Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer

Sergio Kaiser^*¹ , Young-Kyu Park^*² , Jeffrey L Franklin² , Richard B Halberg³ , Ming Yu⁴ , Walter J Jessen¹ , Johannes Freudenberg¹ , Xiaodi Chen³ , Kevin Haigis⁵ , Anil G Jegga¹ , Sue Kong¹ , Bhuvaneswari Sakthivel¹ , Huan Xu¹ , Timothy Reichling⁶ , Mohammad Azhar⁷ , Gregory P Boivin⁸ , Reade B Roberts⁴ , Anika C Bissahoyo⁴ , Fausto Gonzales⁹ , Greg C Bloom⁹ , Steven Eschrich⁹ , Scott L Carter¹⁰ , Jeremy E Aronow¹ , John Kleimeyer¹ , Michael Kleimeyer¹ , Vivek Ramaswamy¹ , Stephen H Settle² , Braden Boone² , Shawn Levy² , Jonathan M Graff¹¹ , Thomas Doetschman⁷ , Joanna Groden⁶ , William F Dove³ , David W Threadgill⁴ , Timothy J Yeatman⁹ , Robert J Coffey Jr² and Bruce J Aronow¹

¹Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA

²Departments of Medicine, and Cell and Developmental Biology, Vanderbilt University and Department of Veterans Affairs Medical Center, Nashville, TN 37232, USA

³McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706, USA

⁴Department of Genetics and Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA

⁵Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA

⁶Division of Human Cancer Genetics, The Ohio State University College of Medicine, Columbus, Ohio 43210-2207, USA

⁷Institute for Collaborative BioResearch, University of Arizona, Tucson, AZ 85721-0036, USA

⁸University of Cincinnati, Department of Pathology and Laboratory Medicine, Cincinnati, OH 45267, USA

⁹H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA

¹⁰Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology (CHIP@HST), Harvard Medical School, Boston, Massachusetts 02115, USA

¹¹University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA

author email corresponding author email* Contributed equally

Genome Biology 2007, 8:R131doi:10.1186/gb-2007-8-7-r131


Published:	5 July 2007

Subject areas: Cancer, Development, Genome studies

Abstract

Background

The expression of carcino-embryonic antigen by colorectal cancer is an example of oncogenic activation of embryonic gene expression. Hypothesizing that oncogenesis-recapitulating-ontogenesis may represent a broad programmatic commitment, we compared gene expression patterns of human colorectal cancers (CRCs) and mouse colon tumor models to those of mouse colon development embryonic days 13.5-18.5.

Results

We report here that 39 colon tumors from four independent mouse models and 100 human CRCs encompassing all clinical stages shared a striking recapitulation of embryonic colon gene expression. Compared to normal adult colon, all mouse and human tumors over-expressed a large cluster of genes highly enriched for functional association to the control of cell cycle progression, proliferation, and migration, including those encoding MYC, AKT2, PLK1 and SPARC. Mouse tumors positive for nuclear β-catenin shifted the shared embryonic pattern to that of early development. Human and mouse tumors differed from normal embryonic colon by their loss of expression modules enriched for tumor suppressors (EDNRB, HSPE, KIT and LSP1). Human CRC adenocarcinomas lost an additional suppressor module (IGFBP4, MAP4K1, PDGFRA, STAB1 and WNT4). Many human tumor samples also gained expression of a coordinately regulated module associated with advanced malignancy (ABCC1, FOXO3A, LIF, PIK3R1, PRNP, TNC, TIMP3 and VEGF).

Conclusion

Cross-species, developmental, and multi-model gene expression patterning comparisons provide an integrated and versatile framework for definition of transcriptional programs associated with oncogenesis. This approach also provides a general method for identifying pattern-specific biomarkers and therapeutic targets. This delineation and categorization of developmental and non-developmental activator and suppressor gene modules can thus facilitate the formulation of sophisticated hypotheses to evaluate potential synergistic effects of targeting within- and between-modules for next-generation combinatorial therapeutics and improved mouse models.