title: Targeting neuropilin 1 as an antitumor strategy in lung cancer.
abstract: OBJECTIVE
  Neuropilin 1 (NRP1) is a mediator of lung branching and angiogenesis in embryonic development and angiogenesis in cancer. The role of NRP1 in cancer progression is not fully elucidated. We investigated the role of NRP1 in cancer invasion and tumor angiogenesis, its signaling pathways, prognostic significance, and therapeutic implications.
  
  
  METHODS
  Sixty patients with non-small cell lung cancer (NSCLC) were studied. NRP1 mRNA expression was measured using real-time quantitative reverse-transcription PCR. NRP1 and cancer cell invasion, angiogenesis, and signaling pathways were studied using NRP1 stimulation by vascular endothelial growth factor 165 (VEGF(165)) and NRP1 inhibition by small interfering RNAs (siRNA), soluble NRP1 (sNRP1), and NRP1-inhibition peptides. The NRP1-inhibition peptides were identified using a phage display peptide library.
  
  
  RESULTS
  NSCLC patients with high expression of NRP1 had shorter disease-free (P = 0.0162) and overall survival (P = 0.0164; log-rank test). Multivariate analyses showed NRP1 is an independent prognostic factor in overall (HR, 2.37, 95% CI = 1.15 to 4.9, P = 0.0196) and disease-free survival [hazard ratio (HR), 2.38; 95% confidence interval (95% CI), 1.15-4.91; P = 0.0195] of NSCLC patients. Knockdown of NRP1 suppressed cancer cell migration, invasion, filopodia formation, tumorigenesis, angiogenesis, and in vivo metastasis. NRP1 signaling pathways involved VEGF receptor 2 and phosphoinositide-3-kinase (PI3K) and Akt activation. Two potent synthetic anti-NRP1 peptides, DG1 and DG2, which block NRP1 signaling pathways and suppress tumorigenesis, cancer invasion, and angiogenesis, were identified.
  
  
  CONCLUSIONS
  NRP1 is a cancer invasion and angiogenesis enhancer. NRP1 expression is an independent predictor of cancer relapse and poor survival in NSCLC patients. NRP1 plays a critical role in tumorigenesis, cancer invasion, and angiogenesis through VEGF, PI3K, and Akt pathways. NRP1 may have potential as a new therapeutic target in NSCLC.
authors: National Taiwan University Center for Genomic Medicine, College of Medicine, National Taiwan University, Tainan, Taiwan.
authors: Tse-Ming
authors: TM
authors: Hong
authors: Yuh-Ling
authors: YL
authors: Chen
authors: Yi-Ying
authors: YY
authors: Wu
authors: Ang
authors: A
authors: Yuan
authors: Yu-Chih
authors: YC
authors: Chao
authors: Yi-Chuan
authors: YC
authors: Chung
authors: Ming-Heng
authors: MH
authors: Wu
authors: Shuenn-Chen
authors: SC
authors: Yang
authors: Szu-Hua
authors: SH
authors: Pan
authors: Jin-Yuan
authors: JY
authors: Shih
authors: Wing-Kai
authors: WK
authors: Chan
authors: Pan-Chyr
authors: PC
authors: Yang
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000628:therapy; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000517:prevention & control; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D019869:Phosphatidylinositol 3-Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt