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Increased STAT-3 and synchronous activation of Raf-1-MEK-1-MAPK, and phosphatidylinositol 3-Kinase-Akt-mTOR pathways in atypical and anaplastic meningiomas

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Abstract

The intracellular events promoting meningioma cell proliferation in high grade tumors are not established. In this study we compared 45 WHO grade I and 35 grade II or III meningiomas by Western blot or immunohistochemistry for phosphorylation/activation of the MEK-1-MAPK, PI3 K-Akt-mTOR-PRAS40 and STAT3 pathways. By Western blot, STAT3 activation was detected in 75% of grade I compared to 100% of grade II and III meningiomas. By immunohistochemistry p-STAT3 was detected in 28% of grade I compared to 65 or 66% of grade II and III meningiomas, respectively. Phosphorylated MEK-1 and p-MAPK were activated in nearly all grade I, II and III tumors. Phosphorylated Akt was also detected in the majority of meningiomas of each grade although downstream pathway component activation was less widespread. These findings suggest that there is increased STAT3 activation in WHO grade II and III meningiomas compared with grade I tumors. Moreover, each of the three major growth regulatory pathways is concomitantly activated in higher grade meningiomas.

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References

  1. Johnson M, Toms S (2006) Mitogenic signal transduction pathways in meningiomas: novel targets for meningioma chemotherapy? J Neuropathol Exp Neurol 64:1029–1036. doi:10.1097/01.jnen.0000189834.63951.81

    Article  Google Scholar 

  2. Norden AD, Drappatz J, Wen PY (2007) Targeted drug therapy for meningiomas. Neurosurg Focus 23:1–12. doi:10.3171/FOC-07/10/E12

    Article  Google Scholar 

  3. Johnson MD, Horiba M, Arteaga C (1994) The epidermal growth factor receptor is associated with phospholipase C γ in meningiomas. Hum Pathol 25:146–153. doi:10.1016/0046-8177(94)90270-4

    Article  PubMed  CAS  Google Scholar 

  4. Johnson MD, Woodard A, Kim P, Frexes-Steed M (2001) Evidence for mitogen associated protein kinase activation and transduction of mitogenic signals from platelet derived growth factor in human meningioma cells. J Neurosurg 94:303–310

    Google Scholar 

  5. Johnson MD, Okediji E, Woodard A, Toms SA (2002) Evidence for phosphatidylinositol 3-kinase Akt-p70S6K pathway activation and transduction of mitogenic signals by platelet derived growth factor in human meningioma cells. J Neurosurg 97:668–675

    PubMed  CAS  Google Scholar 

  6. Bromberg J (2002) STAT proteins and oncogenesis. J Clin Invest 109:1139–1142

    PubMed  CAS  Google Scholar 

  7. Johanson CE, Duncan JA III, Klinge PM, Brinker T, Stopa EG, Silverberg GD (2008) Multiplicity of cerebrospinal fluid functions: New challenges in health and Disease. Cerebrospinal Fluid Res 5:10. doi:10.1186/1743-8454-5-10

    Article  PubMed  CAS  Google Scholar 

  8. Jones NR, Rossi ML, Gregoriou M, Hughes JT (1990) Epidermal growth factor receptor expression in 72 meningiomas. Cancer 66:152–155. doi:10.1002/1097-0142(19900701)66:1<152::AID-CNCR2820660127>3.0.CO;2-5

    Article  PubMed  CAS  Google Scholar 

  9. Weisman AS, Raguet SS, Kelly PA (1987) Characterization of the epidermal growth factor receptor in human meningioma. Cancer Res 47:2172–2176

    PubMed  CAS  Google Scholar 

  10. Maxwell M, Galanopoulos T, Hedley-Whyte ET, Black PML, Antoniades HN (1990) Human meningiomas co-express platelet-derived growth factor (PDGF) and PDGF-receptor genes and their protein products. Int J Cancer 46:16–21. doi:10.1002/ijc.2910460106

    Article  PubMed  CAS  Google Scholar 

  11. Shamah SM, Alberta JA, Giannobile WV, Guha A, Kwon YK, Carroll RS, Black PM, Stiles CD et al (1997) Detection of activated platlet-derived growth factor receptors in human meningioma. Cancer Res 57:4141–4147

    PubMed  CAS  Google Scholar 

  12. Adams EF, Schrell UMH, Thieruf P, White MC, Fahlbusch R (1991) Autocrine control of human meningioma proliferation: secretion of platelet-derived growth factor-like molecules. Int J Cancer 49:398–402. doi:10.1002/ijc.2910490315

    Article  PubMed  CAS  Google Scholar 

  13. Nordqvist AC, Peyrard M, Petterson H et al (1997) A high ratio of insulin-like growth factor II/insulin-like growth factor binding protein 2 messenger RNA as a marker for anaplasia in meningiomas. Cancer Res 57:2611–2614

    PubMed  CAS  Google Scholar 

  14. Watson MA, Gutmann DH, Peterson K et al (2002) Molecular characterization of human meningiomas by gene expression profiling using high-density oligonucleotide microarrays. Am J Pathol 161:665–672

    PubMed  CAS  Google Scholar 

  15. Magrassi L, De-Fraja C, Conti L, Butti G, Infuso L, Govoni S et al (1999) Expression of the JAK and STAT superfamilies in human meningiomas. J Neurosurg 91:440–446

    Article  PubMed  CAS  Google Scholar 

  16. Mawrin C, Sasse T, Kirches E, Kropf S, Schneider T, Grimm C et al (2005) Different activation of mitogen activated protein kinase and Akt signalling is associated with aggressive phenotype of human meningiomas. Clin Cancer Res 11:4074–4082. doi:10.1158/1078-0432.CCR-04-2550

    Article  PubMed  CAS  Google Scholar 

  17. Perry A, Louis DN, Scheithauer BW, Budka H, von Deimling A (2007) Meningiomas. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) Tumours of the nervous system. WHO Press, Geneva, Switzerland, pp 164–172

    Google Scholar 

  18. Klampfer L (2006) Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs. Curr Cancer Drug Targets 6:107–121. doi:10.2174/156800906776056491

    Article  PubMed  CAS  Google Scholar 

  19. Kortylewski M, Hua Y (2007) Stat3 as a potential target for cancer immunotherapy. J Immunother 30:131–139. doi:10.1097/01.cji.0000211327.76266.65

    Article  PubMed  CAS  Google Scholar 

  20. Germain D, Frank DA (2007) Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. Clin Cancer Res 13:5665–5669. doi:10.1158/1078-0432.CCR-06-2491

    Article  PubMed  CAS  Google Scholar 

  21. Silva CM (2004) Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene 23:8017–8023. doi:10.1038/sj.onc.1208159

    Article  PubMed  CAS  Google Scholar 

  22. Garcia R, Bowman TL, Niu G et al (2001) Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 20:2499–2513. doi:10.1038/sj.onc.1204349

    Article  PubMed  CAS  Google Scholar 

  23. Kohno M, Pouyssegur J (2006) Targeting the ERK signaling pathway in cancer therapy. Ann Med 38:200–211. doi:10.1080/07853890600551037

    Article  PubMed  CAS  Google Scholar 

  24. McKay MM, Morrison DK (2007) Integrating signals from RTKs to ERK/MAPK. Oncogene 26:3113–3121. doi:10.1038/sj.onc.1210394

    Article  PubMed  CAS  Google Scholar 

  25. Yoon S, Seger R (2006) The extracellular signal-regulated-kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24:21–44. doi:10.1080/02699050500284218

    Article  PubMed  CAS  Google Scholar 

  26. Barnett SF, Bilodeau MT, Lindsley CW (2005) The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress toward target validation. Curr Top Med Chem 5:109–125. doi:10.2174/1568026053507714

    Article  PubMed  CAS  Google Scholar 

  27. Shayesteh L, Lu Y, Kuo W-L, Baldocchi R, Godfrey T, Collins C et al (1999) PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21:99–102. doi:10.1038/5042

    Article  PubMed  CAS  Google Scholar 

  28. Sun M, Wang G, Paciga JE, Feldman RI, Yuan ZQ, Ma XL et al (2001) AKT1/PKB alpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am J Pathol 159:431–437

    PubMed  CAS  Google Scholar 

  29. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Cell Signal 14:381–395. doi:10.1016/S0898-6568(01)00271-6

    Article  Google Scholar 

  30. Crowell JA, Steele VE, Fay JR (2007) Targeting the Akt protein kinase for cancer prevention. Mol Cancer Ther 6:2319–2418. doi:10.1158/1535-7163.MCT-07-0120

