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.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Originally published in Science Express on 24 February 2005
Science 25 March 2005:
Vol. 307. no. 5717, pp. 1976 - 1978
DOI: 10.1126/science.1108080
Prev | Table of Contents | Next

Reports

Loss of Imprinting of Igf2 Alters Intestinal Maturation and Tumorigenesis in Mice

Takashi Sakatani,1* Atsushi Kaneda,1* Christine A. Iacobuzio-Donahue,2,3* Mark G. Carter,5 Sten de Boom Witzel,2 Hideyuki Okano,6 Minoru S. H. Ko,5 Rolf Ohlsson,7 Dan L. Longo,5 Andrew P. Feinberg1,3,4{dagger}

Loss of imprinting (LOI) of the insulin-like growth factor II gene (IGF2) is an epigenetic alteration that results in a modest increase in IGF2 expression, and it is present in the normal colonic mucosa of about 30% of patients with colorectal cancer. To investigate its role in intestinal tumorigenesis, we created a mouse model of Igf2 LOI by crossing female H19+/– mice with male Apc+/Min mice. Mice with LOI developed twice as many intestinal tumors as did control littermates. Notably, these mice also showed a shift toward a less differentiated normal intestinal epithelium, reflected by an increase in crypt length and increased staining with progenitor cell markers. A similar shift in differentiation was seen in the normal colonic mucosa of humans with LOI. Thus, altered maturation of nonneoplastic tissue may be one mechanism by which epigenetic changes affect cancer risk.

