
摘要: The adenomatous polyposis coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. To determine whether Apc disruption required for maintenance, we developed a mouse model CRC whereby can be conditionally suppressed using doxycycline-regulated shRNA. suppression produces adenomas both small intestine colon that, presence Kras p53 mutations, progress invasive carcinoma. In established tumors, restoration drives rapid widespread tumor-cell differentiation sustained regression without relapse. Tumor accompanied by re-establishment normal crypt-villus homeostasis, such that once aberrantly proliferating cells reacquire self-renewal multi-lineage capability. Our study reveals revert functioning given appropriate signals provide compelling vivo validation pathway as therapeutic target treatment CRC.
narcis.nl参考文章(57)
David I. Bellovin, Bikul Das, Dean W. Felsher, Tumor Dormancy, Oncogene Addiction, Cellular Senescence, and Self-Renewal Programs Advances in Experimental Medicine and Biology. ,vol. 734, pp. 91- 107 ,(2013) , 10.1007/978-1-4614-1445-2_6
Peter Buske, Jens Przybilla, Markus Loeffler, Norman Sachs, Toshiro Sato, Hans Clevers, Joerg Galle, On the biomechanics of stem cell niche formation in the gut--modelling growing organoids. FEBS Journal. ,vol. 279, pp. 3475- 3487 ,(2012) , 10.1111/J.1742-4658.2012.08646.X
Wade Samowitz, Mark Meuth, Lisa Spirio, Sean Egan, Sean Egan, Nitai Bhattacharyya, Andrew Thliveris, Margaret Robertson, David Jones, Joanna Groden, Joanna Groden, Geoff Joslyn, Geoff Joslyn, Ray White, Ray White, Response of colon cancer cell lines to the introduction of APC, a colon-specific tumor suppressor gene Cancer Research. ,vol. 55, pp. 1531- 1539 ,(1995)
Toshiro Sato, Robert G. Vries, Hugo J. Snippert, Marc van de Wetering, Nick Barker, Daniel E. Stange, Johan H. van Es, Arie Abo, Pekka Kujala, Peter J. Peters, Hans Clevers, Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche Nature. ,vol. 459, pp. 262- 265 ,(2009) , 10.1038/NATURE07935
P. J. Morin, B. Vogelstein, K. W. Kinzler, APOPTOSIS AND APC IN COLORECTAL TUMORIGENESIS Proceedings of the National Academy of Sciences of the United States of America. ,vol. 93, pp. 7950- 7954 ,(1996) , 10.1073/PNAS.93.15.7950
Halit Ongen, Claus L. Andersen, Jesper B. Bramsen, Bodil Oster, Mads H. Rasmussen, Pedro G. Ferreira, Juan Sandoval, Enrique Vidal, Nicola Whiffin, Alexandra Planchon, Ismael Padioleau, Deborah Bielser, Luciana Romano, Ian Tomlinson, Richard S. Houlston, Manel Esteller, Torben F. Orntoft, Emmanouil T. Dermitzakis, Putative cis -regulatory drivers in colorectal cancer Nature. ,vol. 512, pp. 87- 90 ,(2014) , 10.1038/NATURE13602
Lukas E Dow, Meredith J Taylor, Gregory J Hannon, Scott W Lowe, Johannes Zuber, Katherine McJunkin, Christof Fellmann, Toolkit for evaluating genes required for proliferation and survival using tetracycline-regulated RNAi Nature Biotechnology. ,vol. 29, pp. 79- 83 ,(2011) , 10.1038/NBT.1720
S. Nelson, I. S. Nathke, Interactions and functions of the adenomatous polyposis coli (APC) protein at a glance. Journal of Cell Science. ,vol. 126, pp. 873- 877 ,(2013) , 10.1242/JCS.100479
Tae-Hee Kim, Fugen Li, Isabel Ferreiro-Neira, Li-Lun Ho, Annouck Luyten, Kodandaramireddy Nalapareddy, Henry Long, Michael Verzi, Ramesh A. Shivdasani, Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity Nature. ,vol. 506, pp. 511- 515 ,(2014) , 10.1038/NATURE12903
Nick Barker, Johan H. van Es, Jeroen Kuipers, Pekka Kujala, Maaike van den Born, Miranda Cozijnsen, Andrea Haegebarth, Jeroen Korving, Harry Begthel, Peter J. Peters, Hans Clevers, Identification of stem cells in small intestine and colon by marker gene Lgr5 Nature. ,vol. 449, pp. 1003- 1007 ,(2007) , 10.1038/NATURE06196