Expression of NRP-1 and NRP-2 in Endometrial Cancer

Author(s): Marcin Oplawski*, Konrad Dziobek, Beniamin Grabarek, Nikola Zmarzły, Dariusz Dąbruś, Piotr Januszyk, Ryszard Brus, Barbara Tomala, Dariusz Boroń.

Journal Name: Current Pharmaceutical Biotechnology

Volume 20 , Issue 3 , 2019

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Graphical Abstract:


Abstract:

Background: Neuropilins (NRPs) participate in many processes related to cancer development such as angiogenesis, lymphangiogenesis and metastasis. Although endometrial cancer is one of the most common gynecological cancers, it has not been studied in terms of NRPs expression.

Objective: The aim of this study was to investigate the potential utility of NRPs as important factors in the diagnosis and treatment of endometrial cancer.

Methods: Our study consisted of 45 women diagnosed with endometrial cancer at the following degrees of histological differentiation: G1, 17; G2, 15; G3, 13 cases. The control group included 15 women without neoplastic changes. The immunohistochemical reactions were evaluated using light microscopy.

Results: We did not detect the expression of NRP-1 and NRP-2 in the control group. NRP-1 expression was found exclusively in cancer cells. It was higher in G2 and G3 and reached about 190% of G1. NRP-2 expression was observed in the endothelium and was similar across all three cancer grades. In cancer cells, NRP-2 expression increased with the degree of histological differentiation.

Conclusion: NRP1 and NRP2 are candidates for complementary diagnostic molecular markers and promising new targets for molecular, personalized anticancer therapies.

Keywords: Tumor growth, endometrial cancer, neuropilins (NRPs), molecular marker, endothelium, cancer grade.

