ArticleJournal of experimental & clinical cancer research : CR2021
Neuropilin 1 and Neuropilin 2 gene invalidation or pharmacological inhibition reveals their relevance for the treatment of metastatic renal cell carcinoma.
Article in Journal of experimental & clinical cancer research : CR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Fibrogenesis-driven tumor progression in clear cell renal cell carcinoma: prognostic, therapeutic implications and the dual role of neuropilin-1.Cancer cell international · 2025Article
- Neuropilin Antagonists (NRPas) Block the Phosphorylation of the Cancer Therapeutic Key Factor p38α Kinase Triggering Cell Death.Molecules (Basel, Switzerland) · 2025Article
- Combination of Anti-Angiogenics and Immunotherapies in Renal Cell Carcinoma Show Their Limits: Targeting Fibrosis to Break through the Glass Ceiling?Biomedicines · 2024Review
- Potential therapeutic target secretogranin II might cooperate with hypoxia-inducible factor 1α in sunitinib-resistant renal cell carcinoma.Cancer science · 2023Article
- Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation.Acta pharmacologica Sinica · 2023Article
- NRP1 promotes prostate cancer progression via modulating EGFR-dependent AKT pathway activation.Cell death & disease · 2023Article
- Endothelial VEGFR Coreceptors Neuropilin-1 and Neuropilin-2 Are Essential for Tumor Angiogenesis.Cancer research communications · 2022Article
- Neuropilin (NRPs) Related Pathological Conditions and Their Modulators.International journal of molecular sciences · 2022Review
- Transgelin Contributes to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment.Biomedicines · 2021Article
- Article
- Neuropilin-2 and Its Transcript Variants Correlate with Clinical Outcome in Bladder Cancer.Genes · 2021Article
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Authors and funding
15 authors.
Funding
Abstract
backgroundDespite the improvement of relapse-free survival mediated by anti-angiogenic drugs like sunitinib (Sutent®), or by combinations of anti-angiogenic drugs with immunotherapy, metastatic clear cell Renal Cell Carcinoma (mccRCC) remain incurable. Hence, new relevant treatments are urgently needed. The VEGFs coreceptors, Neuropilins 1, 2 (NRP1, 2) are expressed on several tumor cells including ccRCC. We analyzed the role of the VEGFs/NRPs signaling in ccRCC aggressiveness and evaluated the relevance to target this pathway.
methodsWe correlated the NRP1, 2 levels to patients' survival using online available data base. Human and mouse ccRCC cells were knocked-out for the NRP1 and NRP2 genes by a CRISPR/Cas9 method. The number of metabolically active cells was evaluated by XTT assays. Migration ability was determined by wound closure experiments and invasion ability by using Boyden chamber coated with collagen. Production of VEGFA and VEGFC was evaluated by ELISA. Experimental ccRCC were generated in immuno-competent/deficient mice. The effects of a competitive inhibitor of NRP1, 2, NRPa-308, was tested in vitro and in vivo with the above-mentioned tests and on experimental ccRCC. NRPa-308 docking was performed on both NRPs.
resultsKnock-out of the NRP1 and NRP2 genes inhibited cell metabolism and migration and stimulated the expression of VEGFA or VEGFC, respectively. NRPa-308 presented a higher affinity for NRP2 than for NRP1. It decreased cell metabolism and migration/invasion more efficiently than sunitinib and the commercially available NRP inhibitor EG00229. NRPa-308 presented a robust inhibition of experimental ccRCC growth in immunocompetent and immunodeficient mice. Such inhibition was associated with decreased expression of several pro-tumoral factors. Analysis of the TCGA database showed that the NRP2 pathway, more than the NRP1 pathway correlates with tumor aggressiveness only in metastatic patients.
conclusionsOur study strongly suggests that inhibiting NRPs is a relevant treatment for mccRCC patients in therapeutic impasses and NRPa-308 represents a relevant hit.
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