Neurosurgical Review

, Volume 41, Issue 4, pp 931–944 | Cite as

Vascular hyperpermeability as a hallmark of phacomatoses: is the etiology angiogenesis related to or comparable with mechanisms seen in inflammatory pathways? Part II: angiogenesis- and inflammation-related molecular pathways, tumor-associated macrophages, and possible therapeutic implications: a comprehensive review

  • Yosef LavivEmail author
  • Burkhard Kasper
  • Ekkehard M. Kasper


Phacomatoses are a special group of familial hamartomatous syndromes with unique neurocutaneous manifestations as well as characteristic tumors. Neurofibromatosis type 2 (NF2) and tuberous sclerosis complex (TSC) are representatives of this family. A vestibular schwannoma (VS) and subependymal giant cell tumor (SGCT) are two of the most common intracranial tumors associated with these syndromes, related to NF2 and TSC, respectively. These tumors can present with an obstructive hydrocephalus due to their location adjacent to or in the ventricles. Remarkably, both tumors are also known to have a unique association with elevated protein concentrations in the cerebrospinal fluid (CSF), sometimes in association with a non-obstructive (communicating) hydrocephalus. Of the two, SGCT has been shown to be associated with a predisposition to CSF clotting, causing a debilitating recurrent shunt obstruction. However, the exact relationship between high protein levels and clotting of CSF remains unclear, nor do we understand the precise mechanism of CSF clotting observed in SGCT. Elevated protein levels in the CSF are thought to be caused by increased vascular permeability and dysregulation of the blood–brain barrier. The two presumed underlying pathophysiological processes for that in the context of tumorigenesis are angiogenesis and inflammation. Both these processes are correlated to the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin pathway which is tumorigenesis related in many neoplasms and nearly all phacomatoses. In this review, we discuss the influence of angiogenesis and inflammation pathways on vascular permeability in VSs and SGCTs at the phenotypic level as well as their possible genetic and molecular determinants. Part I described the historical perspectives and clinical aspects of the relationship between vascular permeability, abnormal CSF protein levels, clotting of the CSF, and communicating hydrocephalus. Part II hereafter describes the different cellular and molecular pathways involved in angiogenesis and inflammation observed in both tumors and explores the existing metabolic overlap between inflammation and coagulation. Interestingly, while increased angiogenesis can be observed in both tumors, inflammatory processes seem significantly more prominent in SGCT. Both SGCT and VS are characterized by different subgroups of tumor-associated macrophages (TAMs): the pro-inflammatory M1 type is predominating in SGCTs, while the pro-angiogenetic M2 type is predominating in VSs. We suggest that a lack of NF2 protein in VS and a lack of TSC1/TSC2 proteins in SGCT significantly influence this fundamental difference between the two tumor types by changing the dominant TAM type. Since inflammatory reactions and coagulation processes are tightly connected, the pro-inflammatory state of SGCT may also explain the associated tendency for CSF clotting. The underlying cellular and molecular differences observed can potentially serve as an access point for direct therapeutic interventions for tumors that are specific to certain phacomatoses or others that also carry such genetic changes.


Phacomatoses Tuberous sclerosis complex Vestibular schwannoma Tumor associated macrophages Vascular permeability 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


This work was not founded or financially supported.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Ethical approval

For this type of study, formal consent is not required.


  1. 1.
    Abbott NJ (2000) Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol Neurobiol 20:131–147PubMedCrossRefGoogle Scholar
  2. 2.
    Adams RA, Bauer J, Flick MJ, Sikorski SL, Nuriel T, Lassmann H, Degen JL, Akassoglou K (2007) The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med 204:571–582PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Adams RA, Passino M, Sachs BD, Nuriel T, Akassoglou K (2004) Fibrin mechanisms and functions in nervous system pathology. Mol Interv 4:163–176PubMedGoogle Scholar
  4. 4.
