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Key rates for the grades and transformation ability of glioma: model simulations and clinical cases

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Abstract

Tumor progression to higher grade is a fundamental property of cancer. The malignant advancement of the pathological features may either develop during the later stages of cancer growth (natural evolution) or it may necessitate new mutations or molecular events that alter the rates of growth, dispersion, or neovascularization (transformation). Here, we model the pathological and radiological features of grades 2–4 gliomas at the times of diagnosis and death and study grade development and the progression to higher grades. We perform a retrospective review of clinical cases based on model predictions. Simulations uncover two unusual patterns of glioma progression, which are supported by clinical cases: (1) some grades 2 and 3 gliomas lack the ability of progression to higher grades, and (2) grade 3 glioma may evolve to GBM in a few weeks. All 13 gliomas that recurred at the same grade carry either the IDH1-R132H or the ATRX mutation. All (five of five) grade 3 tumors are 1p/19q co-deleted, IDH1-R132H mutated and ATRX wt. Furthermore, three of seven grade 2 gliomas are both IDH1-R132H mutated and ATRX mutated. Simulations replicate the good prognosis of secondary GBM. The results support the hypothesis that constant rates of dispersion, proliferation, and angiogenesis prescribe either a natural evolution or the inability to progress to higher grades. Furthermore, the accrual of molecular events that change a tumor’s ability to infiltrate, proliferate or neovascularize may transform the glioma either into a more aggressive tumor at the same grade or elevate its grade.

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References

  1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109

    Article  PubMed  PubMed Central  Google Scholar 

  2. Johannessen AL, Torp SH (2006) The clinical value of Ki-67/MIB-1 labeling index in human astrocytomas. Pathol Oncol Res 12(3):143–147

    Article  PubMed  Google Scholar 

  3. Neder L, Colli BO, Machado HR, Carlotti CG, Santos AC, Chimelli L (2004) MIB-1 labeling index in astrocytic tumors—a clinicopathologic study. Clin Neuropathol 23(6):262–270

    CAS  PubMed  Google Scholar 

  4. Shelton LM, Mukherjee P, Huysentruyt LC, Urits I, Rosenberg JA, Seyfried TN (2010) A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion. J Neurooncol 99(2):165–176

    Article  CAS  PubMed  Google Scholar 

  5. Candolfi M, Curtin JF, Nichols WS, Muhammad AG, King GD, Pluhar GE et al (2007) Intracranial glioblastoma models in preclinical neuro-oncology: neuropathological characterization and tumor progression. J Neurooncol 85(2):133–148

    Article  PubMed  PubMed Central  Google Scholar 

  6. Tang Z, Araysi L, Fathallah-Shaykh HM (2013) c-Src and neural Wiskott-Aldrich syndrome protein (N-WASP) promote low oxygen-induced accelerated brain invasion by gliomas. PLoS ONE 8(9):e75436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Scribner E, Saut O, Province P, Bag A, Colin T et al (2014) Glioblastoma grows during anti-angiogenesis: model to clinical predictions. PLoS ONE 9(12):e115018

    Article  PubMed  PubMed Central  Google Scholar 

  8. Raman F, Scribner E, Saut O, Wenger C, Colin T, Fathallah-Shaykh HM (2016) Computational trials: unraveling motility phenotypes, progression patterns, and treatment options for glioblastoma multiforme. PLoS ONE 11(1):e0146617

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML, Cavanee W, Vogelstein B (1992) Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 355(6363):846–847

    Article  CAS  PubMed  Google Scholar 

  10. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897):1807–1812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, Cooper LA et al (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372(26):2481–2498

    Article  CAS  PubMed  Google Scholar 

  13. Shohat O, Greenberg M, Reisman D, Oren M, Rotter V (1987) Inhibition of cell growth mediated by plasmids encoding p53 anti-sense. Oncogene 1(3):277–283

    CAS  PubMed  Google Scholar 

  14. Sager R (1989) Tumor suppressor genes: the puzzle and the promise. Science 246(4936):1406–1412

    Article  CAS  PubMed  Google Scholar 

  15. Eliyahu D, Raz A, Gruss P, Givol D, Oren M (1984) Participation of p53 cellular tumour antigen in transformation of normal embryonic cells. Nature 312(5995):646–649

    Article  CAS  PubMed  Google Scholar 

  16. Jenkins JR, Rudge K, Currie GA (1984) Cellular immortalization by a cDNA clone encoding the transformation-associated phosphoprotein p53. Nature 312(5995):651–654

