Vaskularijzacija, proliferativna aktivnost i status p53 kod glioblastoma
Ključne reči:
glioblastom, mikrovaskularna gustina, angiogeneza, imunohistohemija, MIB-1 proliferativni indeks, p53
Sažetak
Uvod/Cilj. Glioblastomi (GBM) su među najvaskularizovanije humane tumore, a prisustvo mikrovaskularne proliferacije je jedan od dijagnostičkih obeležja ovih maligniteta. Cilj ove studije bio je da ispita stepen vaskularizacije u odnosu na proliferativnu aktivnost i p53 status u GBM-a.
Metode: Imunohistohemijski, u tkivnim uzorcima 100 odabranih primarnih GBM-a analizirana je ekspresija CD34 u vaskularnim endotelnim ćelijama, Ki-67 antigena (primenom MIB-1 antitela) i p53 u tumorskim ćelijama. Mikrovaskularna gustina (MVG), mera stepena tumorske vaskularizacije, određivana je na CD34-imunobojenim presecima u tri “vruće tačke” i prezentovana kao prosečna vrednost za svaki uzorak tumora.
Rezultati.Visoka MVG bila je češći nalaz u tumorima sa viskim MIB- 1 indeksom u poređenju sa onima koji su imali nizak MIB-1 indeks, ali razlika nije bila statistički značajna. Razlika u stepenu vaskularizacije između p53-negativnih i p53-poztivnih tumora takođe nije bila značajna. Nivo MVG i proporcija GBM-a sa niskom odnosno visokom MVG nisu se značajno razlikovali u odnosu na nivo ekspresije p53 (nizak odnosno visok). Nije nađena povezanost MVG sa MIB-1 indeksom tumorskih ćelija i p53 statusom u primarnim GBM-a.
Zaključak. Ovi podaci sugerišu da efekat p53 na vaskularizaciju primarnih GBM-a nije bio detektovan moguće zbog uticaja određenih faktora, uključujući prisustvo drugih ili dodatnih molekularnih alteracija u tumorskim ćelijama i hipoksične mikrosredine tumora.
Reference
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43. Liu X, Zhang Q, Mu Y et al. Clinical significance of vasculogenic mimicry in human gliomas. J Neurooncol 2011; 105: 173-179.
44. Yu JL, Rak JW, Coomber BL et al. Effect of p53 status on tumor response to antiangiogenic therapy. Science 2002; 295: 1526-1528.
45. Lu-Emerson C, Duda DG, Emblem KE et al. Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma. J Clin Oncol 2015; 33:1197-1213.
2. Alexander BM, Cloughesy TF. Adult glioblastoma. J Clin Oncol 2017; 35: 2402-2409.
3. Stupp R, Hegi ME, Mason WP et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10:459-466.
4. Machein MR, Plate KH. Role of VEGF in developmental angiogenesis and in tumor angiogenesis in the brain. Cancer Treat Res 2004; 117: 191-218..
5. Louis DN, Ohgaki H, Wiestler OD et al. WHO classification of tumours of the central nervous system. Lyon: IARC, 2007.
6. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 2011; 473: 298-307.
7. Fischer I, Gagner JP, Law M et al. Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol 2005; 15: 297-310.
8. Du R, Lu KV, Petritsch C et al. HIF1 alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 2008; 13: 206-220.
9. Rafat N, Beck G, Schulte J et al. Circulating endothelial progenitor cells in malignant gliomas. J Neurosurg 2010; 112: 43-49.
10 Ricci-Vitiani L, Pallini R, Biffoni M et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 2010; 468: 824-828.
11. Wang R, Chadalavada K, Wilshire J et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 2010; 468: 829-833.
12. Scully S, Francescone R, Faibish M et al. Transdifferentiation of glioblastoma stem-like cells into mural cells drives vasculogenic mimicry in glioblastomas. J Neurosci 2012; 32:12950-12960.
13. Jain RK, di Tomaso E, Duda DG et al. Angiogenesis in brain tumours. Nat Rev Neurosci 2007; 8: 610-622.
14. Brat DJ, Van Meir EG. Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma. Lab Invest 2004; 84: 397-405.
15. Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol 2007; 8: 275-283.
16. Teodoro JG, Evans SK, Green MR. Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome. J Mol Med 2007; 85: 1175-1186.
17. Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol 2007; 170: 1445-1453.
18. Watanabe K, Tachibana O, Sata K et al. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 1996; 6: 217-224.
19. Korshunov A, Golanov A, Sycheva R. Immunohistochemical markers for prognosis of cerebral glioblastomas. J Neuro-Oncol 2002; 58: 217-236.
