Journal
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
Volume 101, Issue 4, Pages 237-247Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djn491
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Funding
- Centre Nationale de la Recherche Scientifique
- Institut National de la Sante et de la Recherche Medicale
- Centre Leon Berard
- Universite de Lyon
- Ligue Contre le Cancer
- INCa
- Canceropole CLARA POC
- EC
- PNESINCa
- PHRC Biomarkscan and Micromethods in pathology
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Background Netrin-1 may promote colorectal and breast tumorigenesis, by inhibiting apoptosis induced by its dependence receptors, deleted in colorectal cancer (DCC) and uncoordinated-5-homolog (UNC5H). The status of netrin-1 and its receptors in non-small cell lung cancer (NSCLC) was unknown. Methods The levels of netrin-1 and its receptors were analyzed in a panel of 92 NSCLC and 25 human lung cancer cell lines by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. In lung cancer cell lines that express netrin-1, the expression of netrin-1 was inhibited by using small interfering RNA (siRNA), or interference with netrin-1 was performed by treatment with a decoy recombinant DCC ectodomain protein (DCC-5Fbn). Cell death was monitored with a trypan blue exclusion assay or by measuring caspase-3 activity. The effect of netrin-1 interference on tumor growth was analyzed by DCC-5Fbn intratumoral or netrin-1 siRNA intraperitoneal injection in mice engrafted with lung cancer cell lines. All statistical tests were two-sided. Results High levels of netrin-1 were found in 43 of the 92 NSCLC tumor samples (47%). Interference with netrin-1 in human lung cancer cell lines was associated with UNC5H-mediated cell death in vitro (percentage of cell death in untreated and in DCC-5Fbn-treated cells = 8% and 26%, respectively, difference = 18%, 95% confidence interval [CI] = 10% to 26%; P =.049) and with lung tumor growth inhibition and/or regression in xenografted nude mice (12 mice in DCC-5Fbn-treated group and 13 mice in control group). Mean volume of control and DCC-5Fbn-treated tumors on day 46 was 489 and 84 mm 3, respectively (difference = 404 mm 3, 95% CI = 145 to 664 mm 3; P<.001). Conclusions Almost half of the NSCLC tissue samples examined expressed high levels of netrin-1. Extracellular targeting of the interaction between netrin-1 and UNC5H may be a promising therapeutic approach for NSCLCs that express netrin-1. J Natl Cancer Inst 2009; 101: 237-247
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