This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nambiar, P. R. Articles by Rosenberg, D. W. Search for Related Content PubMed PubMed Citation Articles by Nambiar, P. R. Articles by Rosenberg, D. W.

Genetic signatures of High- and Low-Risk Aberrant Crypt Foci in a Mouse Model of Sporadic Colon Cancer

¹ Center for Molecular Medicine and Program in Colorectal Cancer, University of Connecticut Health Center, Farmington, Connecticut; Departments of ² Pathobiology and Veterinary Sciences and ³ Chemical Engineering, University of Connecticut, Storrs, Connecticut; ⁴ Arcturus Bioscience, Inc., Mountain View, California; and ⁵ Department of Medicine and Program in Colorectal Cancer, University of Connecticut Health Center, Farmington, Connecticut

To determine whether cancer risk is related to histopathological features of preneoplastic aberrant crypt foci (ACF), gene expression analysis was performed on ACF from two mouse strains with differing tumor sensitivity to the colonotropic carcinogen, azoxymethane. ACF from sensitive A/J mice were considered at high risk, whereas ACF from resistant AKR/J mice were considered at low risk for tumorigenesis. A/J and AKR/J mice received weekly injections of azoxymethane (10 mg/kg body weight), and frozen colon sections were prepared 6 weeks later. Immunohistochemistry was performed using biomarkers associated with colon cancer, including adenomatous polyposis coli, ß-catenin, p53, c-myc, cyclin D1, and proliferating cell nuclear antigen. Hyperplastic ACF, dysplastic ACF, microadenomas, adjacent normal-appearing epithelium, and vehicle-treated colons were laser captured, and RNA was linearly amplified (LCM-LA) and subjected to cDNA microarray-based expression analysis. Patterns of gene expression were identified using adaptive centroid algorithm. ACF from low- and high-risk colons were not discriminated by immunohistochemistry, with the exception of membrane staining of ß-catenin. To develop genetic signatures that predict cancer risk, LCM-LA RNA from ACF was hybridized to cDNA arrays. Of 4896 interrogated genes, 220 clustered into six broad clusters. A total of 226 and 202 genes was consistently altered in lesions from A/J and AKR/J mice, respectively. Although many alterations were common to both strains, expression profiles stratified high- and low- risk lesions. These data demonstrate that ACF with distinct tumorigenic potential have distinguishing molecular features. In addition to providing insight into colon cancer promotion, our data identify potential biomarkers for determining colon cancer risk in humans.

This article has been cited by other articles:

				M. Nakanishi, D. C. Montrose, P. Clark, P. R. Nambiar, G. S. Belinsky, K. P. Claffey, D. Xu, and D. W. Rosenberg Genetic Deletion of mPGES-1 Suppresses Intestinal Tumorigenesis Cancer Res., May 1, 2008; 68(9): 3251 - 3259. [Abstract] [Full Text] [PDF]

				A. B Glick The High Risk Premalignant Lesion: Experimental Evidence and Clinical Implications Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 513 - 516. [Abstract] [Full Text] [PDF]

				T. Sasada, K. Azuma, T. Hirai, H. Hashida, M. Kanai, T. Yanagawa, and A. Takabayashi Prognostic Significance of the Immediate Early Response Gene X-1 (IEX-1) Expression in Pancreatic Cancer Ann. Surg. Oncol., February 1, 2008; 15(2): 609 - 617. [Abstract] [Full Text] [PDF]

				A. B. Rogers, E. J. Theve, Y. Feng, R. C. Fry, K. Taghizadeh, K. M. Clapp, C. Boussahmain, K. S. Cormier, and J. G. Fox Hepatocellular Carcinoma Associated with Liver-Gender Disruption in Male Mice Cancer Res., December 15, 2007; 67(24): 11536 - 11546. [Abstract] [Full Text] [PDF]

				E. J. Greenspan, J. L. Cyr, D. C. Pleau, J. Levine, T. V. Rajan, D. W. Rosenberg, and C. D. Heinen Microsatellite instability in aberrant crypt foci from patients without concurrent colon cancer Carcinogenesis, April 1, 2007; 28(4): 769 - 776. [Abstract] [Full Text] [PDF]

				O. K. Glebov, L. M. Rodriguez, P. Soballe, J. DeNobile, J. Cliatt, K. Nakahara, and I. R. Kirsch Gene Expression Patterns Distinguish Colonoscopically Isolated Human Aberrant Crypt Foci from Normal Colonic Mucosa. Cancer Epidemiol. Biomarkers Prev., November 1, 2006; 15(11): 2253 - 2262. [Abstract] [Full Text] [PDF]

				E. J. Greenspan, M. A. Jablonski, T. V. Rajan, J. Levine, G. S. Belinsky, and D. W. Rosenberg Epigenetic alterations in RASSF1A in human aberrant crypt foci Carcinogenesis, July 1, 2006; 27(7): 1316 - 1322. [Abstract] [Full Text] [PDF]

				P. R. Nambiar, S. M. Kirchain, K. Courmier, S. Xu, N. S. Taylor, E. J. Theve, M. M. Patterson, and J. G. Fox Progressive Proliferative and Dysplastic Typhlocolitis in Aging Syrian Hamsters Naturally Infected with Helicobacter spp.: A Spontaneous Model of Inflammatory Bowel Disease Vet. Pathol., January 1, 2006; 43(1): 2 - 14. [Abstract] [Full Text] [PDF]

				P. R. Nambiar, S. R. Boutin, R. Raja, and D. W. Rosenberg Global Gene Expression Profiling: A Complement to Conventional Histopathologic Analysis of Neoplasia Vet. Pathol., November 1, 2005; 42(6): 735 - 752. [Abstract] [Full Text] [PDF]

				S.W. Barth, C. Fahndrich, A. Bub, H. Dietrich, B. Watzl, F. Will, K. Briviba, and G. Rechkemmer Cloudy apple juice decreases DNA damage, hyperproliferation and aberrant crypt foci development in the distal colon of DMH-initiated rats Carcinogenesis, August 1, 2005; 26(8): 1414 - 1421. [Abstract] [Full Text] [PDF]

				M. Krajewska, H. Kim, C. Kim, H. Kang, K. Welsh, S.-i. Matsuzawa, M. Tsukamoto, R. G. Thomas, N. Assa-Munt, Z. Piao, et al. Analysis of Apoptosis Protein Expression in Early-Stage Colorectal Cancer Suggests Opportunities for New Prognostic Biomarkers Clin. Cancer Res., August 1, 2005; 11(15): 5451 - 5461. [Abstract] [Full Text] [PDF]

				M.-L. Kruse, A. Arlt, A. Sieke, F. Grohmann, M. Grossmann, J. Minkenberg, U. R. Folsch, and H. Schafer Immediate Early Gene X1 (IEX-1) Is Organized in Subnuclear Structures and Partially Co-localizes with Promyelocytic Leukemia Protein in HeLa Cells J. Biol. Chem., July 1, 2005; 280(26): 24849 - 24856. [Abstract] [Full Text] [PDF]