Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 337 (6095): 730-735

Copyright © 2012 by the American Association for the Advancement of Science

Lineage Tracing Reveals Lgr5+ Stem Cell Activity in Mouse Intestinal Adenomas

Arnout G. Schepers,* Hugo J. Snippert,*,{dagger} Daniel E. Stange, Maaike van den Born, Johan H. van Es, Marc van de Wetering, Hans Clevers{ddagger}

Abstract: The concept that tumors are maintained by dedicated stem cells, the so-called cancer stem cell hypothesis, has attracted great interest but remains controversial. Studying mouse models, we provide direct, functional evidence for the presence of stem cell activity within primary intestinal adenomas, a precursor to intestinal cancer. By "lineage retracing" using the multicolor Cre-reporter R26R-Confetti, we demonstrate that the crypt stem cell marker Lgr5 (leucine-rich repeat–containing heterotrimeric guanine nucleotide–binding protein–coupled receptor 5) also marks a subpopulation of adenoma cells that fuel the growth of established intestinal adenomas. These Lgr5+ cells, which represent about 5 to 10% of the cells in the adenomas, generate additional Lgr5+ cells as well as all other adenoma cell types. The Lgr5+ cells are intermingled with Paneth cells near the adenoma base, a pattern reminiscent of the architecture of the normal crypt niche.

Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen, and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, Netherlands.

* These authors contributed equally to this work.

{dagger} Present address: Molecular Cancer Research, Centre of Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, Netherlands.

{ddagger} To whom correspondence should be addressed. E-mail: h.clevers{at}hubrecht.eu


