Artikel
A Gene Expression Signature for Chemoradiosensitivity of Colorectal Cancer Cells
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Autoren
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Melanie Spitzner
- University Medical Center Göttingen, Department for General and Visceral Surgery, Göttingen
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Georg Emons
- University Medical Center Göttingen, Department for General and Visceral Surgery, Göttingen
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Frank Kramer
- University Medical Center Göttingen, Department for Medical Statistics, Göttingen
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Jochen Gaedcke
- University Medical Center Göttingen, Department for General and Visceral Surgery, Göttingen
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Margret Rave-Fränk
- University Medical Center Göttingen, Department for Radiotherapy and Radio-oncology, Göttingen
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Heinz Becker
- University Medical Center Göttingen, Department for General and Visceral Surgery, Göttingen
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Tim Beißbarth
- University Medical Center Göttingen, Department for Medical Statistics, Göttingen
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B. Michael Ghadimi
- University Medical Center Göttingen, Department for General and Visceral Surgery, Göttingen
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Thomas Ried
- National Cancer Institute, National Institutes of Health, Genetics Branch, Bethesda, MD
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Marian Grade
- University Medical Center Göttingen, Department for General and Visceral Surgery, Göttingen
| Veröffentlicht: | 20. Mai 2011 |
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Gliederung
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Introduction: The standard treatment of patients with locally advanced rectal cancers comprises preoperative 5-fluorouracil–based chemoradiotherapy followed by standardized surgery. However, the 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.
Materials and 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 < 0.05), 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 the 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.
Conclusion: 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.