    Agnihotri S, Gugel I, Remke M, Bornemann A, Pantazis G, Mack SC, Shih D, Singh SK, Sabha N, Taylor MD et al (2014) Gene-expression profiling elucidates molecular signaling networks that can be therapeutically targeted in vestibular schwannoma. J Neurosurg 121:1434–1445PubMedCrossRefGoogle Scholar
  5. 5.
    Altomare DA, Testa JR (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24:7455–7464PubMedCrossRefGoogle Scholar
  6. 6.
    An J, Rettig MB (2005) Mechanism of von Hippel-Lindau protein-mediated suppression of nuclear factor kappa B activity. Mol Cell Biol 25:7546–7556PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Arbiser JL, Brat D, Hunter S, D’Armiento J, Henske EP, Arbiser ZK, Bai X, Goldberg G, Cohen C, Weiss SW (2002) Tuberous sclerosis-associated lesions of the kidney, brain, and skin are angiogenic neoplasms. J Am Acad Dermatol 46:376–380PubMedCrossRefGoogle Scholar
  8. 8.
    Atochina-Vasserman EN, Abramova E, James ML, Rue R, Liu AY, Ersumo NT, Guo CJ, Gow AJ, Krymskaya VP (2015) Pharmacological targeting of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis. Am J Physiol Lung Cell Mol Physiol 309:L1447–L1454PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Baek SY, Kim SU (1998) Proliferation of human Schwann cells induced by neu differentiation factor isoforms. Dev Neurosci 20:512–517PubMedCrossRefGoogle Scholar
  10. 10.
    Baggenstos MA, Butman JA, Oldfield EH, Lonser RR (2007) Role of edema in peritumoral cyst formation. Neurosurg Focus 22:E9PubMedCrossRefGoogle Scholar
  11. 11.
    Bardehle S, Rafalski VA, Akassoglou K (2015) Breaking boundaries—coagulation and fibrinolysis at the neurovascular interface. Front Cell Neurosci 9Google Scholar
  12. 12.
    Bates DO (2010) Vascular endothelial growth factors and vascular permeability. Cardiovasc Res 87:262–271PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Blakeley JO, Ye X, Duda DG, Halpin CF, Bergner AL, Muzikansky A, Merker VL, Gerstner ER, Fayad LM, Ahlawat S et al (2016) Efficacy and biomarker study of bevacizumab for hearing loss resulting from neurofibromatosis type 2-associated vestibular schwannomas. J Clin Oncol 14Google Scholar
  14. 14.
    Boer K, Jansen F, Nellist M, Redeker S, van den Ouweland AM, Spliet WG, van Nieuwenhuizen O, Troost D, Crino PB, Aronica E (2008) Inflammatory processes in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex. Epilepsy Res 78:7–21PubMedCrossRefGoogle Scholar
  15. 15.
    Bruce JN, Criscuolo GR, Merrill MJ, Moquin RR, Blacklock JB, Oldfield EH (1987) Vascular permeability induced by protein product of malignant brain tumors: inhibition by dexamethasone. J Neurosurg 67:880–884PubMedCrossRefGoogle Scholar
  16. 16.
    Brueton MJ, Breeze GR, Stuart J (1976) Fibrin-fibrinogen degradation products in cerebrospinal fluid. J Clin Pathol 29:341–344PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Brugarolas J, Kaelin WG Jr (2004) Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell 6:7–10PubMedCrossRefGoogle Scholar
  18. 18.
    Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG Jr (2003) TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4:147–158PubMedCrossRefGoogle Scholar
  19. 19.
    Byles V, Covarrubias AJ, Ben-Sahra I, Lamming DW, Sabatini DM, Manning BD, Horng T (2013) The TSC-mTOR pathway regulates macrophage polarization. Nat Commun 4Google Scholar
  20. 20.
    Cannarile MA, Ries CH, Hoves S, Ruttinger D (2014) Targeting tumor-associated macrophages in cancer therapy and understanding their complexity. Oncoimmunology 3:e955356 eCollection 952014 OctPubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Caye-Thomasen P, Werther K, Nalla A, Bog-Hansen TC, Nielsen HJ, Stangerup SE, Thomsen J (2005) VEGF and VEGF receptor-1 concentration in vestibular schwannoma homogenates correlates to tumor growth rate. Otol Neurotol 26:98–101PubMedCrossRefGoogle Scholar
  22. 22.
