Vol 56, No 2 (2018)
Original paper
Published online: 2018-06-04
Immunohistochemical study on neuropilin 1 (NRP1) immunoexpression in oral squamous cell carcinoma
Abstract
Introduction. Neuropilins (NRPs) are multifunctional glycoproteins that play an important role in angiogenesis and cancer progression. The aim of the study was to examine the immunoexpression of neuropilin 1 (NRP1), the number of NRP1+ infiltrating cells and CD163+ macrophages, and density of microvessels (MVD) in oral squamous cell carcinoma (OSCC).
Material and methods. The study was performed on 45 OSCC patients with metastases (OSCCM+), 51 patients without metastases (OSCCM-) and 17 control cases. The microvessels were identified by the presence of CD31 and the expression of the studied proteins was assessed by immunohistochemistry.
Results. The immunoexpression of NRP1, the mean numbers of NRP1+, CD163+ infiltrating cells, and MVD were significantly increased in OSCCM+ patients in comparison to OSCCM-, and control groups. Moreover, in OSCCM- patients all these parameters were also significantly increased in comparison to controls. In OSCCM+ and OSCCM- groups, there were positive correlations between the immunoexpression of NRP1 and MVD (r = 0.41, p < 0.006; r = 0.51, p < 0.001, respectively), and between the number of NRP1+ infiltrating cells and CD163+ macrophages (r = 0.56, p < 0.001, r = 0.49, p < 0.001, respectively).
Conclusions. The present study revealed overexpression of NRP1 in OSCC, especially in OSCC patients with metastasis, suggesting that NRP1 could potentially contribute to metastasis of oral cancer. The correlation between the number of NRP1+ infiltrating cells and CD163+ macrophages suggests that NRP1+ infiltrating macrophages are present in tumor microenvironment and may play a role in the progressions of oral cancer.
Keywords: neuropilin 1macrophagesangiogenesisoral cancermetastasisIHC
References
- Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. http://globocan.iarc.fr, accessed on 03/09/2016.
- Forastiere AA, Ang K, Brizel D, et al. National Comprehensive Cancer Network. Head and neck cancers. J Natl Compr Canc Netw. 2005; 3(3): 316–391.
- Hunter KD, Parkinson EK, Harrison PR. Profiling early head and neck cancer. Nat Rev Cancer. 2005; 5(2): 127–135.
- Folkman J. Is angiogenesis an organizing principle in biology and medicine? J Pediatr Surg. 2007; 42(1): 1–11.
- Wang L, Zeng H, Wang P, et al. Neuropilin-1-mediated vascular permeability factor/vascular endothelial growth factor-dependent endothelial cell migration. J Biol Chem. 2003; 278(49): 48848–48860.
- Wang L, Mukhopadhyay D, Xu X. C terminus of RGS-GAIP-interacting protein conveys neuropilin-1-mediated signaling during angiogenesis. FASEB J. 2006; 20(9): 1513–1515.
- Prud'homme GJ, Glinka Y. Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity. Oncotarget. 2012; 3(9): 921–939.
- Pellet-Many C, Frankel P, Jia H, et al. Neuropilins: structure, function and role in disease. Biochem J. 2008; 411(2): 211–226.
- Uniewicz KA, Fernig DG. Neuropilins: a versatile partner of extracellular molecules that regulate development and disease. Front Biosci. 2008; 13: 4339–4360.
- Shimizu A, Zankov DP, Kurokawa-Seo M, et al. Vascular Endothelial Growth Factor-A Exerts Diverse Cellular Effects via Small G Proteins, Rho and Rap. Int J Mol Sci. 2018; 19(4).
- Bruder D, Probst-Kepper M, Westendorf AM, et al. Neuropilin-1: a surface marker of regulatory T cells. Eur J Immunol. 2004; 34(3): 623–630.
- Plein A, Fantin A, Ruhrberg C. Neuropilin regulation of angiogenesis, arteriogenesis, and vascular permeability. Microcirculation. 2014; 21(4): 315–323.
- Parikh AA, Fan F, Liu WB, et al. Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis. Am J Pathol. 2004; 164(6): 2139–2151.
- Zhou R, Curry JM, Roy LD, et al. A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis. Oncogene. 2016; 35(43): 5608–5618.
- Broholm H, Laursen H. Vascular endothelial growth factor (VEGF) receptor neuropilin-1's distribution in astrocytic tumors. APMIS. 2004; 112(4-5): 257–263.
- Song X, Zhang W, Zhang Y, et al. Expression of semaphorin 3A and neuropilin 1 with clinicopathological features and survival in human tongue cancer. Med Oral Patol Oral Cir Bucal. 2012; 17(6): e962–e968.
- Hansel DE, Wilentz RE, Yeo CJ, et al. Expression of neuropilin-1 in high-grade dysplasia, invasive cancer, and metastases of the human gastrointestinal tract. Am J Surg Pathol. 2004; 28(3): 347–356.
