Neuropilin-1 is upregulated in hepatocellular carcinoma and contributes to tumour growth and vascular remodelling

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• 作者：Mathieu Bergé ; ¹ ; ² ; David Allanic¹ ; ² ; Philippe Bonnin² ; ³ ; Catherine de Montrion⁵ ; Johann Richard⁵ ; Michel Suc⁵ ; Jean-Franç ; ois Boivin⁵ ; Jean-Olivier Contrer&egrave ; s¹ ; ² ; Brian P. Lockhart⁵ ; Marc Pocard² ; ³ ; Bernard I. Lé ; vy¹ ; ² ; ³ ; ⁴ ; Gordon C. Tucker⁶ ; Gé ; rard Tobelem¹ ; ² ; ³ ; Tatyana Merkulova-Rainon¹ ; ² ; ^{tatiana.merkoulova@inserm.fr}
• 关键词：HCC ; hepatocellular carcinoma ; VEGF ; vascular endothelial growth factor ; VEGFR ; vascular endothelial growth factor receptor ; NRP1 ; neuropilin-1 ; HGF ; hepatocyte growth factor ; PDGF-B ; platelet-derived growth factor-B ; LSEC ; liver sinusoidal endothelial ce
• 刊名：Journal of Hepatology
• 出版年：2011
• 出版时间：October, 2011
• 年：2011
• 卷：55
• 期：4
• 页码：866-875
• 全文大小：1K

文摘

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Background & Aims

Neuropilin-1 (NRP1) is a transmembrane co-receptor for semaphorins and heparin-binding pro-angiogenic cytokines, principally members of the vascular endothelial growth factor family. Recent studies revealed an important role of NRP1 in angiogenesis and malignant progression of many cancers. The role of NRP1 in the development of hepatocellular carcinoma (HCC) is not completely understood.

Methods

We used human tissue microarrays and a mouse transgenic model of HCC to establish the spatio-temporal patterns of NRP1 expression in HCC. To evaluate the therapeutic potential of targeting NRP1 in HCC, we treated HCC mice with peptide N, an NRP1 binding recombinant protein and competitive inhibitor of the VEGF-A₁₆₅/NRP1 interaction.

Results

We demonstrate that NRP1 is expressed in hepatic endothelial cells of both human healthy biopsies and in HCC samples, but not in normal hepatocytes. We found that increased NRP1 expression in human tumour hepatocytes is significantly associated with primary HCC. Using RT-PCR, Western blot and immunofluorescence analysis we show that NRP1 expression in the liver of transgenic HCC mice is increased with disease progression, in both vascular and tumour compartments. Blocking NRP1 function with peptide N leads to the inhibition of vascular remodelling and tumour liver growth in HCC mice.

Conclusions

Our results indicate a specific role of NRP1 in HCC growth and vascular remodelling and highlight the possibility of therapeutically targeting NRP1 for the treatment of HCC.