Targeting neuropilin 1 as an antitumor strategy in lung cancer.
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.
Hong
Tse-Ming
TM
National Taiwan University Center for Genomic Medicine, College of Medicine, National Taiwan University, Tainan, Taiwan.
Chen
Yuh-Ling
YL
Wu
Yi-Ying
YY
Yuan
Ang
A
Chao
Yu-Chih
YC
Chung
Yi-Chuan
YC
Wu
Ming-Heng
MH
Yang
Shuenn-Chen
SC
Pan
Szu-Hua
SH
Shih
Jin-Yuan
JY
Chan
Wing-Kai
WK
Yang
Pan-Chyr
PC
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
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