Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer
| Autor: | Mohammad Azhar, Johannes M. Freudenberg, Braden Boone, Jeremy Aronow, Richard B. Halberg, Timothy J. Yeatman, Greg Bloom, Scott L. Carter, Steven A. Eschrich, Thomas Doetschman, Sue Kong, Young-Kyu Park, Joanna Groden, Huan Xu, Stephen H. Settle, Sergio Kaiser, Jeffrey L. Franklin, Robert J. Coffey, Anika C. Bissahoyo, Reade B. Roberts, Gregory P. Boivin, Anil G. Jegga, Bruce J. Aronow, Jonathan M. Graff, Shawn Levy, Bhuvaneswari Sakthivel, Walter J. Jessen, Fausto Gonzales, William F. Dove, Xiaodi Chen, Vivek Ramaswamy, Timothy Reichling, David W. Threadgill, Ming Yu, John Kleimeyer, Michael Kleimeyer, Kevin M. Haigis |
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| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Transcription
Genetic Colorectal cancer Colon Embryonic Development AKT2 PDGFRA Biology medicine.disease_cause PLK1 03 medical and health sciences Mice 0302 clinical medicine Gene expression WNT4 medicine Animals Humans beta Catenin 030304 developmental biology Oligonucleotide Array Sequence Analysis Regulation of gene expression 0303 health sciences Research Gene Expression Regulation Developmental medicine.disease Molecular biology digestive system diseases Gene Expression Regulation Neoplastic Wnt Proteins Disease Models Animal 030220 oncology & carcinogenesis Colonic Neoplasms Cancer research Carcinogenesis |
| Zdroj: | Genome Biology |
| ISSN: | 1465-6914 1465-6906 |
| Popis: | Colon tumors from four independent mouse models and 100 human colorectal cancers all exhibited striking recapitulation of embryonic colon gene expression from embryonic days 13.5-18.5. 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. |
| Databáze: | OpenAIRE |
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