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

Bergé, Mathieu; Allanic, David; Bonnin, Philippe; Montrion, Catherine de; Richard, Johann; Suc, Michel; Boivin, Jean‐François; Contrerès, Jean-Olivier; Lockhart, Brian P.; Pocard, Marc; Lévy, Bernard; Tucker, Gordon C.; Tobelem, Gérard; Merkulova-Rainon, Tatyana

doi:10.1016/j.jhep.2011.01.033

Cited by 88 publications

(93 citation statements)

References 48 publications

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“…Considering the conservation of the effect of iRGD in different human tumor xenograft and spontaneous mouse tumor models (5) and the expression of the a v integrin and NRP1 in the vessels and the tumor cells of human HCC (6,(25)(26)(27)(28)(29), it appears possible that the enhanced tumor penetrability to the drugs due to the action of iRGD described in the present study in HCC mouse models may translate to patients with HCC. However, this remains to be investigated.…”

Section: Discussionmentioning

confidence: 96%

Improving Drug Penetrability with iRGD Leverages the Therapeutic Response to Sorafenib and Doxorubicin in Hepatocellular Carcinoma

et al. 2015

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AbstractiRGD is a derivative of the integrin-binding peptide RGD, which selectively increases the penetrability of tumor tissue to various coadministered substances in several preclinical models. In this study, we investigated the ability of iRGD to improve the delivery of sorafenib and doxorubicin therapy in hepatocellular carcinoma (HCC) using established mouse models of the disease. A contrast-enhanced MRI method was developed in parallel to assess the in vivo effects of iRGD in this setting. We found that iRGD improved the delivery of marker substances to the tumors of HCC-bearing mice about three-fold without a parallel increase in normal tissues. Control peptides lacking the critical CendR motif had no effect. Similarly, iRGD also selectively increased the signal intensity from tumors in Gd-DTPAenhanced MRI. In terms of antitumor efficacy, iRGD coadministration significantly augmented the individual inhibitory effects of sorafenib and doxorubicin without increasing systemic toxicity. Overall, our results offered a preclinical proof of concept for the use of iRGD coadministration as a strategy to widen the therapeutic window for HCC chemotherapy, as monitored by Gd-DTPA-enhanced MRI as a noninvasive, clinically applicable method to identify iRGD-reactive tumors.Cancer Res; 75(15); 3147-54. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 96%

Improving Drug Penetrability with iRGD Leverages the Therapeutic Response to Sorafenib and Doxorubicin in Hepatocellular Carcinoma

et al. 2015

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“…5-13.5) and display completely disorganized vascular networks [10]. NRP-1 has been found widely distributed in adult tissues with low expression [11] but significantly increases in various tumors such as glioma [12], pancreatic [13], gastric [14], colon [15,16], breast [17,18], and non-small-cell lung cancers [19] and in acute myeloid leukemia [20,21]. Increased expression of NRP-1 is significantly associated with poor outcomes in breast [18], colon [16], and non-small-cell lung cancer [19] patients, and is correlated with invasivity and metastatic potential in glioma [22] and gastrointestinal [23] and prostate carcinomas [24], which suggests that NRP-1 expression could be used as a diagnostic and prognostic marker for these tumors.…”

Section: Introductionmentioning

confidence: 99%

“…Small interfering RNA targeting NRP-1 significantly reduces angiogenesis and tumor growth and metastasis in various human cancer models, such as hepatocellular carcinoma [25,26], acute myeloid leukemia [27], and lung cancer [19]. Several peptide inhibitors have been developed to target NRP-1, including EG3287 [28][29][30], A7R [31][32][33][34], peptide N [11], DG1/2 [19], and CendR [35,36], which prevent NRP-1 from regulating growth factor receptor function and suppress tumor growth and metastasis. For example, EG3287, a bicycle peptide based on the C-terminal NRP-1 binding domain of VEGF, specifically blocks VEGF binding to NRP-1, inhibits cell migration and adhesion, and improves chemotherapeutic effects of 5-FU and paclitaxel [30].…”

Section: Introductionmentioning

confidence: 99%

A monoclonal antibody targeting neuropilin-1 inhibits adhesion of MCF7 breast cancer cells to fibronectin by suppressing the FAK/p130cas signaling pathway

Zeng

Luo

et al. 2014

Anti-Cancer Drugs

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Neuropilin-1 (NRP-1) is a nontyrosine kinase coreceptor for semaphorin 3A and the vascular endothelial growth factor involved in tumor angiogenesis, growth, and metastasis and is regarded as a promising target for cancer therapy. In the present study, we investigated the effects of an anti-NRP-1 monoclonal antibody (mAb) that we generated for MCF7 breast cancer cellular adhesion studies. MTT, colony formation, and adhesion assays showed that our anti-NRP-1 mAb dose-dependently inhibited MCF7 proliferation and fibronectin adhesion, leading to a rounded cellular morphology. Further, rhodamine phalloidin stain revealed that fibronectin-dependent formation of actin stress fibers was inhibited by anti-NRP-1 mAb. Immunoprecipitation and western blot showed that anti-NRP-1 mAb treatment inhibited the formation of NRP-1-α5β1 integrin complexes and suppressed the phosphorylation of focal adhesion kinase and p130cas in MCF7 cells. These findings contribute to further understanding the NRP-1 function in cell adhesion and tumor metastasis. Moreover, our anti-NRP-1 mAb is a prospective drug candidate for tumor treatment.

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“…In the adult, both Nrps are downregulated on quiescent EC but become upregulated during times of inflammation, ischemia or injury (Klagsbrun et al, 2002; Bielenberg et al, 2006). Adult blood vessels express Nrp1 or Nrp2 (Berge et al, 2011; Bielenberg et al, 2012). Lymphatic vessels express NRP2 in capillary endothelial cells and along the length of collecting ducts (Figure 3), but valves do not express NRP2 (Bouvree et al, 2012).…”

Section: Neuropilin (Nrp) Receptorsmentioning

confidence: 99%

Lymphangiogenesis and metastasis—A closer look at the neuropilin/semaphorin3 axis

Migliozzi

Mucka

Bielenberg

2014

Microvascular Research

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Metastasis is the leading cause of cancer-related deaths. Understanding how the lymphatic system responds to its environment and local stimuli may lead to therapies to combat metastasis and other lymphatic-associated diseases. This review compares lymphatic vessels and blood vessels, discusses markers of lymphatic vasculature, and elucidates some of the signaling motifs involved in lymphangiogenesis. Recent progress implicating the neuropilin and semaphorin axes in this process is discussed.

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

Cited by 88 publications

References 48 publications

Improving Drug Penetrability with iRGD Leverages the Therapeutic Response to Sorafenib and Doxorubicin in Hepatocellular Carcinoma

Improving Drug Penetrability with iRGD Leverages the Therapeutic Response to Sorafenib and Doxorubicin in Hepatocellular Carcinoma

A monoclonal antibody targeting neuropilin-1 inhibits adhesion of MCF7 breast cancer cells to fibronectin by suppressing the FAK/p130cas signaling pathway

Lymphangiogenesis and metastasis—A closer look at the neuropilin/semaphorin3 axis

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