    Chai Q, He WQ, Zhou M, Lu H, Fu ZF (2014) Enhancement of blood-brain barrier permeability and reduction of tight junction protein expression are modulated by chemokines/cytokines induced by rabies virus infection. J Virol 88:4698–4710PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Chu AJ (2006) Role of tissue factor in thrombosis. Coagulation-inflammation-thrombosis circuit. Front Biosci 11:256–271PubMedCrossRefGoogle Scholar
  24. 24.
    Claesson-Welsh L (2015) Vascular permeability—the essentials. Ups J Med Sci 120:135–143PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Claesson-Welsh L, Welsh M (2013) VEGFA and tumour angiogenesis. J Intern Med 273:114–127PubMedCrossRefGoogle Scholar
  26. 26.
    Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J (1989) Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 84:1470–1478PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Criscuolo GR (1993) The genesis of peritumoral vasogenic brain edema and tumor cysts: a hypothetical role for tumor-derived vascular permeability factor. Yale J Biol Med 66:277–314PubMedPubMedCentralGoogle Scholar
  28. 28.
    Criscuolo GR, Merrill MJ, Oldfield EH (1988) Further characterization of malignant glioma-derived vascular permeability factor. J Neurosurg 69:254–262PubMedCrossRefGoogle Scholar
  29. 29.
    Dalgorf DM, Rowsell C, Bilbao JM, Chen JM (2008) Immunohistochemical investigation of hormone receptors and vascular endothelial growth factor concentration in vestibular schwannoma. Skull Base 18:377–384PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Davalos D, Akassoglou K (2012) Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 34:43–62. doi: 10.1007/s00281-00011-00290-00288 PubMedCrossRefGoogle Scholar
  31. 31.
    de Vries M, Briaire-de Bruijn I, Malessy MJ, de Bruine SF, van der Mey AG, Hogendoorn PC (2013) Tumor-associated macrophages are related to volumetric growth of vestibular schwannomas. Otol Neurotol 34:347–352PubMedCrossRefGoogle Scholar
  32. 32.
    Dilwali S, Briet MC, Kao SY, Fujita T, Landegger LD, Platt MP, Stankovic KM (2015) Preclinical validation of anti-nuclear factor-kappa B therapy to inhibit human vestibular schwannoma growth. Mol Oncol 9:1359–1370PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Dinarello CA (1994) The interleukin-1 family: 10 years of discovery. FASEB J 8:1314–1325PubMedCrossRefGoogle Scholar
  34. 34.
    Dodd KM, Yang J, Shen MH, Sampson JR, Tee AR (2015) mTORC1 drives HIF-1alpha and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene 34:2239–2250PubMedCrossRefGoogle Scholar
  35. 35.
    Duran WN, Breslin JW, Sanchez FA (2010) The NO cascade, eNOS location, and microvascular permeability. Cardiovasc Res 87:254–261PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Dvorak HF, Nagy JA, Berse B, Brown LF, Yeo KT, Yeo TK, Dvorak AM, van de Water L, Sioussat TM, Senger DR (1992) Vascular permeability factor, fibrin, and the pathogenesis of tumor stroma formation. Ann N Y Acad Sci 667:101–111PubMedCrossRefGoogle Scholar
  37. 37.
    Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562PubMedCrossRefGoogle Scholar
  38. 38.
    Erstad DJ, Cusack JC Jr (2013) Targeting the NF-kappaB pathway in cancer therapy. Surg Oncol Clin N Am 22:705–746PubMedCrossRefGoogle Scholar
  39. 39.
    Fong B, Barkhoudarian G, Pezeshkian P, Parsa AT, Gopen Q, Yang I (2011) The molecular biology and novel treatments of vestibular schwannomas. J Neurosurg 115:906–914PubMedCrossRefGoogle Scholar
  40. 40.
    Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY et al (2014) Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol 15:1513–1520PubMedCrossRefGoogle Scholar
  42. 42.