    Article  CAS  PubMed  Google Scholar 

  17. Burdelya LG, Komarova EA, Hill JE, Browder T, Tararova ND, Mavrakis L et al (2006) Inhibition of p53 response in tumor stroma improves efficacy of anticancer treatment by increasing antiangiogenic effects of chemotherapy and radiotherapy in mice. Cancer Res 66(19):9356–9361

    Article  CAS  PubMed  Google Scholar 

  18. Tse V, Yung Y, Santarelli JG, Juan D, Hsiao M, Haas M et al (2004) Effects of tumor suppressor gene (p53) on brain tumor angiogenesis and expression of angiogenic modulators. Anticancer Res 24(1):1–10

    CAS  PubMed  Google Scholar 

  19. Duda DG, Sunamura M, Lozonschi L, Yokoyama T, Yatsuoka T, Motoi F et al (2002) Overexpression of the p53-inducible brain-specific angiogenesis inhibitor 1 suppresses efficiently tumour angiogenesis. Br J Cancer 86(3):490–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang L, Yu D, Hu M, Xiong S, Lang A, Ellis LM et al (2000) Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. Cancer Res 60(13):3655–3661

    CAS  PubMed  Google Scholar 

  21. Mukhopadhyay D, Tsiokas L, Sukhatme VP (1995) Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res 55(24):6161–6165

    CAS  PubMed  Google Scholar 

  22. Sundaram P, Hultine S, Smith LM, Dews M, Fox JL, Biyashev D et al (2011) p53-responsive miR-194 inhibits thrombospondin-1 and promotes angiogenesis in colon cancers. Cancer Res 71(24):7490–7501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yamakuchi M, Lotterman CD, Bao C, Hruban RH, Karim B, Mendell JT et al (2010) P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis. Proc Natl Acad Sci USA 107(14):6334–6339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Oda S, Oda T, Nishi K, Takabuchi S, Wakamatsu T, Tanaka T et al (2008) Macrophage migration inhibitory factor activates hypoxia-inducible factor in a p53-dependent manner. PLoS ONE 3(5):e2215

    Article  PubMed  PubMed Central  Google Scholar 

  25. Van Meir EG, Polverini PJ, Chazin VR, Su Huang HJ, de Tribolet N, Cavenee WK (1994) Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nat Genet 8(2):171–176

    Article  PubMed  Google Scholar 

  26. Toschi E, Rota R, Antonini A, Melillo G, Capogrossi MC (2000) Wild-type p53 gene transfer inhibits invasion and reduces matrix metalloproteinase-2 levels in p53-mutated human melanoma cells. J Invest Dermatol 114(6):1188–1194

    Article  CAS  PubMed  Google Scholar 

  27. Karamitopoulou E, Perentes E, Diamantis I, Maraziotis T (1994) Ki-67 immunoreactivity in human central nervous system tumors: a study with MIB 1 monoclonal antibody on archival material. Acta Neuropathol 87(1):47–54

    Article  CAS  PubMed  Google Scholar 

  28. Nowosielski M, Wiestler B, Goebel G, Hutterer M, Schlemmer HP, Stockhammer G et al (2014) Progression types after antiangiogenic therapy are related to outcome in recurrent glioblastoma. Neurology 82(19):1684–1692

    Article  CAS  PubMed  Google Scholar 

  29. Scribner E, Fathallah-Shaykh HM (2017) Single cell mathematical model successfully replicates key features of GBM: go-or-grow is not necessary. PLoS ONE 12(1):e0169434

    Article  PubMed  PubMed Central  Google Scholar 

  30. Sant M, Crosignani P, Bordo BM, Nicola G, Bianchi M, Berrino F (1988) Incidence and survival of brain tumors: a population-based study. Tumori 74(3):243–252

    CAS  PubMed  Google Scholar 

  31. Ullen H, Mattsson B, Collins VP (1990) Long-term survival after malignant glioma. A clinical and histopathological study on the accuracy of the diagnosis in a population-based cancer register. Acta Oncol 29(7):875–878

    Article  CAS  PubMed  Google Scholar 

  32. Kallio M, Sankila R, Jaaskelainen J, Karjalainen S, Hakulinen T (1991) A population-based study on the incidence and survival rates of 3857 glioma patients diagnosed from 1953 to 1984. Cancer 68(6):1394–1400

