TY - JOUR
T1 - Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer
AU - Kaiser, Sergio
AU - Park, Young Kyu
AU - Franklin, Jeffrey L.
AU - Halberg, Richard B.
AU - Yu, Ming
AU - Jessen, Walter J.
AU - Freudenberg, Johannes
AU - Chen, Xiaodi
AU - Haigis, Kevin
AU - Jegga, Anil G.
AU - Kong, Sue
AU - Sakthivel, Bhuvaneswari
AU - Xu, Huan
AU - Reichling, Timothy
AU - Azhar, Mohammad
AU - Boivin, Gregory P.
AU - Roberts, Reade B.
AU - Bissahoyo, Anika C.
AU - Gonzales, Fausto
AU - Bloom, Greg C.
AU - Eschrich, Steven
AU - Carter, Scott L.
AU - Aronow, Jeremy E.
AU - Kleimeyer, John
AU - Kleimeyer, Michael
AU - Ramaswamy, Vivek
AU - Settle, Stephen H.
AU - Boone, Braden
AU - Levy, Shawn
AU - Graff, Jonathan M.
AU - Doetschman, Thomas
AU - Groden, Joanna
AU - Dove, William F.
AU - Threadgill, David W.
AU - Yeatman, Timothy J.
AU - Coffey, Robert J.
AU - Aronow, Bruce J.
PY - 2007/7/5
Y1 - 2007/7/5
N2 - 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.
AB - 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.
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U2 - 10.1186/gb-2007-8-7-r131
DO - 10.1186/gb-2007-8-7-r131
M3 - Article
C2 - 17615082
AN - SCOPUS:39749137048
SN - 1474-7596
VL - 8
JO - Genome biology
JF - Genome biology
IS - 7
M1 - R131
ER -