    Fukumura D, Gohongi T, Kadambi A, Izumi Y, Ang J, Yun CO, Buerk DG, Huang PL, Jain RK (2001) Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci U S A 98:2604–2609PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Gao Y, Gartenhaus RB, Lapidus RG, Hussain A, Zhang Y, Wang X, Dan HC (2015) Differential IKK/NF-kappaB activity is mediated by TSC2 through mTORC1 in PTEN-null prostate cancer and tuberous sclerosis complex tumor cells. Mol Cancer Res 13:1602–1614PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Gerstner ER, Duda DG, di Tomaso E, Ryg PA, Loeffler JS, Sorensen AG, Ivy P, Jain RK, Batchelor TT (2009) VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer. Nat Rev Clin Oncol 6:229–236PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Ghosh S, Tergaonkar V, Rothlin CV, Correa RG, Bottero V, Bist P, Verma IM, Hunter T (2006) Essential role of tuberous sclerosis genes TSC1 and TSC2 in NF-kappaB activation and cell survival. Cancer Cell 10:215–226PubMedCrossRefGoogle Scholar
  46. 46.
    Glidden EJ, Gray LG, Vemuru S, Li D, Harris TE, Mayo MW (2012) Multiple site acetylation of rictor stimulates mammalian target of rapamycin complex 2 (mTORC2)-dependent phosphorylation of Akt protein. J Biol Chem 287:581–588PubMedCrossRefGoogle Scholar
  47. 47.
    Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35PubMedCrossRefGoogle Scholar
  48. 48.
    Goutagny S, Raymond E, Esposito-Farese M, Trunet S, Mawrin C, Bernardeschi D, Larroque B, Sterkers O, Giovannini M, Kalamarides M (2015) Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas. J Neuro-Oncol 122:313–320CrossRefGoogle Scholar
  49. 49.
    Grajkowska W, Kotulska K, Jurkiewicz E, Matyja E (2010) Brain lesions in tuberous sclerosis complex. Review. Folia Neuropathol 48:139–149PubMedGoogle Scholar
  50. 50.
    Guba M, Koehl GE, Neppl E, Doenecke A, Steinbauer M, Schlitt HJ, Jauch KW, Geissler EK (2005) Dosing of rapamycin is critical to achieve an optimal antiangiogenic effect against cancer. Transpl Int 18:89–94PubMedCrossRefGoogle Scholar
  51. 51.
    Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22PubMedCrossRefGoogle Scholar
  52. 52.
    Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, Robinson SC, Balkwill FR (2008) “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med 205:1261–1268PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Hansen MR, Roehm PC, Chatterjee P, Green SH (2006) Constitutive neuregulin-1/ErbB signaling contributes to human vestibular schwannoma proliferation. Glia 53:593–600PubMedCrossRefGoogle Scholar
  54. 54.
    He Y, Li D, Cook SL, Yoon MS, Kapoor A, Rao CV, Kenis PJ, Chen J, Wang F (2013) Mammalian target of rapamycin and rictor control neutrophil chemotaxis by regulating Rac/Cdc42 activity and the actin cytoskeleton. Mol Biol Cell 24:3369–3380PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Hobday TJ, Qin R, Reidy-Lagunes D, Moore MJ, Strosberg J, Kaubisch A, Shah M, Kindler HL, Lenz HJ, Chen H et al (2015) Multicenter phase II trial of temsirolimus and bevacizumab in pancreatic neuroendocrine tumors. J Clin Oncol 33:1551–1556PubMedCrossRefGoogle Scholar
  56. 56.
    Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56:549–580PubMedCrossRefGoogle Scholar
  57. 57.
    Hoesel B, Schmid JA (2013) The complexity of NF-kappaB signaling in inflammation and cancer. Mol Cancer 12:1476–4598CrossRefGoogle Scholar
  58. 58.
