Napolitano, Virginia (2018) Neuropilin-1 in head and neck cancer. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Lingua: English
Title: Neuropilin-1 in head and neck cancer
Date: 11 December 2018
Number of Pages: 49
Institution: Università degli Studi di Napoli Federico II
Department: Scienze Biomediche Avanzate
Dottorato: Scienze biomorfologiche e chirurgiche
Ciclo di dottorato: 31
Coordinatore del Corso di dottorato:
Staibano, StefaniaUNSPECIFIED
Date: 11 December 2018
Number of Pages: 49
Uncontrolled Keywords: Neuropilin-1, head and neck cancer, cisplatin.
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/08 - Anatomia patologica
Date Deposited: 21 Dec 2018 08:45
Last Modified: 22 Jun 2020 09:23


Head and neck squamous cell carcinoma (HNSCC), the sixth most common tumor worldwide, accounts for more than 550,000 new cases and 380,000 deaths per year. Patients diagnosed with locally advanced disease often require multimodal treatment approaches. Chemoradiation, with high cisplatin dose, remains the standard of care for this category of patients. Molecular target therapies have been introduced, such as the combination of the Epidermal Growth Factor Receptor (EGFR) monoclonal antibody (cetuximab) with cisplatin and 5-fluorouracil for the treatment of recurrent or metastatic HNSCC. EGFR is one of the most studied molecular target, since it is overexpressed in about 90% of HNSCC and Neuropilin-1 (Nrp-1), that is a co-receptor of EGFR, represents an interesting candidate to investigate in HNSCC. Nrp-1 has been first discovered as regulator of the nervous system development, acting together with Plexins as co-receptor for Semaphorins (SEMAs); then, Nrp-1 has been identified as receptor for several Vascular Endothelial Growth Factors (VEGFs). Recent findings determined that Nrp-1 is able to enhance the signaling activated by the ligands and tyrosine kinase receptors (RTKs) interaction. In particular, upon ligand stimulation, Nrp-1 can elicit EGFR clustering, endocytosis and signaling. Consequently, Nrp-1 results involved in multiple oncogenic processes, such as cellular proliferation, survival, invasion and migration. Few evidences reported a Nrp-1 contribution in response to cancer therapy, even if its role in chemotherapy still is in need of further investigation. In this study, we aim to address three main issues: 1) to investigate in a study population of human head and neck cancers (N=217), the Nrp-1 expression and its correlation with the clinicopathological features of patients, by statistical analysis; 2) to explore, in vitro, in stable Nrp-1 silenced head and neck cancer cells, the Nrp-1 contribution to cisplatin sensitivity; 3) to analyse the Nrp-1 role in sustaining the cisplatin-induced EGFR activation. In the HNSCC cohort of surgical samples, organized in tissue microarrays, we investigated the Nrp-1 expression by IHC analysis, showing the Nrp-1 overexpression in malignant tissues compared to the normal counterpart. Performing survival and multivariate analysis, Nrp-1 expression resulted an independent prognostic factor for HNSCC patients. By transduction with lentiviral vectors, we obtained the Nrp-1 depleted HNSCC cellular models. Interestingly, we observed the increase of cellular sensitivity to cisplatin treatment in the Nrp-1 silenced cells, compared to control cells, transduced with the empty lentiviral vector. Finally, we showed that Nrp-1 is able to sustain the cisplatin induced EGFR activation together with the tyrosine-protein kinase Src, a mechanism proposed to serve as a cell-survival response to cytotoxic stress. In conclusion, these results propose Nrp-1 as a novel prognostic marker for HNSCC. Furthermore, we provide preliminary evidences of Nrp-1 contribution to cisplatin sensitivity. Additionally, we showed, for the first time, the Nrp-1 ability to enhance the cisplatin induced EGFR activation, expanding the repertoire of signalling processes involving Nrp-1 and suggesting the need of further investigations on Nrp-1 as a suitable target for HNSCC therapies.


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