Top

European Archives of Oto-Rhino-Laryngology

Published in:

01-01-2019 | Rhinology

Molecular interactions in juvenile nasopharyngeal angiofibroma: preliminary signature and relevant review

Authors: Anupam Mishra, Riddhi Jaiswal, Pandey Amita, S. C. Mishra

Published in: European Archives of Oto-Rhino-Laryngology | Issue 1/2019

Abstract

Background

The molecular profile of juvenile nasopharyngeal angiofibroma (JNA) is extremely variable. In absence of established molecular signature the molecular targeting seems difficult for this heterogeneous disease. To establish a basic molecular signature, this paper analyses the interaction of 7 markers according to their ranks as per the decreasing scale of molecular expression.

Materials and methods

Fourteen samples of JNA were obtained following surgical excision and mRNA expressions were established through real-time polymerase chain reaction (RT-PCR) for vasculoendothelial growth factor (VEGF), fibroblastic growth factor (FGF), c-Kit, c-myc, Ras, platelet-derived growth factor (PDGF) and tumor suppressor gene p53. Nasal polyp was taken as control. The quantitative expressions for every marker were ranked on a decreasing scale and were compared by Spearman’s rank correlation test to define the statistically significant interaction. An attempt was also made to overview the basic clinical parameters (age, duration of symptoms, radiological staging, intraoperative haemorrhage and tumor-volume/weight) associated with enhanced molecular expressions for every marker. Results: Five significant molecular interactions were identified on the basis of rank-correlation: (1) FGF/VEGF (p < 0.01); (2) Ras/FGF (p < 0.01); (3) Ras/VEGF (p < 0.001), (4) FGF/c-Kit (p < 0.05); (5) c-Myc/p53 (p < 0.05). These basic ‘molecular signatures’ suggested a preliminary ‘molecular classification’. The implication of the interactions between FGF, VEGF and Ras were the most outstanding observation that not only revealed a direct relationship but were also consistent with the clinical behaviour. In addition, a non-significant interaction was identified with c-Myc/PDGF and also an inverse relationship between FGF/c-Kit.

Conclusions

FGF, VEGF, and Ras being significantly interrelated seemed to be the ‘most soft’ molecular targets for JNA. The other targets observed included FGF/c-Kit and c-Myc/p53 interactions that seemed equally important but only after VEGF/FGF/Ras complex per se. These preliminary signatures are likely to provide a background for further expansion of the molecular classification of JNA.

Mishra A, Mishra SC (2016) Changing trends in the incidence of juvenile nasopharyngeal angiofibroma: seven decades of experience at King George’s Medical University, Lucknow, India. J Laryngol Otol. https://doi.org/10.1017/S0022215116000268 CrossRefPubMed

Mishra A, Mishra SC, Pandey A (2017) Variations in molecular expressions of juvenile nasopharyngeal angiofibroma. J Laryngol Otol 131(9):752–759CrossRefPubMed

Mishra A, Mishra SC, Verma V, Singh HP, Kumar S, Tripathi AM, Patel B, Singh V (2016) In defence of transpalatal, transpalatal-circumaxillary (transpterygopalatine) and transpalatal-circumaxillary-sublabial approaches to lateral extensions of juvenile nasopharyngeal angiofibroma. J Laryngol Otol 130(5):462–473. https://doi.org/10.1017/S0022215116000773 CrossRefPubMed

Pandey P, Mishra A, Tripathi AM, Verma V, Trivedi R, Singh HP, Kumar S, Patel B, Singh V, Pandey S, Pandey A, Mishra SC (2016) Current molecular profile of juvenile nasopharyngeal angiofibroma: first comprehensive study from India. Laryngoscope. https://doi.org/10.1002/lary.26250 CrossRefPubMed

Mishra A, Sachadeva M, Jain A, Mishra Shukla N, Pandey A (2016) Human Papilloma virus in Juvenile Nasopharyngeal Angiofibroma: possible recent trend. Am J Otolaryngol Head Neck Med Surg 37:317–322