    Hofer E, Schweighofer B (2007) Signal transduction induced in endothelial cells by growth factor receptors involved in angiogenesis. Thromb Haemost 97:355–363PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Houshmandi SS, Emnett RJ, Giovannini M, Gutmann DH (2009) The neurofibromatosis 2 protein, merlin, regulates glial cell growth in an ErbB2- and Src-dependent manner. Mol Cell Biol 29:1472–1486PubMedCrossRefGoogle Scholar
  60. 60.
    Huang J, Dibble CC, Matsuzaki M, Manning BD (2008) The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 28:4104–4115PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Huang J, Manning BD (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 37:217–222PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Hugelshofer M, Achermann Y, Kovari H, Dent W, Hombach M, Bloemberg G (2012) Meningoencephalitis with subdural empyema caused by toxigenic Clostridium perfringens type a. J Clin Microbiol 50:3409–3411PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Humar R, Kiefer FN, Berns H, Resink TJ, Battegay EJ (2002) Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J 16:771–780PubMedCrossRefGoogle Scholar
  64. 64.
    Israel A (2010) The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol 2:a000158PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6:1122–1128PubMedCrossRefGoogle Scholar
  66. 66.
    Jain S, Gautam V, Naseem S (2011) Acute-phase proteins: as diagnostic tool. J Pharm Bioallied Sci 3:118–127PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    James MF, Han S, Polizzano C, Plotkin SR, Manning BD, Stemmer-Rachamimov AO, Gusella JF, Ramesh V (2009) NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth. Mol Cell Biol 29:4250–4261PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    James MF, Stivison E, Beauchamp R, Han S, Li H, Wallace MR, Gusella JF, Stemmer-Rachamimov AO, Ramesh V (2012) Regulation of mTOR complex 2 signaling in neurofibromatosis 2-deficient target cell types. Mol Cancer Res 10:649–659PubMedCrossRefGoogle Scholar
  69. 69.
    Jiang BH, Liu LZ (2009) PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res 102:19–65PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Jiang BH, Liu LZ (2008) PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta 1784:150–158PubMedCrossRefGoogle Scholar
  71. 71.
    Karajannis MA, Legault G, Hagiwara M, Giancotti FG, Filatov A, Derman A, Hochman T, Goldberg JD, Vega E, Wisoff JH et al (2014) Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro-Oncology 16:292–297PubMedCrossRefGoogle Scholar
  72. 72.
    Kasantikul V, Netsky MG (1979) Combined neurilemmoma and angioma. Tumor of ectomesenchyme and a source of bleeding. J Neurosurg 50:81–87PubMedCrossRefGoogle Scholar
  73. 73.
    Kato S, Esumi H, Hirano A, Kato M, Asayama K, Ohama E (2003) Immunohistochemical expression of inducible nitric oxide synthase (iNOS) in human brain tumors: relationships of iNOS to superoxide dismutase (SOD) proteins (SOD1 and SOD2), Ki-67 antigen (MIB-1) and p53 protein. Acta Neuropathol 105:333–340PubMedGoogle Scholar
  74. 74.
    Kim JY, Kim H, Jeun SS, Rha SJ, Kim YH, Ko YJ, Won J, Lee KH, Rha HK, Wang YP (2002) Inhibition of NF-kappaB activation by merlin. Biochem Biophys Res Commun 296:1295–1302PubMedCrossRefGoogle Scholar
  75. 75.
    Kim MS, Kuehn HS, Metcalfe DD, Gilfillan AM (2008) Activation and function of the mTORC1 pathway in mast cells. J Immunol 180:4586–4595PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Korpos E, Wu C, Sorokin L (2009) Multiple roles of the extracellular matrix in inflammation. Curr Pharm Des 15:1349–1357PubMedCrossRefGoogle Scholar
  77. 77.
    Kulke MH, Niedzwiecki D, Foster NR, Fruth B, Kunz PL, Kennecke HF, Wolin EM, Venook AP (2015) Randomized phase II study of everolimus (E) versus everolimus plus bevacizumab (E+B) in patients (Pts) with locally advanced or metastatic pancreatic neuroendocrine tumors (pNET), CALGB 80701 (Alliance). J Clin Oncol 33(suppl) abstr:4005. doi: 10.1200/jco.2015.33.15_suppl.4005 CrossRefGoogle Scholar
  78. 78.
