Clinical impact of soluble Neuropilin-1 in ovarian cancer patients and its association with its circulating ligands of the HGF/c-MET axis

Abstract

BackgroundNeuropilin (NRP) is a transmembrane protein, which has been shown to be a pro-angiogenic mediator and implicated as a potential driver of cancer progression. NRP-1 up-regulation in ovarian cancer tissue predicts poor prognosis. However, the clinical relevance of the soluble form of NRP-1 (sNRP-1) as a circulating biomarker in ovarian cancer patients is unknown.Methods/patients cohortsNRP-1 levels were quantified in a cohort of 88 clinically documented ovarian cancer patients by a commercially available sNRP-1 enzyme-linked immunosorbent assay (ELISA) kit (Biomedica, Vienna, Austria). Patients (81.8% with FIGOIII/IV) received primary cytoreductive surgery with the aim of macroscopic complete resection (achieved in 55.7% of patients) and the recommendation of adjuvant chemotherapy in line with national guidelines.ResultsHigher levels of sNRP-1 reflected more advanced disease (FIGO III/IV) and indicated a trend towards suboptimal surgical outcome, i.e. any residual tumor. sNRP-1 was neither related to the patients’ age nor the BRCA1/2 mutational status. Patients with higher sNRP-1 levels at primary diagnosis had a significantly reduced progression-free survival (PFS) (HR = 0.541, 95%CI: 0.304 - 0.963; p = 0.037) and overall survival (OS) (HR = 0.459, 95%CI: 0.225 - 0.936; p = 0.032). Principal component analysis showed that sNRP-1 levels were unrelated to the circulating hepatocyte growth factor (HGF) and the soluble ectodomain of its receptor the tyrosine kinase mesenchymal–epithelial transition (c-MET), suggesting that there is no proportional serological concentration gradient of soluble components of the NRP-1/HGF/c-MET signaling axis.ConclusionsIn line with the previously shown tissue-based prognostic role, we demonstrated for the first time that sNRP-1 can also act as a readily accessible, prognostic biomarker in the circulation of patients with ovarian cancer at primary diagnosis. Given its known role in angiogenesis and conferring resistance to the poly ADP-ribose polymerase (PARP) inhibitor olaparib in vitro, our results encourage more detailed investigation into sNRP-1 as a potential predictive biomarker for bevacizumab and/or PARP-inhibitor treatment.

Biological and Clinical Implications of the Vascular Endothelial Growth Factor Coreceptor Neuropilin-1 in Human Immunodeficiency Virus

“…Our finding may reflect the summation of comorbidities in which NRP-1 has contributing pathologic roles. Several studies have assessed systemic and tissue-level NRP-1 and associated it with mortality, but only in participants with diagnosed cancer to assess prognosis [ 4 , 5 ]. None to our knowledge have evaluated all-cause mortality in a broader population without a prevalent cancer diagnosis.…”

“…NRP-1 was initially identified relating to signal transduction, cell migration, angiogenesis, and vascular permeability [ 3 ]. In pathologic states, NRP-1 is most studied in malignancy, where increased plasma and tissue expression is associated with worse outcomes across numerous cancers [ 4 , 5 ]. NRP-1 also has key immunologic functions involving T-cell maturation, upregulation on activated CD4 + T cells, and an immunoregulatory and cell migration role with T-regulatory (Treg) cells and macrophages [ 6 , 7 ].…”

Revealing neuropilin expression patterns in pancreatic cancer: From single‑cell to therapeutic opportunities (Review)

“…A family gene, NRP-2 (human chromosome 2q33.3), encoding a novel member of the family protein neuropilin-2 (NRP-2) that contains 931 amino acids with 104 kDa, was identified as a high-affinity receptor for the Semaphorins ( 2 ). Previous studies revealed that NRP family proteins exert multiple functions as co-receptors for vascular endothelial growth factor (VEGF) ( 3 ), transforming growth factor beta (TGF-β) ( 4 ), hepatocyte growth factor ( 5 ), fibroblast growth factor (FGF) ( 6 ), and Semaphorin 3 (SEMA3) ( 7 ). NRP family proteins are involved in the interaction with multiple ligand receptors, thus NRP family proteins may be involved in cancer occurrence and development and might serve as therapeutic targets for gastric cancer ( 8 ), glioma ( 9 ), endometrial cancer ( 10 ), bladder cancer ( 11 ), thyroid cancer ( 12 ), breast cancer ( 13 ), gallbladder cancer ( 14 ), colorectal cancer ( 15 ), and pancreatic adenocarcinoma (PDAC) ( 16 ).…”

Soluble Neuropilin-1 Is Elevated in Sepsis and Correlates with Organ Dysfunction and Long-Term Mortality in Critical Illness

“…Measurement of the total soluble NRP-1 has become available using a novel sandwich ELISA [31]. However, the extent of sNRP-1 functions remains incompletely understood [17,[32][33][34].…”

“…It has been proposed as a potential therapeutic target [35][36][37][38][39]. NRP-1 has been extensively researched as a prognostic biomarker and therapeutic target in cancer and leukemia [17,19,24,25,28,33,34]. Interestingly, NRP-1 has also been found to be expressed in liver cells and appears to be upregulated in various liver-related pathologies [39][40][41].…”