    Article  CAS  PubMed  Google Scholar 

  33. Sant M, van der Sanden G, Capocaccia R (1998) Survival rates for primary malignant brain tumours in Europe. Eur J Cancer 34(14):2241–2247

    Article  CAS  PubMed  Google Scholar 

  34. Okamoto Y, Di Patre PL, Burkhard C, Horstmann S, Jourde B, Fahey M et al (2004) Population-based study on incidence, survival rates, and genetic alterations of low-grade diffuse astrocytomas and oligodendrogliomas. Acta Neuropathol 108(1):49–56

    Article  PubMed  Google Scholar 

  35. Ohgaki H, Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64(6):479–489

    Article  CAS  PubMed  Google Scholar 

  36. Ohgaki H, Kleihues P (2013) The definition of primary and secondary glioblastoma. Clin Cancer Res 19(4):764–772

    Article  CAS  PubMed  Google Scholar 

  37. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O et al (2012) IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483(7390):474–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C et al (2013) An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340(6132):626–630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bralten LB, Kloosterhof NK, Balvers R, Sacchetti A, Lapre L, Lamfers M et al (2011) IDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo. Ann Neurol 69(3):455–463

    Article  CAS  PubMed  Google Scholar 

  40. Cui D, Ren J, Shi J, Feng L, Wang K, Zeng T et al (2016) R132H mutation in IDH1 gene reduces proliferation, cell survival and invasion of human glioma by downregulating Wnt/\(\beta\)-catenin signaling. Int J Biochem Cell Biol 73:72–81

    Article  CAS  PubMed  Google Scholar 

  41. Bai H, Harmancı AS, Erson-Omay EZ, Li J, Coçkun S, Simon M et al (2016) Integrated genomic characterization of IDH1-mutant glioma malignant progression. Nat Genet 48(1):59–66

    Article  CAS  PubMed  Google Scholar 

  42. Ichikawa T, Otani Y, Kurozumi K, Date I (2016) Phenotypic transition as a survival strategy of glioma. Neurol Med Chir 56(7):387–395

    Article  Google Scholar 

  43. Stojković S, Podolski-Renić A, Dinić J, Pavković Ž, Ayuso JM, Fernández LJ (2016) Resistance to DNA damaging agents produced invasive phenotype of rat glioma cells-characterization of a new in vivo model. Molecules 21(7):843

    Article  Google Scholar 

  44. Saito R, Bringas J, Mirek H, Berger MS, Bankiewicz KS (2004) Invasive phenotype observed in 1,3-bis(2-chloroethyl)-1-nitrosourea-resistant sublines of 9L rat glioma cells: a tumor model mimicking a recurrent malignant glioma. J Neurosurg 101(5):826–831

    Article  PubMed  Google Scholar 

  45. Kegelman TP, Wu B, Das SK, Talukdar S, Beckta JM, Hu B, et al (2016) Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin. Proc Natl Acad Sci USA. doi:10.1073/pnas.1616100114

  46. Heaphy CM, Subhawong AP, Hong SM, Goggins MG, Montgomery EA, Gabrielson E et al (2011) Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am J Pathol 179(4):1608–1615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ et al (2015) Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 347(6219):273–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Henson JD, Hannay JA, McCarthy SW, Royds JA, Yeager TR, Robinson RA et al (2005) A robust assay for alternative lengthening of telomeres in tumors shows the significance of alternative lengthening of telomeres in sarcomas and astrocytomas. Clin Cancer Res 11(1):217–225

    CAS  PubMed  Google Scholar 

  49. Henson JD, Reddel RR (2010) Assaying and investigating alternative lengthening of telomeres activity in human cells and cancers. FEBS Lett 584(17):3800–3811

    Article  CAS  PubMed  Google Scholar 

  50. Lovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J, de Lange T et al (2012) Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet 8(7):e1002772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Koschmann C, Lowenstein PR, Castro MG (2016) ATRX mutations and glioblastoma: impaired DNA damage repair, alternative lengthening of telomeres, and genetic instability. Mol Cell Oncol 3(3):e1167158

    Article  PubMed  PubMed Central  Google Scholar 

  52. Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA et al (2016) Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164(3):550–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Koschmann C, Calinescu AA, Nunez FJ, Mackay A, Fazal-Salom J, Thomas D (2016) ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. Sci Transl Med 8(328):328ra28

    Article  PubMed  PubMed Central  Google Scholar 

  54. Cai J, Zhang C, Zhang W, Wang G, Yao K, Wang Z et al (2016) ATRX, IDH1-R132H and Ki-67 immunohistochemistry as a classification scheme for astrocytic tumors. Oncoscience 3(7–8):258–265