    Lal BK, Varma S, Pappas PJ, Hobson RW 2nd, Duran WN (2001) VEGF increases permeability of the endothelial cell monolayer by activation of PKB/Akt, endothelial nitric-oxide synthase, and MAP kinase pathways. Microvasc Res 62:252–262PubMedCrossRefGoogle Scholar
  79. 79.
    Lane HA, Wood JM, McSheehy PM, Allegrini PR, Boulay A, Brueggen J, Littlewood-Evans A, Maira SM, Martiny-Baron G, Schnell CR et al (2009) mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin Cancer Res 15:1612–1622PubMedCrossRefGoogle Scholar
  80. 80.
    Laoui D, Van Overmeire E, De Baetselier P, Van Ginderachter JA, Raes G (2014) Functional relationship between tumor-associated macrophages and macrophage colony-stimulating factor as contributors to cancer progression. Front Immunol 5Google Scholar
  81. 81.
    Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Lawrence T (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1:a001651PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Leidi M, Mariotti M, Maier JA (2010) EDF-1 contributes to the regulation of nitric oxide release in VEGF-treated human endothelial cells. Eur J Cell Biol 89:654–660PubMedCrossRefGoogle Scholar
  84. 84.
    Levi M (2010) The coagulant response in sepsis and inflammation. Hamostaseologie 30(10–12):14–16Google Scholar
  85. 85.
    Levi M, van der Poll T (2005) Two-way interactions between inflammation and coagulation. Trends Cardiovasc Med 15:254–259PubMedCrossRefGoogle Scholar
  86. 86.
    Lin HY, Chang KT, Hung CC, Kuo CH, Hwang SJ, Chen HC, Hung CH, Lin SF (2014) Effects of the mTOR inhibitor rapamycin on monocyte-secreted chemokines. BMC Immunol 15:014–0037CrossRefGoogle Scholar
  87. 87.
    Lopez-Lago MA, Okada T, Murillo MM, Socci N, Giancotti FG (2009) Loss of the tumor suppressor gene NF2, encoding merlin, constitutively activates integrin-dependent mTORC1 signaling. Mol Cell Biol 29:4235–4249PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Lowenstein CJ, Dinerman JL, Snyder SH (1994) Nitric oxide: a physiologic messenger. Ann Intern Med 120:227–237PubMedCrossRefGoogle Scholar
  89. 89.
    Madonna G, Ullman CD, Gentilcore G, Palmieri G, Ascierto PA (2012) NF-kappaB as potential target in the treatment of melanoma. J Transl Med 10:1479–5876CrossRefGoogle Scholar
  90. 90.
    Manning BD, Cantley LC (2003) United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem Soc Trans 31:573–578PubMedCrossRefGoogle Scholar
  91. 91.
    Mautner VF, Nguyen R, Kutta H, Fuensterer C, Bokemeyer C, Hagel C, Friedrich RE, Panse J (2010) Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2. Neuro-Oncology 12:14–18. doi: 10.1093/neuonc/nop1010 PubMedCrossRefGoogle Scholar
  92. 92.
    Mayhan WG (1996) Role of nitric oxide in histamine-induced increases in permeability of the blood-brain barrier. Brain Res 743:70–76PubMedCrossRefGoogle Scholar
  93. 93.
    McClatchey AI, Giovannini M (2005) Membrane organization and tumorigenesis—the NF2 tumor suppressor, merlin. Genes Dev 19:2265–2277PubMedCrossRefGoogle Scholar
  94. 94.
    Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Murohara T, Horowitz JR, Silver M, Tsurumi Y, Chen D, Sullivan A, Isner JM (1998) Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin. Circulation 97:99–107PubMedCrossRefGoogle Scholar
  96. 96.
    Okamoto S, Takahashi H, Minoura K, Fujita N, Yoshimura M (1991) FDP levels in the cerebrospinal fluid are elevated in patients with meningitis. Rinsho Byori 39:651–655PubMedGoogle Scholar
  97. 97.
