DOI QR코드

DOI QR Code

Immunohistochemical Expression of Receptor Tyrosine Kinase (RTK) in Canine Brain Tumors

  • Jung, Hae-Won (Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University) ;
  • Song, Joong-Hyun (Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University) ;
  • Yu, Do-Hyeon (Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University) ;
  • An, Su-Jin (Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University) ;
  • Sur, Jung-Hyang (Department of Pathobiology, Small Animal Tumor Diagnostic Center, College of Veterinary Medicine, Konkuk University) ;
  • Kim, Young Joo (College of Veterinary Medicine, Western University of Health Sciences) ;
  • Han, Donghyun (Section of Veterinary Research and Academic Consulting, Veteran, Inc.) ;
  • Jung, Dong-In (Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University)
  • Received : 2019.03.25
  • Accepted : 2019.11.28
  • Published : 2019.12.31

Abstract

Receptor tyrosine kinases (RTK) are major promising targets in anticancer therapy in human and veterinary medicine. Using immunohistochemistry method, we evaluated the expressionof five types RTK (PDGFR-α, PDGFR-β, VEGFR 2, c-Kit and Abl) in the six canine brain tumor samples (2 meningioma, 2 astrocytoma, 1 ependymoma and 1 choroid plexus papilloma). A total of five samples expressed PDGFR-β (5/6), one sample, the choroid plexus papilloma, expressed c-Kit (1/6), and a total of two samples expressed Abl (2/6). None of the samples showed expression of PDGFR-α and VEGFR 2. We demonstrate that a significant portion of canine brain tumors express tyrosine receptors for growth factors and show that these receptors generally localize to tumor cell membranes and the cytoplasm. Evaluation of immunohistochemical expression for the RTKs PDGFR-β, c-Kit, and Alb in canine brain samples reveals an interesting potential for molecular targeting by TKIs in therapeutic studies of canine brain tumors, and more studies will be needed to assess the interactions and efficacy of these RTKs and TKIs. Based on these results, we have some evidence for novel chemotherapeutic trials using TKIs for canine nervous tumors.