[1]
Kolodkin, A.L.; Levengood, D.V.; Rowe, E.G.; Tai, Y.T.; Giger, R.J.; Ginty, D.D. Neuropilin is a semaphorin III receptor. Cell, 1997, 90(4), 753-762.
[2]
Chen, H.; Chédotal, A.; He, Z.; Goodman, C.S.; Tessier-Lavigne, M. Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron, 1997, 19(3), 547-559.
[3]
Gaur, P.; Bielenberg, D.R.; Samuel, S.; Bose, D.; Zhou, Y.; Gray, M.J.; Dallas, N.A.; Fan, F.; Xia, L.; Lu, J.; Ellis, L.M. Role of class 3 semaphorins and their receptors in tumor growth and angiogenesis. Clin. Cancer Res., 2009, 15(22), 6763-6770.
[4]
Grandclement, C.; Borg, C. Neuropilins: A new target for cancer therapy. Cancers (Basel), 2011, 3(2), 1899-1928.
[5]
Winberg, M.L.; Noordermeer, J.N.; Tamagnone, L.; Comoglio, P.M.; Spriggs, M.K.; Tessier-Lavigne, M.; Goodman, C.S. Plexin A is a neuronal semaphorin receptor that controls axon guidance. Cell, 1998, 95(7), 903-916.
[6]
Takahashi, T.; Fournier, A.; Nakamura, F.; Wang, L.H.; Murakami, Y.; Kalb, R.G.; Fujisawa, H.; Strittmatter, S.M. Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell, 1999, 99(1), 59-69.
[7]
He, Z.; Tessier-Lavigne, M. Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell, 1997, 90(4), 739-751.
[8]
Staton, C.A.; Kumar, I.; Reed, M.W.; Brown, N.J. Neuropilins in physiological and pathological angiogenesis. J. Pathol., 2007, 212(3), 237-248.
[9]
Kärpänen, T.; Heckman, C.A.; Keskitalo, S.; Jeltsch, M.; Ollila, H.; Neufeld, G.; Tamagnone, L.; Alitalo, K. Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J., 2006, 20(9), 1462-1472.
[10]
Goel, H.L.; Mercurio, A.M. VEGF targets the tumour cell. Nat. Rev. Cancer, 2013, 13(12), 871-882.
[11]
Glinka, Y.; Stoilova, S.; Mohammed, N.; Prud’homme, G.J. Neuropilin-1 exerts co-receptor function for TGF-beta-1 on the membrane of cancer cells and enhances responses to both latent and active TGF-beta. Carcinogenesis, 2011, 32(4), 613-621.
[12]
Nasarre, P.; Gemmill, R.M.; Potiron, V.A.; Roche, J.; Lu, X.; Barón, A.E.; Korch, C.; Garrett-Mayer, E.; Lagana, A.; Howe, P.H.; Drabkin, H.A. Neuropilin-2 Is upregulated in lung cancer cells during TGF-β1-induced epithelial-mesenchymal transition. Cancer Res., 2013, 73(23), 7111-7121.
[13]
Evans, I.M.; Yamaji, M.; Britton, G.; Pellet-Many, C.; Lockie, C.; Zachary, I.C.; Frankel, P. Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells. Mol. Cell. Biol., 2011, 31(6), 1174-1185.
[14]
Banerjee, S.; Sengupta, K.; Dhar, K.; Mehta, S.; D’Amore, P.A.; Dhar, G.; Banerjee, S.K. Breast cancer cells secreted platelet-derived growth factor-induced motility of vascular smooth muscle cells is mediated through neuropilin-1. Mol. Carcinog., 2006, 45(11), 871-880.
[15]
Stępka, K.; Wierzbowska, A. Neuropilins - structure, function, role in cancerogenesis. Acta Haematol. Pol., 2015, 46(5), 339-346.
[16]
Ellis, L.M. The role of neuropilins in cancer. Mol. Cancer Ther., 2006, 5(5), 1099-1107.
[17]
Yamagata, M.; Herman, J.P.; Sanes, J.R. Lamina-specific expression of adhesion molecules in developing chick optic tectum. J. Neurosci., 1995, 15(6), 4556-4571.
[18]
Jubb, A.M.; Strickland, L.A.; Liu, S.D.; Mak, J.; Schmidt, M.; Koeppen, H. Neuropilin-1 expression in cancer and development. J. Pathol., 2012, 226(1), 50-60.
[19]
Jubb, A.M.; Sa, S.M.; Ratti, N.; Strickland, L.A.; Schmidt, M.; Callahan, C.A.; Koeppen, H. Neuropilin-2 expression in cancer. Histopathology, 2012, 61(3), 340-349.
[20]
Hansen, W.; Hutzler, M.; Abel, S.; Alter, C.; Stockmann, C.; Kliche, S.; Albert, J.; Sparwasser, T.; Sakaguchi, S.; Westendorf, A.M.; Schadendorf, D.; Buer, J.; Helfrich, I. Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth. J. Exp. Med., 2012, 209(11), 2001-2016.
[21]
Yaqoob, U.; Cao, S.; Shergill, U.; Jagavelu, K.; Geng, Z.; Yin, M.; de Assuncao, T.M.; Cao, Y.; Szabolcs, A.; Thorgeirsson, S.; Schwartz, M.; Yang, J.D.; Ehman, R.; Roberts, L.; Mukhopadhyay, D.; Shah, V.H. Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment. Cancer Res., 2012, 72(16), 4047-4059.
[22]