Mishra A, Mishra SC, Tripathi AM, Verma V, Pandey A (2018) Clinical Correlation of Molecular (VEGF, FGF, PDGF, c-Myc, c-Kit, Ras, p53) Expression in Juvenile Nasopharyngeal Angiofibroma. Eur Arch Otorhinolaryngol. https://doi.org/10.1007/s00405-018-5110-5 CrossRefPubMed

Schuon R, Brieger J, Heinrich UR, Roth Y, Szyfter W, Mann WJ (2007) Immunohistochemical analysis of growth mechanisms in juvenile angiofibroma. Eur Arch Otorhinolaryngol 264:389–394CrossRefPubMed

Xiao L, Du Y, Shen Y, He Y, Zhao H, Li Z (2012) TGF-beta 1 induced fibroblast proliferation is mediated by the FGF-2/ERK pathway. Front Biosci (Landmark Ed) 17:2667–2674CrossRef

Thomas KA, Rios-Candelore M, Gimenez-Gallego G, DiSalvo J, Bennett C, Rodkey J, Fitzpatrick S (1985) Pure brain-derived acidic Fibroblast Growth Factor is a potent angiogenic vascular endothelial cell mitogen with sequence homology to interleukin 1. Proc Natl Acad Sci USA 82:6409–6413CrossRefPubMedPubMedCentral

10.

Schiff M, Gonzalez A, Ong M, Baird A (1992) Juvenile nasopharyngeal angiofibroma contain an angiogenic growth factor: basic FGF. Laryngoscope 102:940–945CrossRefPubMed

11.

Narasimhan P (2009) VEGF stimulates the ERK 1/2 signalling pathway and apoptosis in cerebral endothelial cells after ischemic conditions. Stroke 40:1467–1473CrossRefPubMedPubMedCentral

12.

Abid MR, Guo S, Minami T, Spokes KC, Ueki K, Skurk C, Walsh K, Aird WC (2004) Vascular endothelial growth factor activates PI3K/Akt/forkhead signaling in endothelial cells. Arterioscler Thromb Vasc Biol 24(2):294–300 (Epub 2003 Dec 1) CrossRefPubMed

13.

Shiojima I, Walsh K (2002) Role of Akt signalling in vascular homeostasis and angiogenesis. Circ Res 90(12):1243–1250CrossRefPubMed

14.

Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16:159–178CrossRefPubMed

15.

Pepper MS, Ferrara N, Orci L, Montesano R (1992) Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun 189:824–831CrossRefPubMed

16.

Tille JC, Wood J, Mandriota SJ, Schnell C, Ferrari S, Mestan J, Zhu Z, Witte L, Pepper MS (2001) Vascular endothelial growth factor (VEGF) receptor-2 antagonists inhibit VEGF- and basic fibroblast growth factor-induced angiogenesis in vivo and in vitro. J Pharmacol Exp Ther 299:1073–1085PubMed

17.

Giavazzi R, Sennino B, Coltrini D, Garofalo A, Dossi R, Ronca R, Tosatti MP, Presta M (2003) Distinct role of fibroblast growth factor-2 and vascular endothelial growth factor on tumor growth and angiogenesis. Am J Pathol 162:1913–1926CrossRefPubMedPubMedCentral

18.

Shi YH, Bingle L, Gong LH, Wang YX, Corke KP, Fang WG (2007) Basic FGF augments hypoxia induced HIF-1-alpha expression and VEGF release in T47D breast cancer cells. Pathology 39:396–400CrossRefPubMed

19.

Seghezzi G, Patel S, Ren CJ, Gualandris A, Pintucci G, Robbins ES, Shapiro RL, Galloway AC, Rifkin DB, Mignatti P (1998) Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol 141(7):1659–1673CrossRefPubMedPubMedCentral

20.