- Wu YY, Chen YL, Jao YC, et al. miR-320 regulates tumor angiogenesis driven by vascular endothelial cells in oral cancer by silencing neuropilin 1. Angiogenesis. 2014; 17(1): 247–260.
- Barnes L, Everson JW, Reichart P, et al. World Health Organization Classification of Tumours. Pathology and Genetics Head and Neck Tumours. IARC Press Lyon. ; 2005: 168–176.
- Vermeulen PB, Gasparini G, Fox SB, et al. Second international consensus on the methodology and criteria of evaluation of angiogenesis quantification in solid human tumours. Eur J Cancer. 2002; 38(12): 1564–1579.
- Cheng W, Fu D, Wei ZF, et al. NRP-1 expression in bladder cancer and its implications for tumor progression. Tumour Biol. 2014; 35(6): 6089–6094.
- Matkar PN, Singh KK, Rudenko D, et al. Novel regulatory role of neuropilin-1 in endothelial-to-mesenchymal transition and fibrosis in pancreatic ductal adenocarcinoma. Oncotarget. 2016; 7(43): 69489–69506.
- Shahrabi-Farahani S, Gallottini M, Martins F, et al. Neuropilin 1 Receptor Is Up-Regulated in Dysplastic Epithelium and Oral Squamous Cell Carcinoma. Am J Pathol. 2016; 186(4): 1055–1064.
- Chu W, Song X, Yang X, et al. Neuropilin-1 promotes epithelial-to-mesenchymal transition by stimulating nuclear factor-kappa B and is associated with poor prognosis in human oral squamous cell carcinoma. PLoS One. 2014; 9(7): e101931.
- Lu J, Cheng Y, Zhang G, et al. Increased expression of neuropilin 1 in melanoma progression and its prognostic significance in patients with melanoma. Mol Med Rep. 2015; 12(2): 2668–2676.
- Jiang H, Xi Q, Wang F, et al. Increased expression of neuropilin 1 is associated with epithelial ovarian carcinoma. Mol Med Rep. 2015; 12(2): 2114–2120.
- Shahrabi-Farahani S, Wang L, Zwaans BMM, et al. Neuropilin 1 expression correlates with differentiation status of epidermal cells and cutaneous squamous cell carcinomas. Lab Invest. 2014; 94(7): 752–765.
- Beck B, Driessens G, Goossens S, et al. A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature. 2011; 478(7369): 399–403.
- Miao HQ, Lee P, Lin H, et al. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. FASEB J. 2000; 14(15): 2532–2539.
- Kawasaki T, Kitsukawa T, Bekku Y, et al. A requirement for neuropilin-1 in embryonic vessel formation. Development. 1999; 126(21): 4895–4902.
- Jones EAV, Yuan Li, Breant C, et al. Separating genetic and hemodynamic defects in neuropilin 1 knockout embryos. Development. 2008; 135(14): 2479–2488.
- Kawakami T, Tokunaga T, Hatanaka H, et al. Neuropilin 1 and neuropilin 2 co-expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma. Cancer. 2002; 95(10): 2196–2201.
- Ben Q, Zheng J, Fei J, et al. High neuropilin 1 expression was associated with angiogenesis and poor overall survival in resected pancreatic ductal adenocarcinoma. Pancreas. 2014; 43(5): 744–749.
- Marone G, Varricchi G, Loffredo S, et al. Mast cells and basophils in inflammatory and tumor angiogenesis and lymphangiogenesis. Eur J Pharmacol. 2016; 778: 146–151.
- Kawaguchi K, Suzuki E, Nishie M, et al. Downregulation of neuropilin-1 on macrophages modulates antibody-mediated tumoricidal activity. Cancer Immunol Immunother. 2017; 66(9): 1131–1142.
- Stasikowska-Kanicka O, Wągrowska-Danilewicz M, Danilewicz M. T cells are involved in the induction of macrophage phenotypes in oral leukoplakia and squamous cell carcinoma-a preliminary report. J Oral Pathol Med. 2018; 47(2): 136–143.
- Ribatti D. Mast cells and macrophages exert beneficial and detrimental effects on tumor progression and angiogenesis. Immunol Lett. 2013; 152(2): 83–88.
- Stasikowska-Kanicka O, Wągrowska-Danilewicz M, Danilewicz M. Association of infiltrating cells with microvessel density in oral squamous cell carcinoma. Pol J Pathol. 2017; 68(1): 40–48.
- Ji JD, Park-Min KH, Ivashkiv LB. Expression and function of semaphorin 3A and its receptors in human monocyte-derived macrophages. Hum Immunol. 2009; 70(4): 211–217.
- Casazza A, Laoui D, Wenes M, et al. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell. 2013; 24(6): 695–709.