Kim, W.H.; Lee, S.H.; Jung, M.H.; Seo, J.H.; Kim, J.; Kim, M.A.; Lee, Y.M. Neuropilin2 expressed in gastric cancer endothelial cells increases the proliferation and migration of endothelial cells in response to VEGF. Exp. Cell Res., 2009, 315(13), 2154-2164.
[23]
Kölbl, A.C.; Birk, A.E.; Kuhn, C.; Jeschke, U.; Andergassen, U. Influence of VEGFR and LHCGR on endometrial adenocarcinoma. Oncol. Lett., 2016, 12(3), 2092-2098.
[24]
Trimble, C.L.; Method, M.; Leitao, M.; Lu, K.; Ioffe, O.; Hampton, M.; Higgins, R.; Zaino, R.; Mutter, G.L. Management of endometrial precancers. Obstet. Gynecol., 2012, 120(5), 1160-1175.
[25]
Opławski, M.; Michalski, M.; Witek, A.; Michalski, B.; Zmarzły, N.; Jęda-Golonka, A.; Styblińska, M.; Gola, J.; Kasprzyk-Żyszczyńska, M.; Mazurek, U.; Plewka, A. Identification of a gene expression profile associated with the regulation of angiogenesis in endometrial cancer. Mol. Med. Rep., 2017, 16(3), 2547-2555.
[26]
Goel, H.L.; Mercurio, A.M. Enhancing integrin function by VEGF/ neuropilin signaling: Implications for tumor biology. Cell Adhes. Migr., 2012, 6(6), 554-560.
[27]
Handa, A.; Tokunaga, T.; Tsuchida, T.; Lee, Y.H.; Kijima, H.; Yamazaki, H.; Ueyama, Y.; Fukuda, H.; Nakamura, M. Neuropilin-2 expression affects the increased vascularization and is a prognostic factor in osteosarcoma. Int. J. Oncol., 2000, 17(2), 291-295.
[28]
Kawakami, T.; Tokunaga, T.; Hatanaka, H.; Kijima, H.; Yamazaki, H.; Abe, Y.; Osamura, Y.; Inoue, H.; Ueyama, Y.; Nakamura, M. 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.
[29]
Yasuoka, H.; Kodama, R.; Tsujimoto, M.; Yoshidome, K.; Akamatsu, H.; Nakahara, M.; Inagaki, M.; Sanke, T.; Nakamura, Y. Neuropilin-2 expression in breast cancer: Correlation with lymph node metastasis, poor prognosis, and regulation of CXCR4 expression. BMC Cancer, 2009, 9, 220.
[30]
Miao, H.Q.; Klagsbrun, M. Neuropilin is a mediator of angiogenesis. Cancer Metastasis Rev., 2000, 19(1-2), 29-37.
[31]
Neufeld, G.; Kessler, O.; Herzog, Y. The interaction of Neuropilin-1 and Neuropilin-2 with tyrosine-kinase receptors for VEGF. Adv. Exp. Med. Biol., 2002, 515, 81-90.
[32]
Takagi, S.; Hirata, T.; Agata, K.; Mochii, M.; Eguchi, G.; Fujisawa, H. The A5 antigen, a candidate for the neuronal recognition molecule, has homologies to complement components and coagulation factors. Neuron, 1991, 7(2), 295-307.
[33]
Gluzman-Poltorak, Z.; Cohen, T.; Herzog, Y.; Neufeld, G. Neuropilin-2 and neuropilin-1 are receptors for VEGF165 and PLGF-2, but only neuropilin-2 functions as a receptor for VEGF145. J. Biol. Chem., 2000, 275, 18040-18045.
[34]
Goel, H.L.; Chang, C.; Pursell, B.; Leav, I.; Lyle, S.; Xi, H.S.; Hsieh, C.C.; Adisetiyo, H.; Roy-Burman, P.; Coleman, I.M.; Nelson, P.S.; Vessella, R.L.; Davis, R.J.; Plymate, S.R.; Mercurio, A.M. VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer. Cancer Discov., 2012, 2(10), 906-921.
[35]
Nguyen, H.; Ivanova, V.S.; Kavandi, L.; Rodriguez, G.C.; Maxwell, G.L.; Syed, V. Progesterone and 1,25-dihydroxyvitamin D3 inhibit endometrial cancer cell growth by upregulating semaphorin 3B and semaphorin 3F. Mol. Cancer Res., 2011, 9(11), 1479-1492.
[36]
Straume, O.; Akslen, L.A. Increased expression of VEGF-receptors (FLT-1, KDR, NRP-1) and thrombospondin-1 is associated with glomeruloid microvascular proliferation, an aggressive angiogenic phenotype, in malignant melanoma. Angiogenesis, 2003, 6(4), 295-301.
[37]
Okon, I.S.; Ding, Y.; Coughlan, K.A.; Wang, O.; Song, P.; Benbrook, D.M.; Zou, M. Aberrant NRP-1 expression serves as predicator of metastatic endometrial and lung cancers Logo of oncotarget. Oncotarget, 2016, 7(7), 7970-7978.
[38]
Bednarek, W.; Mazurek-Kociubowska, M.; Sobstyl, M.; Wertel, I.; Czekierdowski, A. Expression of lymphangiogenesis marker neuropilin-1 in different types of ovarian cancer. Ginekol. Pol., 2010, 81(3), 176-182.


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Article Details

VOLUME: 20
ISSUE: 3
Year: 2019
Page: [254 - 260]
Pages: 7
DOI: 10.2174/1389201020666190219121602

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