Okumura N, Yoshida H, Kitagishi Y, Murakami M, Nishimura Y, Matsuda S (2012) PI3K/AKT/PTEN signaling as a molecular target in leukemia angiogenesis. Adv Hematol 2012:843085. https://doi.org/10.1155/2012/843085 CrossRefPubMedPubMedCentral

21.

Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22CrossRefPubMed

22.

Meadows KN, Bryant P, Vincent PA, Pumiglia KM (2004) Activated ras induces a proangiogenic phenotype in primary endothelial cells. Oncogene 23:192–200. https://doi.org/10.1038/sj.onc.1206921 CrossRefPubMed

23.

Coutinho CM, Bassini AS, Gutie´rrez LG et al (1999) Genetic alterations in Ki-ras and Ha-ras genes in juvenile nasopharyngeal angiofibromas and head and neck cancer. Sao Paulo Med J 117:113–120CrossRefPubMed

24.

Breieri G, Blumi S, Peli J, Grooti M, Wild C, Risau W, Richmann E (2002) Transforming growth factor-b and Ras regulate the VEGF/VRGF receptor system during tumour angiogenesis. Int J Cancer 97:142–148CrossRef

25.

Jones MK, Itani RM, Wang H, Tomikawa M, Sarfeh IJ, Szabo S, Tarnawski AS (1999) Activation of VEGF and Ras genes in gastric mucosa during angiogenic response to ethanol injury. Am J Physiol 276(6 Pt 1):G1345–G1355PubMed

26.

Meadows KN, Bryant P, Pumiglia K (2001) Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation. J Biol Chem 276(52):49289–49298CrossRefPubMed

27.

Yamada S, Yoshimura A (2002) Computer modeling of Ras-MAPK signal transduction pathway. Genome Inform 13:361–362

28.

Klint P, Kanda S, Kloog Y, Claesson-Welsh L (1999) Contribution of Src and Ras pathways in FGF-2 induced endothelial cell differentiation. Oncogene 18:3354–3364CrossRefPubMed

29.

Yan D, Ellman MB, Muddasani P, Cs-Szabo G, Im HJ (2012) FGF-2 promotes catabolism via FGFR1-Ras-Raf-MEK1/2-ERK1/2 axis and PKCd pathway in articular chondrocytes. Poster No. 1718 • ORS 2012 Annual Meeting

30.

Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W, Wang R, Green DR, Tessarollo L, Casellas R, Zhao K, Levens D (2012) c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151(1):68–79. https://doi.org/10.1016/j.cell.2012.08.033. (PMC 3471363.PMID 23021216) CrossRefPubMedPubMedCentral

31.

Levens D (2002) Disentangling the MYC web. Proc Natl Acad Sci USA 99:5757–5759CrossRefPubMedPubMedCentral

32.

Nagai MA, Butugan O, Logullo A, Brentani MM (1996) Expression of growth factors, protooncogenes and p53 in nasopharyngeal angiofibromas. Laryngoscope 106:190–195CrossRefPubMed

33.

Schick B, Veldung B, Wemmert S, Jung V, Montenarh M, Meese E, Urbschat S (2005) p53 and Her-2/neu in juvenile angiofibromas. Oncol Rep 13:453–457PubMed

34.

Ho JSL, Ma W, Mao DYL, Benchimol S (2005) p53-dependent transcriptional repression of c-myc is required for G1 cell cycle arrest. Mol Cell Biol 25(17):7423–7431CrossRefPubMedPubMedCentral

35.

Symonds HL. Krall L, Remington M, Saenz-Robles S, Lowe T, Jacks, Van Dyke T (1994) p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 78:703–711CrossRefPubMed

36.

Hundley JE, Koester SK, Troyer DA, Hilsenbeck SG, Subler MA, Windle JJ (1997) Increased tumor proliferation and genomic instability without decreased apoptosis in MMTV-ras mice deficient in p53. Mol Cell Biol 17:723–731CrossRefPubMedPubMedCentral

37.

Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL (1999) Disruption of the ARFMdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev 13:2658–2669CrossRefPubMedPubMedCentral

38.

Phesse TJ, Myant KB, Cole AM, Ridgway RA, Pearson H, Muncan V, van den Brink GR, Vousden KH, Sears R, Vassilev LT, Clarke AR, Sansom OJ (2014) Endogenous c-Myc is essential for p53-induced apoptosis in response to DNA damage in vivo. Cell Death Differ 21:956–966. https://doi.org/10.1038/cdd.2014.15 CrossRefPubMedPubMedCentral

39.

Sachdeva M, Zhua S, Wua F, Wua H, Waliab V, Kumarb S, Elbleb R, Watabea K, Moa YY (2009) p53 represses c-Myc through induction of the tumor suppressor miR-145. Proc Natl Acad Sci USA 106(9):3207–3212. https://doi.org/10.1073/pnas.0808042106 CrossRefPubMedPubMedCentral

40.

Zhang PJ, Weber R, Liang H, Pasha TL, LiVolsi VA (2003) Growth factors and receptors in juvenile nasopharyngeal angiofibroma and nasal polyps. Arch Pathol Lab Med 127:1480–1484PubMed

41.

Pauli J, Gundelach R, Vanelli-Rees A, Rees G, Campbell C, Dubey S, Perry C (2008) Juvenile nasopharyngeal angiofibroma: an immunohistochemical characterisation of the stromal cell. Pathology 40(4):396–400. https://doi.org/10.1080/00313020802035857 CrossRefPubMed

42.

Koritschoner NP, Bartunek P, Knespel S, Blendinger G, Zenke M (1999) The Fibroblast growth factor receptor FGFR-4 acts as a ligand dependent modulator of erythroid cell proliferation. Oncogene 18:5904–5914CrossRefPubMed

43.

Burger PE, Lukey PT, Coetzee S, Wilson EL (2002) Basic fibroblast growth factor modulates the expression of glycophorin A and c-kit and inhibits erythroid differentiation in K562 Cells. J Cell Physiol 190:83–91CrossRefPubMed

44.

Singla D, Wang J (2016) Fibroblast growth factor-9 Activates c-Kit progenitor cells and enhances angiogenesis in the infarcted diabetic heart. Oxidative Med Cell Longev (Hindawi Publishing Corporation). https://doi.org/10.1155/2016/5810908 (Article ID 5810908) CrossRef

45.

Bardeesy N, Bastian BC, Hezel A, Pinkel D, DePinho RA, Chin L (2001) Dual inactivation of RB and p53 pathways in RAS-induced melanomas. Mol Cell Biol 21:2144–2153CrossRefPubMedPubMedCentral

Title: Molecular interactions in juvenile nasopharyngeal angiofibroma: preliminary signature and relevant review
Authors: Anupam Mishra
Riddhi Jaiswal
Pandey Amita
S. C. Mishra
Publication date: 01-01-2019
Publisher: Springer Berlin Heidelberg
Published in: European Archives of Oto-Rhino-Laryngology / Issue 1/2019
Print ISSN: 0937-4477
Electronic ISSN: 1434-4726
DOI: https://doi.org/10.1007/s00405-018-5178-y

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Molecular interactions in juvenile nasopharyngeal angiofibroma: preliminary signature and relevant review

Abstract

Background

Materials and methods

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Materials and methods

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2019

Mucosal bridges (MB): a 9-year retrospective study of their incidence with a third variant proposed

A comparative retrospective study: hypoglossofacial versus masseterofacial nerve anastomosis using Sunnybrook facial grading system

Facial canal dehiscence rate: a retrospective analysis of 372 chronic otitis media cases

Meta-analysis of Chinese medicine in the treatment of adenoidal hypertrophy in children

Pediatric thyroid surgery: experience in 75 consecutive thyroidectomies

Tranexamic acid and post-tonsillectomy hemorrhage: propensity score and instrumental variable analyses