Keywords

References

  1. Balana C, Gil MJ, Perez P, Reynes G, Gallego O, Ribalta T, Capellades J, Gonzalez S, Verger E. Sunitinib administered prior to radiotherapy in patients with non-resectable glioblastoma: results of a phase II study. Target Oncol 2014; 9: 321-329. https://doi.org/10.1007/s11523-014-0305-1
  2. Berkman RA, Merrill MJ, Reinhold WC, Monacci WT, Saxena A, Clark WC, Robertson JT, Ali IU, Oldfield EH. Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest 1993; 91: 153-159. https://doi.org/10.1172/JCI116165
  3. Cetin N, Dienel G, Gokden M. CD117 expression in glial tumors. J Neurooncol 2005; 75: 195-202. https://doi.org/10.1007/s11060-005-2318-1
  4. Dickinson PJ, Roberts BN, Higgins RJ, Leutenegger CM, Bollen AW, Kass PH, LeCouteur RA. Expression of receptor tyrosine kinases VEGFR-1 (FLT-1), VEGFR-2 (KDR), EGFR-1, PDGFRalpha and c-Met in canine primary brain tumours. Vet Comp Oncol 2006; 4: 132-140. https://doi.org/10.1111/j.1476-5829.2006.00101.x
  5. Dickinson PJ, Sturges BK, Higgins RJ, Roberts BN, Leutenegger CM, Bollen AW, LeCouteur RA. Vascular endothelial growth factor mRNA expression and peritumoral edema in canine primary central nervous system tumors. Vet Pathol 2008; 45: 131-139. https://doi.org/10.1354/vp.45-2-131
  6. Dresemann G. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Ann Oncol 2005; 16: 1702-1708. https://doi.org/10.1093/annonc/mdi317
  7. Figarella-Branger D, Vagner-Capodano AM, Bouillot P, Graziani N, Gambarelli D, Devictor B, Zattara-Cannoni H, Bianco N, Grisoli F, Pellissier JF. Platelet-derived growth factor (PDGF) and receptor (PDGFR) expression in human meningiomas: correlations with clinicopathological features and cytogenetic analysis. Neuropathol Appl Neurobiol 1994; 20: 439-447. https://doi.org/10.1111/j.1365-2990.1994.tb00994.x
  8. Fletcher JA. Role of KIT and platelet-derived growth factor receptors as oncoproteins. Semin Oncol 2004; 31: 4-11. https://doi.org/10.1053/S0093-7754(03)00679-1
  9. Folkman J. Tumor angiogenesis. Adv Cancer Res 1985; 43: 175-203. https://doi.org/10.1016/S0065-230X(08)60946-X
  10. Gomes AL, Reis-Filho JS, Lopes JM, Martinho O, Lambros MB, Martins A, Schmitt F, Pardal F, Reis RM. Molecular alterations of KIT oncogene in gliomas. Cell Oncol 2007; 29: 399-408. https://doi.org/10.1155/2007/926274
  11. Graham JC, Myers RK. The prognostic significance of angiogenesis in canine mammary tumors. J Vet Intern Med 1999; 13: 416-418. https://doi.org/10.1111/j.1939-1676.1999.tb01456.x
  12. Haberler C, Gelpi E, Marosi C, Rossler K, Birner P, Budka H, Hainfellner JA. Immunohistochemical analysis of plateletderived growth factor receptor-alpha, -beta, c-kit, c-abl, and arg proteins in glioblastoma: possible implications for patient selection for imatinib mesylate therapy. J Neurooncol 2006; 76: 105-109. https://doi.org/10.1007/s11060-005-4570-9
  13. Harrigan MR. Angiogenic factors in the central nervous system. Neurosurgery 2003; 53: 639-660. https://doi.org/10.1227/01.NEU.0000079575.09923.59
  14. Higgins RJ, Dickinson PJ, LeCouteur RA, Bollen AW, Wang H, Corely LJ, Moore LM, Zang W, Fuller GN. Spontaneous canine gliomas: overexpression of EGFR, PDGFRalpha and IGFBP2 demonstrated by tissue microarray immunophenotyping. J Neurooncol 2010; 98: 49-55. https://doi.org/10.1007/s11060-009-0072-5
  15. Horak P, Wohrer A, Hassler M, Hainfellner J, Preusser M, Marosi C. Imatinib mesylate treatment of recurrent meningiomas in preselected patients: a retrospective analysis. J Neurooncol 2012; 109: 323-330. https://doi.org/10.1007/s11060-012-0896-2
  16. Ide T, Uchida K, Kikuta F, Suzuki K, Nakayama H. Immunohistochemical characterization of canine neuroepithelial tumors. Vet Pathol 2010; 47: 741-750. https://doi.org/10.1177/0300985810363486
  17. Kinsella P, Howley R, Doolan P, Clarke C, Madden SF, Clynes M, Farrell M, Amberger-Murphy V. Characterization and response of newly developed high-grade glioma cultures to the tyrosine kinase inhibitors, erlotinib, gefitinib and imatinib. Exp Cell Res 2012; 318: 641-652. https://doi.org/10.1016/j.yexcr.2012.01.014
  18. Koleske AJ, Gifford AM, Scott ML, Nee M, Bronson RT, Miczek KA, Baltimore D. Essential roles for the Abl and Arg tyrosine kinases in neurulation. Neuron 1998; 21: 1259-1272. https://doi.org/10.1016/S0896-6273(00)80646-7