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Growth, homeostatic regulation and stem cell dynamics in tissues.
E. Hannezo, J. Prost, and J.- F. Joanny (2014)
J R Soc Interface 11, 20130895
   Abstract »    Full Text »    PDF »
Binary recombinase systems for high-resolution conditional mutagenesis.
M. Hermann, P. Stillhard, H. Wildner, D. Seruggia, V. Kapp, H. Sanchez-Iranzo, N. Mercader, L. Montoliu, H. U. Zeilhofer, and P. Pelczar (2014)
Nucleic Acids Res. 42, 3894-3907
   Abstract »    Full Text »    PDF »
LGR5 positivity defines stem-like cells in colorectal cancer.
D. Hirsch, N. Barker, N. McNeil, Y. Hu, J. Camps, K. McKinnon, H. Clevers, T. Ried, and T. Gaiser (2014)
Carcinogenesis 35, 849-858
   Abstract »    Full Text »    PDF »
Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation.
F. C. Lourenco, J. Munro, J. Brown, J. Cordero, R. Stefanatos, K. Strathdee, C. Orange, S. M. Feller, O. J. Sansom, M. Vidal, et al. (2014)
Gut 63, 480-493
   Abstract »    Full Text »    PDF »
Noninvasive positron emission tomography and fluorescence imaging of CD133+ tumor stem cells.
S. Gaedicke, F. Braun, S. Prasad, M. Machein, E. Firat, M. Hettich, R. Gudihal, X. Zhu, K. Klingner, J. Schuler, et al. (2014)
PNAS 111, E692-E701
   Abstract »    Full Text »    PDF »
Role of Oncogenic K-Ras in Cancer Stem Cell Activation by Aberrant Wnt/{beta}-Catenin Signaling.
B.-S. Moon, W.-J. Jeong, J. Park, T. I. Kim, D. S. Min, and K.-Y. Choi (2014)
J Natl Cancer Inst 106, djt373
   Abstract »    Full Text »    PDF »
Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion.
H. J. Snippert, A. G. Schepers, J. H. van Es, B. D. Simons, and H. Clevers (2014)
EMBO Rep. 15, 62-69
   Abstract »    Full Text »    PDF »
The structure and organization of lanceolate mechanosensory complexes at mouse hair follicles.
L. Li and D. D. Ginty (2014)
eLife Sci 3, e01901
   Abstract »    Full Text »    PDF »
Occult progression by Apc-deficient intestinal crypts as a target for chemoprevention.
J. M. Fischer, A. G. Schepers, H. Clevers, D. Shibata, and R. M. Liskay (2014)
Carcinogenesis 35, 237-246
   Abstract »    Full Text »    PDF »
Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells.
T. Stoyanova, A. R. Cooper, J. M. Drake, X. Liu, A. J. Armstrong, K. J. Pienta, H. Zhang, D. B. Kohn, J. Huang, O. N. Witte, et al. (2013)
PNAS 110, 20111-20116
   Abstract »    Full Text »    PDF »
Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in {gamma}-secretase inhibitor drug responses.
D. J. Azzam, D. Zhao, J. Sun, A. J. Minn, P. Ranganathan, K. Drews-Elger, X. Han, M. Picon-Ruiz, C. A. Gilbert, S. A. Wander, et al. (2013)
EMBO Mol Med. 5, 1502-1522
   Abstract »    Full Text »    PDF »
ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells.
L. Niederreiter, T. M. J. Fritz, T. E. Adolph, A.-M. Krismer, F. A. Offner, M. Tschurtschenthaler, M. B. Flak, S. Hosomi, M. F. Tomczak, N. C. Kaneider, et al. (2013)
J. Exp. Med. 210, 2041-2056
   Abstract »    Full Text »    PDF »
TrAp: a tree approach for fingerprinting subclonal tumor composition.
F. Strino, F. Parisi, M. Micsinai, and Y. Kluger (2013)
Nucleic Acids Res. 41, e165
   Abstract »    Full Text »    PDF »
Cyclin G1 Expands Liver Tumor-Initiating Cells by Sox2 Induction via Akt/mTOR Signaling.
W. Wen, T. Han, C. Chen, L. Huang, W. Sun, X. Wang, S.-Z. Chen, D.-M. Xiang, L. Tang, D. Cao, et al. (2013)
Mol. Cancer Ther. 12, 1796-1804
   Abstract »    Full Text »    PDF »
Cancer heterogeneity--a multifaceted view.
F. D. S. E. Melo, L. Vermeulen, E. Fessler, and J. P. Medema (2013)
EMBO Rep. 14, 686-695
   Abstract »    Full Text »    PDF »
Imaging Mouse Cancer Models In Vivo Using Reporter Transgenes.
S. K. Lyons, P. S. Patrick, and K. M. Brindle (2013)
Cold Spring Harb Protoc 2013, pdb.top069864
   Abstract »    Full Text »    PDF »
Genetic reconstitution of tumorigenesis in primary intestinal cells.
K. Onuma, M. Ochiai, K. Orihashi, M. Takahashi, T. Imai, H. Nakagama, and Y. Hippo (2013)
PNAS 110, 11127-11132
   Abstract »    Full Text »    PDF »
Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution.
A. Humphries, B. Cereser, L. J. Gay, D. S. J. Miller, B. Das, A. Gutteridge, G. Elia, E. Nye, R. Jeffery, R. Poulsom, et al. (2013)
PNAS 110, E2490-E2499
   Abstract »    Full Text »    PDF »
The Notch signaling pathway as a mediator of tumor survival.
K. M. Capaccione and S. R. Pine (2013)
Carcinogenesis 34, 1420-1430
   Abstract »    Full Text »    PDF »
Anti-HDGF Targets Cancer and Cancer Stromal Stem Cells Resistant to Chemotherapy.
J. Zhao, M. Z. Ma, H. Ren, Z. Liu, M. J. Edelman, H. Pan, and L. Mao (2013)
Clin. Cancer Res. 19, 3567-3576
   Abstract »    Full Text »    PDF »
Lgr proteins in epithelial stem cell biology.
N. Barker, S. Tan, and H. Clevers (2013)
Development 140, 2484-2494
   Abstract »    Full Text »    PDF »
Mathematical Modeling of Tumor Cell Proliferation Kinetics and Label Retention in a Mouse Model of Lung Cancer.
Y. Zheng, H. Moore, A. Piryatinska, T. Solis, and E. A. Sweet-Cordero (2013)
Cancer Res. 73, 3525-3533
   Abstract »    Full Text »    PDF »
Growing Self-Organizing Mini-Guts from a Single Intestinal Stem Cell: Mechanism and Applications.
T. Sato and H. Clevers (2013)
Science 340, 1190-1194
   Abstract »    Full Text »    PDF »
Breast cancer stem cells: an update.
J. Iqbal, P. Y. Chong, and P. H. Tan (2013)
J. Clin. Pathol. 66, 485-490
   Abstract »    Full Text »    PDF »
A Novel Tankyrase Small-Molecule Inhibitor Suppresses APC Mutation-Driven Colorectal Tumor Growth.
T. Lau, E. Chan, M. Callow, J. Waaler, J. Boggs, R. A. Blake, S. Magnuson, A. Sambrone, M. Schutten, R. Firestein, et al. (2013)
Cancer Res. 73, 3132-3144
   Abstract »    Full Text »    PDF »
Caught in the act: revealing the metastatic process by live imaging.
M. R. Fein and M. Egeblad (2013)
Dis. Model. Mech. 6, 580-593
   Abstract »    Full Text »    PDF »
LGR5 promotes survival in human colorectal adenoma cells and is upregulated by PGE2: implications for targeting adenoma stem cells with NSAIDs.
M. R. A. Al-Kharusi, H. J. M. Smartt, A. Greenhough, T. J. Collard, E. D. Emery, A. C. Williams, and C. Paraskeva (2013)
Carcinogenesis 34, 1150-1157
   Abstract »    Full Text »    PDF »
Constitutive Internalization of the Leucine-rich G Protein-coupled Receptor-5 (LGR5) to the Trans-Golgi Network.
J. C. Snyder, L. K. Rochelle, H. K. Lyerly, M. G. Caron, and L. S. Barak (2013)
J. Biol. Chem. 288, 10286-10297
   Abstract »    Full Text »    PDF »
New Paradigms and Future Challenges in Radiation Oncology: An Update of Biological Targets and Technology.
S. L. Liauw, P. P. Connell, and R. R. Weichselbaum (2013)
Science Translational Medicine 5, 173sr2
   Full Text »    PDF »
Single-Molecule Genomic Data Delineate Patient-Specific Tumor Profiles and Cancer Stem Cell Organization.
A. Sottoriva, I. Spiteri, D. Shibata, C. Curtis, and S. Tavare (2013)
Cancer Res. 73, 41-49
   Abstract »    Full Text »    PDF »
Skin squamous cell carcinoma propagating cells increase with tumour progression and invasiveness.
G. Lapouge, B. Beck, D. Nassar, C. Dubois, S. Dekoninck, and C. Blanpain (2012)
EMBO J. 31, 4563-4575
   Abstract »    Full Text »    PDF »
Obesity, Energy Balance, and Cancer: New Opportunities for Prevention.
S. D. Hursting, J. DiGiovanni, A. J. Dannenberg, M. Azrad, D. LeRoith, W. Demark-Wahnefried, M. Kakarala, A. Brodie, and N. A. Berger (2012)
Cancer Prevention Research 5, 1260-1272
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882