Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer.
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 beta-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).


CONCLUSIONS
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.
Kaiser
Sergio
S
Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Park
Young-Kyu
YK
Franklin
Jeffrey L
JL
Halberg
Richard B
RB
Yu
Ming
M
Jessen
Walter J
WJ
Freudenberg
Johannes
J
Chen
Xiaodi
X
Haigis
Kevin
K
Jegga
Anil G
AG
Kong
Sue
S
Sakthivel
Bhuvaneswari
B
Xu
Huan
H
Reichling
Timothy
T
Azhar
Mohammad
M
Boivin
Gregory P
GP
Roberts
Reade B
RB
Bissahoyo
Anika C
AC
Gonzales
Fausto
F
Bloom
Greg C
GC
Eschrich
Steven
S
Carter
Scott L
SL
Aronow
Jeremy E
JE
Kleimeyer
John
J
Kleimeyer
Michael
M
Ramaswamy
Vivek
V
Settle
Stephen H
SH
Boone
Braden
B
Levy
Shawn
S
Graff
Jonathan M
JM
Doetschman
Thomas
T
Groden
Joanna
J
Dove
William F
WF
Threadgill
David W
DW
Yeatman
Timothy J
TJ
Coffey
Robert J
RJ
Aronow
Bruce J
BJ
D000818:Animals; D003106:Colon / Q000196:embryology*; D003110:Colonic Neoplasms / Q000235:genetics*; D004195:Disease Models, Animal; D047108:Embryonic Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
D051153:Wnt Proteins; D051176:beta Catenin