Targeting neuropilin 1 as an antitumor strategy in lung cancer

Tse-Ming Hong, Yuh-Ling Chen, Yi Ying Wu, Ang Yuan, Yu Chih Chao, Yi Chuan Chung, Ming Heng Wu, Shuenn Chen Yang, Szu Hua Pan, Jin Yuan Shih, Wing Kai Chan, Pan Chyr Yang

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Experimental Design: 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.

Original languageEnglish
Pages (from-to)4759-4768
Number of pages10
JournalClinical Cancer Research
Volume13
Issue number16
DOIs
Publication statusPublished - 2007 Aug 15

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Neuropilin-1
Lung Neoplasms
Non-Small Cell Lung Carcinoma
Neoplasms
Carcinogenesis
1-Phosphatidylinositol 4-Kinase
Peptides

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Hong, Tse-Ming ; Chen, Yuh-Ling ; Wu, Yi Ying ; Yuan, Ang ; Chao, Yu Chih ; Chung, Yi Chuan ; Wu, Ming Heng ; Yang, Shuenn Chen ; Pan, Szu Hua ; Shih, Jin Yuan ; Chan, Wing Kai ; Yang, Pan Chyr. / Targeting neuropilin 1 as an antitumor strategy in lung cancer. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 16. pp. 4759-4768.
@article{00da006ef768454d8f6fca9e12d4c0d1,
title = "Targeting neuropilin 1 as an antitumor strategy in lung cancer",
abstract = "Purpose: 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. Experimental Design: 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.",
author = "Tse-Ming Hong and Yuh-Ling Chen and Wu, {Yi Ying} and Ang Yuan and Chao, {Yu Chih} and Chung, {Yi Chuan} and Wu, {Ming Heng} and Yang, {Shuenn Chen} and Pan, {Szu Hua} and Shih, {Jin Yuan} and Chan, {Wing Kai} and Yang, {Pan Chyr}",
year = "2007",
month = "8",
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language = "English",
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}

Hong, T-M, Chen, Y-L, Wu, YY, Yuan, A, Chao, YC, Chung, YC, Wu, MH, Yang, SC, Pan, SH, Shih, JY, Chan, WK & Yang, PC 2007, 'Targeting neuropilin 1 as an antitumor strategy in lung cancer', Clinical Cancer Research, vol. 13, no. 16, pp. 4759-4768. https://doi.org/10.1158/1078-0432.CCR-07-0001

Targeting neuropilin 1 as an antitumor strategy in lung cancer. / Hong, Tse-Ming; Chen, Yuh-Ling; Wu, Yi Ying; Yuan, Ang; Chao, Yu Chih; Chung, Yi Chuan; Wu, Ming Heng; Yang, Shuenn Chen; Pan, Szu Hua; Shih, Jin Yuan; Chan, Wing Kai; Yang, Pan Chyr.

In: Clinical Cancer Research, Vol. 13, No. 16, 15.08.2007, p. 4759-4768.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Targeting neuropilin 1 as an antitumor strategy in lung cancer

AU - Hong, Tse-Ming

AU - Chen, Yuh-Ling

AU - Wu, Yi Ying

AU - Yuan, Ang

AU - Chao, Yu Chih

AU - Chung, Yi Chuan

AU - Wu, Ming Heng

AU - Yang, Shuenn Chen

AU - Pan, Szu Hua

AU - Shih, Jin Yuan

AU - Chan, Wing Kai

AU - Yang, Pan Chyr

PY - 2007/8/15

Y1 - 2007/8/15

N2 - Purpose: 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. Experimental Design: 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.

AB - Purpose: 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. Experimental Design: 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.

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