20. Birner P, Piribauer M, Fischer I et al. Vascular patterns in glioblastoma influence clinical outcome and associate with variable expression of angiogenic proteins: evidence for distinct angiogenic subtypes. Brain Pathol 2003; 13: 133-143.
21. Leon SP, Folkerth RD, Black PM. Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 1996; 77: 362-372.
22. Hegi ME, Diserens AC, Gorlia T et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352: 997-1003.
23. Wang X, Chen JX, Liu JP et al. Gain of function of mutant TP53 in glioblastoma: prognosis and response to temozolomide. Ann Surg Oncol 2014; 21: 1337-1344.
24. Furnari FB, Fenton T, Bachoo RM et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 2007; 21: 2683-2710.
25. Sharma S, Sharma MC, Gupta DK et al. Angiogenic patterns and their quantification in high grade astrocytic tumors. J Neuro-Oncol 2006; 79: 19-30.
26. Zhang JF, Chen Y, Qiu XX et al. The vascular delta-like ligand-4 (DLL4)-Notch4 signaling correlates with angiogenesis in primary glioblastoma: an immunohistochemical study. Tumor Biol 2016; 37: 3797-3805.
27. Kiesel B, Mischkulnig M, Woehrer A et al. Systematic histopathological analysis of different 5-aminolevulinic acid-induced fluorescence levels in newly diagnosed glioblastomas. J Neurosurg 2018; 129: 341-353.
28. Heesters MA, Koudstaal J, Go KG et al. Analysis of proliferation and apoptosis in brain gliomas: prognostic and clinical value. J Neuro-Oncol 1999; 44: 255-266.
29. Preusser M, Gelpi E, Matej R et al. No prognostic impact of survivin expression in glioblastoma. Acta Neuropathol 2005; 109: 534-538.
30. Moskowitz SI, Jin T, Prayson RA. Role of MIB1 in predicting survival in patients with glioblastomas. J Neurooncol 2006; 76:193-200.
31.Johannessen AL, Torp SH. The clinical value of Ki-67/MIB-1 labeling index in human astrocytomas. Pathol Oncol Res 2006; 12: 143-147.
32. Wesseling P, Van Der Laak J, Link M et al. Quantitative analysis of microvascular changes in diffuse astrocytic neoplasms with increasing grade of malignancy. Human Pathol 1998; 29: 352-358.
33. England B, Huang T, Karsy M. Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme. Tumor Biol 2013; 34: 2063-2074
34. Ohgaki H, Dessen P, Jourde B et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res 2004; 64: 6892-6899.
35. Kawasoe T, Takeshima H, Yamashita S et al. Detection of p53 mutations in proliferating vascular cells in glioblastoma multiforme. J Neurosurg 2015; 122: 317-323.
36. Zhang Y, Dube C, Gilbert M Jr. et al. The p53 pathway in glioblastoma. Cancers 2018; 10: 297; doi:10.3390/cancers 10090297.
37. Berger B, Capper D, Lemke D et al. Defective p53 antiangiogenic signaling in glioblastoma. Neuro-Oncol 2010; 12: 894-907.
38. Gaiser T, Becker MR, Meyer J et al. p53-mediated inhibition of angiogenesis in diffuse low-grade astrocytomas. Neurochem Int 2009; 54: 458-463.
39. Birlik B, Canda S, Ozer E. Tumour vascularity is of prognostic significance in adult, but not paediatric astrocytomas. Neuropathol Appl Neurobiol 2006; 32: 532-538.
40. Zhen HN, Zhang X, Hu PZ et al. Survivin expression and its relation with proliferation, apoptosis and angiogenesis in brain gliomas. Cancer 2005; 104: 2775-2783.
41. Korkolopoulou P, Patsouris E, Kavantzas N et al. Prognostic implications of microvessel morphometry in diffuse astrocytic neoplasms. Neuropathol Appl Neurobiol 2002; 28: 57-66.
42. Preusser M, Heinzl H, Gelpi E et al. Histopathologic assessment of hot-spot microvessel density and vascular patterns in glioblastoma: poor observer agreement limits clinical utility as prognostic factors: a translational research project of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Cancer 2006; 107: 162-170.
43. Liu X, Zhang Q, Mu Y et al. Clinical significance of vasculogenic mimicry in human gliomas. J Neurooncol 2011; 105: 173-179.
44. Yu JL, Rak JW, Coomber BL et al. Effect of p53 status on tumor response to antiangiogenic therapy. Science 2002; 295: 1526-1528.
45. Lu-Emerson C, Duda DG, Emblem KE et al. Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma. J Clin Oncol 2015; 33:1197-1213.
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2025/11/19
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Rubrika
Originalni rad / Original article