    PubMed  PubMed Central  Google Scholar 

  55. Ebrahimi A, Skardelly M, Bonzheim I, Ott I, Muhleisen H, Eckert F et al (2016) ATRX immunostaining predicts IDH and H3F3A status in gliomas. Acta Neuropathol Commun 4(1):60

    Article  PubMed  PubMed Central  Google Scholar 

  56. Venneti S, Huse JT (2015) The evolving molecular genetics of low-grade glioma. Adv Anat Pathol 22(2):94–101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Cai J, Chen J, Zhang W, Yang P, Zhang C, Li M et al (2015) Loss of ATRX, associated with DNA methylation pattern of chromosome end, impacted biological behaviors of astrocytic tumors. Oncotarget 6(20):18105–18115

    Article  PubMed  PubMed Central  Google Scholar 

  58. Shao LW, Pan Y, Qi XL, Li YX, Ma XL, Yi WN et al (2016) ATRX loss in adult supratentorial diffuse astrocytomas correlates with p53 over expression and IDH1 mutation and predicts better outcome in p53 accumulated patients. Histol Histopathol 31(1):103–114

    CAS  PubMed  Google Scholar 

  59. Leeper HE, Caron AA, Decker PA, Jenkins RB, Lachance DH, Giannini C (2015) IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas. Oncotarget 6(30):30295–30305

    Article  PubMed  PubMed Central  Google Scholar 

  60. Takano S, Ishikawa E, Sakamoto N, Matsuda M, Akutsu H, Noguchi M et al (2016) Immunohistochemistry on IDH 1/2, ATRX, p53 and Ki-67 substitute molecular genetic testing and predict patient prognosis in grade III adult diffuse gliomas. Brain Tumor Pathol 33(2):107–116

    Article  CAS  PubMed  Google Scholar 

  61. Giese A, Loo MA, Tran N, Haskett D, Coons SW, Berens ME (1996) Dichotomy of astrocytoma migration and proliferation. Int J Cancer 67(2):275–282

    Article  CAS  PubMed  Google Scholar 

  62. Hatzikirou H, Basanta D, Simon M, Schaller K, Deutsch A (2012) ’Go or grow’: the key to the emergence of invasion in tumour progression? Math Med Biol 29(1):49–65

    Article  CAS  PubMed  Google Scholar 

  63. Dhruv HD, McDonough Winslow WS, Armstrong B, Tuncali S, Eschbacher J, Kislin K et al (2013) Reciprocal activation of transcription factors underlies the dichotomy between proliferation and invasion of glioma cells. PLoS ONE 8(8):e72134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Xie Q, Mittal S, Berens ME (2014) Targeting adaptive glioblastoma: an overview of proliferation and invasion. Neuro-oncology 16(12):1575–1584

    Article  PubMed  PubMed Central  Google Scholar 

  65. Gao C, Furge K, Koeman J, Dykema K, Su Y, Cutler ML et al (2007) Chromosome instability, chromosome transcriptome, and clonal evolution of tumor cell populations. Proc Natl Acad Sci USA 104(21):8995–9000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research was approved by the Institutional Review Board of the University of Alabama at Birmingham. Waiver of informed consent was granted because the research involves no greater than minimal risk and no procedures for which written consent is normally required outside the research context.

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Authors and Affiliations

  1. Department of Neurology, The University of Alabama, Birmingham, AL, USA

    Elizabeth Scribner, Hannah C. Machemehl, Reina Afiouni, Krishna R. Patel & Hassan M. Fathallah-Shaykh

  2. Department of Pathology, The University of Alabama, Birmingham, AL, USA

    James R. Hackney

  3. Department of Mathematics, The University of Alabama, Birmingham, AL, USA

    Elizabeth Scribner & Hassan M. Fathallah-Shaykh

  4. Division of Neuro-Oncology, The University of Alabama at Birmingham, 510 20th Street South, FOT 1020, Birmingham, AL, 35295, USA

    Hassan M. Fathallah-Shaykh

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  1. Elizabeth Scribner
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Correspondence to Hassan M. Fathallah-Shaykh.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Scribner, E., Hackney, J.R., Machemehl, H.C. et al. Key rates for the grades and transformation ability of glioma: model simulations and clinical cases. J Neurooncol 133, 377–388 (2017). https://doi.org/10.1007/s11060-017-2444-6

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