Interference With Netrin-1 and Tumor Cell Death in Non–Small Cell Lung Cancer

作者：Céline Delloye‐Bourgeois, Élisabeth Brambilla, Marie‐May Coissieux, Céline Guenebeaud, Rémy Pedeux, Virginie Firlej, Florence Cabon, Christian Brambilla, Patrick Mehlen, Agnès Bernet · 发表于：JNCI Journal of the National Cancer Institute · 年份：2009 · DOI：10.1093/jnci/djn491 · 被引用次数：139 · 研究领域：Axon Guidance and Neuronal Signaling、Hedgehog Signaling Pathway Studies、Angiogenesis and VEGF in Cancer

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 xe...