A gene expression signature for chemoradiosensitivity of colorectal cancer cells.
OBJECTIVE
The standard treatment of patients with locally advanced rectal cancers comprises preoperative 5-fluorouracil-based chemoradiotherapy followed by standardized surgery. However, tumor response to multimodal treatment has varied greatly, ranging from complete resistance to complete pathologic regression. The prediction of the response is, therefore, an important clinical need.


METHODS
To establish in vitro models for studying the molecular basis of this heterogeneous tumor response, we exposed 12 colorectal cancer cell lines to 3 μM of 5-fluorouracil and 2 Gy of radiation. The differences in treatment sensitivity were then correlated with the pretherapeutic gene expression profiles of these cell lines.


RESULTS
We observed a heterogeneous response, with surviving fractions ranging from 0.28 to 0.81, closely recapitulating clinical reality. Using a linear model analysis, we identified 4,796 features whose expression levels correlated significantly with the sensitivity to chemoradiotherapy (Q <.05), including many genes involved in the mitogen-activated protein kinase signaling pathway or cell cycle genes. These data have suggested a potential relevance of the insulin and Wnt signaling pathways for treatment response, and we identified STAT3, RASSF1, DOK3, and ERBB2 as potential therapeutic targets. The microarray measurements were independently validated for a subset of these genes using real-time polymerase chain reactions.


CONCLUSIONS
We are the first to report a gene expression signature for the in vitro chemoradiosensitivity of colorectal cancer cells. We anticipate that this analysis will unveil molecular biomarkers predictive of the response of rectal cancers to chemoradiotherapy and enable the identification of genes that could serve as targets to sensitize a priori resistant primary tumors.
Spitzner
Melanie
M
Department of General and Visceral Surgery, Georg-August-University, Göttingen, Germany.
Emons
Georg
G
Kramer
Frank
F
Gaedcke
Jochen
J
Rave-Fränk
Margret
M
Scharf
Jens-Gerd
JG
Burfeind
Peter
P
Becker
Heinz
H
Beissbarth
Tim
T
Ghadimi
B Michael
BM
Ried
Thomas
T
Grade
Marian
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D003131:Combined Modality Therapy / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D005472:Fluorouracil / Q000627:therapeutic use; D020869:Gene Expression Profiling; D018816:Genes, cdc; D018734:Genes, erbB-2; D006801:Humans; D016014:Linear Models; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D050796:STAT3 Transcription Factor / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; C518789:DOK3 protein, human; C411762:RASSF1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D025521:Tumor Suppressor Proteins; D020928:Mitogen-Activated Protein Kinases; D005472:Fluorouracil