1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3 Oncology Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4 Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5 Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
6 Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
7 Department of Development and Genetics, Uppsala University, S-752 36 Uppsala, Sweden.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: afeinberg{at}jhu.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Toward a genetics of cancer resistance.
G. Klein (2009)
PNAS 106, 859-863
   Abstract »    Full Text »    PDF »
Effect of Insulin-Like Growth Factor Gene Polymorphisms Alone or In Interaction with Diabetes on the Risk of Pancreatic Cancer.
H. Suzuki, Y. Li, X. Dong, M. M. Hassan, J. L. Abbruzzese, and D. Li (2008)
Cancer Epidemiol. Biomarkers Prev. 17, 3467-3473
   Abstract »    Full Text »    PDF »
Recurrence of Urothelial Carcinoma of the Bladder: A Role for Insulin-Like Growth Factor-II Loss of Imprinting and Cytoplasmic E-Cadherin Immunolocalization.
E. M. Gallagher, D. M. O'Shea, P. Fitzpatrick, M. Harrison, B. Gilmartin, J. A. Watson, T. Clarke, M. O. Leonard, A. McGoldrick, M. Meehan, et al. (2008)
Clin. Cancer Res. 14, 6829-6838
   Abstract »    Full Text »    PDF »
Cancer Prevention: Epigenetics Steps Up to the Plate.
J.-P. Issa (2008)
Cancer Prevention Research 1, 219-222
   Full Text »    PDF »
The H19 locus acts in vivo as a tumor suppressor.
T. Yoshimizu, A. Miroglio, M.-A. Ripoche, A. Gabory, M. Vernucci, A. Riccio, S. Colnot, C. Godard, B. Terris, H. Jammes, et al. (2008)
PNAS 105, 12417-12422
   Abstract »    Full Text »    PDF »
Aging and Cancer-Related Loss of Insulin-like Growth Factor 2 Imprinting in the Mouse and Human Prostate.
V. X. Fu, J. R. Dobosy, J. A. Desotelle, N. Almassi, J. A. Ewald, R. Srinivasan, M. Berres, J. Svaren, R. Weindruch, and D. F. Jarrard (2008)
Cancer Res. 68, 6797-6802
   Abstract »    Full Text »    PDF »
Differentiation of a murine intestinal epithelial cell line (MIE) toward the M cell lineage.
T. Kanaya, K. Miyazawa, I. Takakura, W. Itani, K. Watanabe, S. Ohwada, H. Kitazawa, M. T. Rose, H. R. McConochie, H. Okano, et al. (2008)
Am J Physiol Gastrointest Liver Physiol 295, G273-G284
   Abstract »    Full Text »    PDF »
Musashi1 Modulates Mammary Progenitor Cell Expansion through Proliferin-Mediated Activation of the Wnt and Notch Pathways.
X.-Y. Wang, Y. Yin, H. Yuan, T. Sakamaki, H. Okano, and R. I. Glazer (2008)
Mol. Cell. Biol. 28, 3589-3599
   Abstract »    Full Text »    PDF »
Transgenerational epigenetic effects of the endocrine disruptor vinclozolin on pregnancies and female adult onset disease.
E. E Nilsson, M. D Anway, J. Stanfield, and M. K Skinner (2008)
Reproduction 135, 713-721
   Abstract »    Full Text »    PDF »
Epigenetics in Cancer.
M. Esteller (2008)
N. Engl. J. Med. 358, 1148-1159
   Full Text »    PDF »
Insulin Receptor Substrate-1 Deficiency Promotes Apoptosis in the Putative Intestinal Crypt Stem Cell Region, Limits Apcmin/+ Tumors, and Regulates Sox9.
N. M. Ramocki, H. R. Wilkins, S. T. Magness, J. G. Simmons, B. P. Scull, G. H. Lee, K. K. McNaughton, and P. K. Lund (2008)
Endocrinology 149, 261-267
   Abstract »    Full Text »    PDF »
Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk.
A. Kaneda, C. J. Wang, R. Cheong, W. Timp, P. Onyango, B. Wen, C. A. Iacobuzio-Donahue, R. Ohlsson, R. Andraos, M. A. Pearson, et al. (2007)
PNAS 104, 20926-20931
   Abstract »    Full Text »    PDF »
Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing.
H. G. Linhart, H. Lin, Y. Yamada, E. Moran, E. J. Steine, S. Gokhale, G. Lo, E. Cantu, M. Ehrich, T. He, et al. (2007)
Genes & Dev. 21, 3110-3122
   Abstract »    Full Text »    PDF »
Homeostatic Control of the Crypt-Villus Axis by the Bacterial Enterotoxin Receptor Guanylyl Cyclase C Restricts the Proliferating Compartment in Intestine.
P. Li, J. E. Lin, I. Chervoneva, S. Schulz, S. A. Waldman, and G. M. Pitari (2007)
Am. J. Pathol. 171, 1847-1858
   Abstract »    Full Text »    PDF »
Biological Functions of DNA Methyltransferase 1 Require Its Methyltransferase Activity.
M. Damelin and T. H. Bestor (2007)
Mol. Cell. Biol. 27, 3891-3899
   Abstract »    Full Text »    PDF »
Up-regulation of DLK1 as an imprinted gene could contribute to human hepatocellular carcinoma.
J. Huang, X. Zhang, M. Zhang, J.-D. Zhu, Y.-L. Zhang, Y. Lin, K.-S. Wang, X.-F. Qi, Q. Zhang, G.-Z. Liu, et al. (2007)
Carcinogenesis 28, 1094-1103
   Abstract »    Full Text »    PDF »
Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors.
Z. Herceg (2007)
Mutagenesis 22, 91-103
   Abstract »    Full Text »    PDF »
Identification of IGF2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma.
L. Soroceanu, S. Kharbanda, R. Chen, R. H. Soriano, K. Aldape, A. Misra, J. Zha, W. F. Forrest, J. M. Nigro, Z. Modrusan, et al. (2007)
PNAS 104, 3466-3471
   Abstract »    Full Text »    PDF »
The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights.
A. A. Samani, S. Yakar, D. LeRoith, and P. Brodt (2007)
Endocr. Rev. 28, 20-47
   Abstract »    Full Text »    PDF »
Functional evaluation of novel soluble insulin-like growth factor (IGF)-II-specific ligand traps based on modified domain 11 of the human IGF2 receptor.
S. N. Prince, E. J. Foulstone, O. J. Zaccheo, C. Williams, and A. B. Hassan (2007)
Mol. Cancer Ther. 6, 607-617
   Abstract »    Full Text »    PDF »
The cancer epigenome--components and functional correlates.
A. H. Ting, K. M. McGarvey, and S. B. Baylin (2006)
Genes & Dev. 20, 3215-3231
   Abstract »    Full Text »    PDF »
Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease.
M. D. Anway, C. Leathers, and M. K. Skinner (2006)
Endocrinology 147, 5515-5523
   Abstract »    Full Text »    PDF »
Neurocytoma Is a Tumor of Adult Neuronal Progenitor Cells.
F. J. Sim, H. M. Keyoung, J. E. Goldman, D. K. Kim, H.-W. Jung, N. S. Roy, and S. A. Goldman (2006)
J. Neurosci. 26, 12544-12555
   Abstract »    Full Text »    PDF »
Suppression of Intestinal Neoplasia by Deletion of Dnmt3b.
H. Lin, Y. Yamada, S. Nguyen, H. Linhart, L. Jackson-Grusby, A. Meissner, K. Meletis, G. Lo, and R. Jaenisch (2006)
Mol. Cell. Biol. 26, 2976-2983
   Abstract »    Full Text »    PDF »
The emerging science of epigenomics..
P. A. Callinan and A. P. Feinberg (2006)
Hum. Mol. Genet. 15, R95-R101
   Abstract »    Full Text »    PDF »
Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus.
R. A. Waterland, J.-R. Lin, C. A. Smith, and R. L. Jirtle (2006)
Hum. Mol. Genet. 15, 705-716
   Abstract »    Full Text »    PDF »
High-throughput DNA methylation profiling using universal bead arrays.
M. Bibikova, Z. Lin, L. Zhou, E. Chudin, E. W. Garcia, B. Wu, D. Doucet, N. J. Thomas, Y. Wang, E. Vollmer, et al. (2006)
Genome Res. 16, 383-393
   Abstract »    Full Text »    PDF »
Decreased Mitochondrial DNA Content in Posttreatment Salivary Rinses from Head and Neck Cancer Patients.
W.-W. Jiang, E. Rosenbaum, E. Mambo, M. Zahurak, B. Masayesva, A. L. Carvalho, S. Zhou, W. H. Westra, A. J. Alberg, D. Sidransky, et al. (2006)
Clin. Cancer Res. 12, 1564-1569
   Abstract »    Full Text »    PDF »
Soluble IGF2 Receptor Rescues ApcMin/+ Intestinal Adenoma Progression Induced by Igf2 Loss of Imprinting.
J. Harper, J. L. Burns, E. J. Foulstone, M. Pignatelli, S. Zaina, and A. B. Hassan (2006)
Cancer Res. 66, 1940-1948
   Abstract »    Full Text »    PDF »
The Relationship of Insulin-Like Growth Factor-II, Insulin-Like Growth Factor Binding Protein-3, and Estrogen Receptor-{alpha} Expression to Disease Progression in Epithelial Ovarian Cancer.
L. Lu, D. Katsaros, A. Wiley, I. A. Rigault de la Longrais, H. A. Risch, M. Puopolo, and H. Yu (2006)
Clin. Cancer Res. 12, 1208-1214
   Abstract »    Full Text »    PDF »
Delayed Onset of Igf2-Induced Mammary Tumors in Igf2r Transgenic Mice.
T. L. Wise and D. D. Pravtcheva (2006)
Cancer Res. 66, 1327-1336
   Abstract »    Full Text »    PDF »
Expression of RNA-Binding Protein Musashi in Hair Follicle Development and Hair Cycle Progression.
Y. Sugiyama-Nakagiri, M. Akiyama, S. Shibata, H. Okano, and H. Shimizu (2006)
Am. J. Pathol. 168, 80-92
   Abstract »    Full Text »    PDF »
Loss of Imprinting of IGF2: A Common Epigenetic Modifier of Intestinal Tumor Risk.
A. Kaneda and A. P. Feinberg (2005)
Cancer Res. 65, 11236-11240
   Abstract »    Full Text »    PDF »
Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis.
Y. Yamada, L. Jackson-Grusby, H. Linhart, A. Meissner, A. Eden, H. Lin, and R. Jaenisch (2005)
PNAS 102, 13580-13585
   Abstract »    Full Text »    PDF »
Diagnostic and Therapeutic Applications of Epigenetics.
K. Miyamoto and T. Ushijima (2005)
Jpn. J. Clin. Oncol. 35, 293-301
   Abstract »    Full Text »    PDF »
How an imprint can lead to cancer.
D. Secko (2005)
Can. Med. Assoc. J. 172, 1286
   Full Text »    PDF »
A Genetic Approach to Cancer Epigenetics.
A.P. FEINBERG (2005)
Cold Spring Harb Symp Quant Biol 70, 335-341
   Abstract »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)