    Article  Google Scholar 

  31. Brognard J, Clark AS, Ni Y, Dennis PA (2001) Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 61:3986–3997

    PubMed  CAS  Google Scholar 

  32. Roymans D, Slegers H (2001) Phosphatidylinositol 3-kinases in tumor progression. Eur J Biochem 268:487–498. doi:10.1046/j.1432-1327.2001.01936.x

    Article  PubMed  CAS  Google Scholar 

  33. Kovacina KS et al (2003) Identification of a praline rich Akt substrate as a 14-3-3 binding partner. J Biol Chem 278:10189–10194. doi:10.1074/jbc.M210837200

    Article  PubMed  CAS  Google Scholar 

  34. Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N (2006) MTOR, translation intiation and cancer. Oncogene 25:6416–6422. doi:10.1038/sj.onc.1209888

    Article  PubMed  CAS  Google Scholar 

  35. Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Natl Rev 6:729–734

    CAS  Google Scholar 

  36. Arteaga CL (2002) Epidermal growth factor dependence in human tumors: more than just expression? Oncologist 7:31–39. doi:10.1634/theoncologist.7-suppl_4-31

    Article  PubMed  CAS  Google Scholar 

  37. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Herman P et al (2004) EGFR mutations in lung cancer: correlation with clinical response to Gefitinib therapy. Science 304:1497–1500. doi:10.1126/science.1099314

    Article  PubMed  CAS  Google Scholar 

  38. Witzig TE, Kaufmann SH (2006) Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol 7:285–294. doi:10.1007/s11864-006-0038-1

    Article  PubMed  Google Scholar 

  39. Madhunapantula SV, Sharma A, Robertson GP (2007) PRAS40 deregulates apoptosis in malignant melanoma cells. Cancer Res 67:3626–3636. doi:10.1158/0008-5472.CAN-06-4234

    Article  PubMed  CAS  Google Scholar 

  40. Gire V, Marshall C, Wynford-Thomas D (2000) PI-3-kinase is an essential anti-apoptotic effector in the proliferative response of primary human epithelial cells to mutant RAS. Oncogene 19:2269–2276. doi:10.1038/sj.onc.1203544

    Article  PubMed  CAS  Google Scholar 

  41. Walker TR, Moore SM, Lawson MF, Panettieri RA, Chilvers ER (1998) Platelet-derived growth factor-BB and thrombin activate phophoinositide 3-kinase and protein kinase B: role in mediating airway smooth muscle proliferation. Mol Pharmacol 54:1007–1015

    PubMed  CAS  Google Scholar 

  42. Faivre S, Djelloul S, Raymond E (2006) New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors. Semin Oncol 33:407–420. doi:10.1053/j.seminoncol.2006.04.005

    Article  PubMed  CAS  Google Scholar 

  43. Stommel JM, Kimmelman AC, Ying H et al (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287–290. doi:10.1126/science.1142946

    Article  PubMed  CAS  Google Scholar 

  44. Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D et al (2007) Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of heptocellular carcinomas cells. Cancer Res 67:2497–2507. doi:10.1158/0008-5472.CAN-06-3075

    Article  PubMed  CAS  Google Scholar 

  45. Nakamura JL, Karlsson A, Arvold ND, Gottschalk Ar, Pieper RO, Stokoe D et al (2005) PKB/Akt mediates radiosensitization by signaling inhibitor LY294002 in human malignant gliomas. J Neurooncol 71:215–222. doi:10.1007/s11060-004-1718-y

    Article  PubMed  CAS  Google Scholar 

  46. Wang MY, Lu KV, Dia EQ et al (2006) Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN intact glioblastoma cells. Cancer Res 66:7864–7869. doi:10.1158/0008-5472.CAN-04-4392

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Neuropathology, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Box 626, Rochester, NY, 14642, USA

    Mahlon D. Johnson, Mary O’Connell & Fran Vito

  2. Neurological Surgery, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    Robert S. Bakos

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  1. Mahlon D. Johnson
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Correspondence to Mahlon D. Johnson.

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Johnson, M.D., O’Connell, M., Vito, F. et al. Increased STAT-3 and synchronous activation of Raf-1-MEK-1-MAPK, and phosphatidylinositol 3-Kinase-Akt-mTOR pathways in atypical and anaplastic meningiomas. J Neurooncol 92, 129–136 (2009). https://doi.org/10.1007/s11060-008-9746-7

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  • DOI: https://doi.org/10.1007/s11060-008-9746-7

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