  19. Kuratsu JI, Seto H, Kochi M, Ushio Y. Expression of PDGF, PDGF-receptor, EGF-receptor and sex hormone receptors on meningioma. Acta Neurochir (Wien) 1994; 131: 289-293. https://doi.org/10.1007/BF01808629
  20. Liang ML, Ma J, Ho M, Solomon L, Bouffet E, Rutka JT, Hawkins C. Tyrosine kinase expression in pediatric high grade astrocytoma. J Neurooncol 2008; 87: 247-253. https://doi.org/10.1007/s11060-007-9513-1
  21. Lipsitz D, Higgins RJ, Kortz GD, Dickinson PJ, Bollen AW, Naydan DK, LeCouteur RA. Glioblastoma multiforme: clinical findings, magnetic resonance imaging, and pathology in five dogs. Vet Pathol 2003; 40: 659-669. https://doi.org/10.1354/vp.40-6-659
  22. London CA. Tyrosine kinase inhibitors in veterinary medicine. Top Companion Anim Med 2009; 24: 106-112. https://doi.org/10.1053/j.tcam.2009.02.002
  23. Ma PC, Maulik G, Christensen J, Salgia R. c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev 2003; 22: 309-325. https://doi.org/10.1023/A:1023768811842
  24. Nobusawa S, Stawski R, Kim YH, Nakazato Y, Ohgaki H. Amplification of the PDGFRA, KIT and KDR genes in glioblastoma: a population-based study. Neuropathology 2011; 31: 583-588. https://doi.org/10.1111/j.1440-1789.2011.01204.x
  25. Nupponen NN, Paulsson J, Jeibmann A, Wrede B, Tanner M, Wolff JE, Paulus W, Ostman A, Hasselblatt M. Plateletderived growth factor receptor expression and amplification in choroid plexus carcinomas. Mod Pathol 2008; 21: 265-270. https://doi.org/10.1038/modpathol.3800989
  26. Pfister C, Pfrommer H, Tatagiba MS, Roser F. Vascular endothelial growth factor signals through platelet-derived growth factor receptor beta in meningiomas in vitro. Br J Cancer 2012; 107: 1702-1713. https://doi.org/10.1038/bjc.2012.459
  27. Platt SR, Scase TJ, Adams V, Wieczorek L, Miller J, Adamo F, Long S. Vascular endothelial growth factor expression in canine intracranial meningiomas and association with patient survival. J Vet Intern Med 2006; 20: 663-668. https://doi.org/10.1111/j.1939-1676.2006.tb02912.x
  28. Rossmeisl JH, Duncan RB, Huckle WR, Troy GC. Expression of vascular endothelial growth factor in tumors and plasma from dogs with primary intracranial neoplasms. Am J Vet Res 2007; 68: 1239-1245. https://doi.org/10.2460/ajvr.68.11.1239
  29. Shamah SM, Alberta JA, Giannobile WV, Guha A, Kwon YK, Carroll RS, Black PM, Stiles CD. Detection of activated platelet-derived growth factor receptors in human meningioma. Cancer Res 1997; 57: 4141-4147.
  30. Shchemelinin I, Sefc L, Necas E. Protein kinase inhibitors. Folia Biol (Praha) 2006; 52: 137-148.
  31. Shchemelinin I, Sefc L, Necas E. Protein kinases, their function and implication in cancer and other diseases. Folia Biol (Praha) 2006; 52: 81-100.
  32. Stoica G, Kim HT, Hall DG, Coates JR. Morphology, immunohistochemistry, and genetic alterations in dog astrocytomas. Vet Pathol 2004; 41: 10-19. https://doi.org/10.1354/vp.41-1-10
  33. Van Etten RA. Cycling, stressed-out and nervous: cellular functions of c-Abl. Trends Cell Biol 1999; 9: 179-186. https://doi.org/10.1016/S0962-8924(99)01549-4
  34. Virag J, Kenessey I, Haberler C, Piurko V, Balint K, Dome B, Timar J, Garami M, Hegedus B. Angiogenesis and angiogenic tyrosine kinase receptor expression in pediatric brain tumors. Pathol Oncol Res 2014; 20: 417-426. https://doi.org/10.1007/s12253-013-9711-4
  35. Wakeling AE. Inhibitors of growth factor signalling. Endocr Relat Cancer 2005; 12 Suppl 1: S183-187. https://doi.org/10.1677/erc.1.01014
  36. Wanebo HJ, Argiris A, Bergsland E, Agarwala S, Rugo H. Targeting growth factors and angiogenesis; using small molecules in malignancy. Cancer Metastasis Rev 2006; 25: 279-292. https://doi.org/10.1007/s10555-006-8508-2
  37. Wergin MC, Ballmer-Hofer K, Roos M, Achermann RE, Inteeworn N, Akens MK, Blattmann H, Kaser-Hotz B. Preliminary study of plasma vascular endothelial growth factor (VEGF) during low- and high-dose radiation therapy of dogs with spontaneous tumors. Vet Radiol Ultrasound 2004; 45: 247-254. https://doi.org/10.1111/j.1740-8261.2004.04045.x
  38. Yang SY, Xu GM. Expression of PDGF and its receptor as well as their relationship to proliferating activity and apoptosis of meningiomas in human meningiomas. J Clin Neurosci 2001; 8 Suppl 1: 49-53. https://doi.org/10.1054/jocn.2001.0877