Journal of the National Cancer Institute Advance Access originally published online on February 10, 2009
JNCI Journal of the National Cancer Institute 2009 101(4):237-247; doi:10.1093/jnci/djn491
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© The Author 2009. Published by Oxford University Press.
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Interference With Netrin-1 and Tumor Cell Death in Non–Small Cell Lung Cancer
Affiliations of authors: Apoptosis, Cancer and Development Laboratory—Equipe labellisée ‘La Ligue’, CNRS UMR5238, Université de Lyon, Centre Léon Bérard, Lyon, France (CD-B, M-MC, CG, PM, AB); Lung Cancer Team, Institut Albert Bonniot, Inserm U823, Université Joseph Fourier, Pathology Department, Centre Hospitalier Universitaire, Grenoble, France (EB, RP, CB); CNRS FRE2944 Epigénétique et cancer, Institut André Lwoff, Villejuif, France (VF, FC)
Correspondence to: Patrick Mehlen, PhD, Apoptosis, Cancer and Development Laboratory—Equipe labellisée ‘La Ligue’, CNRS UMR5238, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France (e-mail: mehlen{at}lyon.fnclcc.fr).
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 mm3, respectively (difference = 404 mm3, 95% CI = 145 to 664 mm3; 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.
| CONTEXT AND CAVEATS Prior knowledge The availability of netrin-1, a ligand for proapoptotic dependence receptors, had been demonstrated to play a role in tumor survival in some cancers. Study design The expression of netrin-1 was measured in non–small cell lung cancers (NSCLC). The activity of netrin-1 and that of individual dependence receptors in cancer cells derived from NSCLCs was modulated using small interfering RNAs and other methods, and the effects of these modifications on apoptosis in vitro, and the growth in mice of tumors derived from these cells, were measured. Contribution This work demonstrated the presence of substantial levels of netrin-1 in a large fraction of human NSCLC tumor samples and suggested that the growth of some NSCLCs may depend on the interaction of netrin-1 and its dependence receptor(s). Implications Targeting netrin-1 or its dependence receptor(s) might represent a potential approach for treating NSCLC. Limitations These studies were confined to cell lines and animal models that may not be adequate models for NSCLC in humans. From the Editors
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Manuscript received May 5, 2008; revised November 17, 2008; accepted December 8, 2008.
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