Vascularization, proliferative activity and the p53 status in glioblastomas
Keywords:
glioblastoma, microvessel density, angiogenesis, immunohistochemistry, MIB-1 proliferation index, p53
Abstract
Introduction/Aim. Glioblastomas (GBMs) are among the most vascularized human tumors and the presence of microvascular proliferation is one of the diagnostic hallmarks of these malignancies. The aim of the present study was to investigate the extent of vascularization and its relation to proliferative activity and p53 status in GBMs.
Methods: Tissue samples from 100 selected primary GBMs were analyzed by immunohistochemistry for expression of CD34 in vascular endothelial cells and Ki-67 antigen (using the MIB-1 antibody) and p53 in tumor cells. The microvessel density (MVD), a measure of the extent of tumor vascularization, was evaluated in CD34-immunostained sections in three hot spots and presented as the mean for each tumor specimen.
Results: We found that the high MVD was more frequent in tumors showing the high MIB-1 LI as compared to those with the low MIB-1 LI, but the difference was not statistically significant. Also, the extent of vascularization did not differ significantly between p53-negative and p53-positive tumors. Both the level of MVD and the proportion of GBMs with low versus high MVD did not differ significantly in relation to the expression levels of p53 (low vs. high or overexpression). No association was found between MVD and tumor cell MIB-1 LI and the p53 status in primary GBMs.
Conclusion: These data suggest that the effect of p53 on primary GBM vascularization failed to detect possibly because the influence of certain factors, including the presence of other or additional molecular alterations in the tumor cells and the hypoxic microenvironment of tumors.
References
1. Ostrom QT, Gittleman H, Liao P et al. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro- Oncol 2017; 19: 1-88.
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.
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.
Published
2025/11/19
Section
Originalni rad / Original article