    Oldford SA, Marshall JS (2015) Mast cells as targets for immunotherapy of solid tumors. Mol Immunol 63:113–124PubMedCrossRefGoogle Scholar
  98. 98.
    Pan H, O’Brien TF, Zhang P, Zhong XP (2012) The role of tuberous sclerosis complex 1 in regulating innate immunity. J Immunol 188:3658–3666PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Parker WE, Orlova KA, Heuer GG, Baybis M, Aronica E, Frost M, Wong M, Crino PB (2011) Enhanced epidermal growth factor, hepatocyte growth factor, and vascular endothelial growth factor expression in tuberous sclerosis complex. Am J Pathol 178:296–305PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Peri S, Devarajan K, Yang DH, Knudson AG, Balachandran S (2013) Meta-analysis identifies NF-kappaB as a therapeutic target in renal cancer. PLoS One 8:e76746PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Plotkin SR, Merker VL, Halpin C, Jennings D, McKenna MJ, Harris GJ, Barker FG 2nd (2012) Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: a retrospective review of 31 patients. Otol Neurotol 33:1046–1052PubMedCrossRefGoogle Scholar
  102. 102.
    Prabowo AS, Anink JJ, Lammens M, Nellist M, van den Ouweland AM, Adle-Biassette H, Sarnat HB, Flores-Sarnat L, Crino PB, Aronica E (2013) Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation. Brain Pathol 23:45–59. doi: 10.1111/j.1750-3639.2012.00616.x PubMedCrossRefGoogle Scholar
  103. 103.
    Rong R, Tang X, Gutmann DH, Ye K (2004) Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L. Proc Natl Acad Sci U S A 101:18200–18205PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Ryder M, Gild M, Hohl TM, Pamer E, Knauf J, Ghossein R, Joyce JA, Fagin JA (2013) Genetic and pharmacological targeting of CSF-1/CSF-1R inhibits tumor-associated macrophages and impairs BRAF-induced thyroid cancer progression. PLoS One 8:e54302PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Ryu JK, Petersen MA, Murray SG, Baeten KM, Meyer-Franke A, Chan JP, Vagena E, Bedard C, Machado MR, Rios Coronado PE et al (2015) Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation. Nat Commun 6Google Scholar
  106. 106.
    Saccani A, Schioppa T, Porta C, Biswas SK, Nebuloni M, Vago L, Bottazzi B, Colombo MP, Mantovani A, Sica A (2006) p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res 66:11432–11440PubMedCrossRefGoogle Scholar
  107. 107.
    Saci A, Cantley LC, Carpenter CL (2011) Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size. Mol Cell 42:50–61. doi: 10.1016/j.molcel.2011.1003.1017 PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Saito W, Kase S, Ohgami K, Mori S, Ohno S (2010) Intravitreal anti-vascular endothelial growth factor therapy with bevacizumab for tuberous sclerosis with macular oedema. Acta Ophthalmol 88:377–380PubMedCrossRefGoogle Scholar
  109. 109.
    Sakurai E, Watanabe T, Yanai K (2009) Uptake of L-histidine and histamine biosynthesis at the blood-brain barrier. Inflamm Res 1:34–35CrossRefGoogle Scholar
  110. 110.
    Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296–1302PubMedCrossRefGoogle Scholar
  111. 111.
    Sedeyn JC, Wu H, Hobbs RD, Levin EC, Nagele RG, Venkataraman V (2015) Histamine induces Alzheimer’s disease-like blood brain barrier breach and local cellular responses in mouse brain organotypic cultures. Biomed Res Int 937148:30Google Scholar
  112. 112.
    Semela D, Piguet AC, Kolev M, Schmitter K, Hlushchuk R, Djonov V, Stoupis C, Dufour JF (2007) Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma. J Hepatol 46:840–848PubMedCrossRefGoogle Scholar
  113. 113.
    Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985PubMedCrossRefGoogle Scholar
  114. 114.
    Sharma M, Ralte A, Arora R, Santosh V, Shankar SK, Sarkar C (2004) Subependymal giant cell astrocytoma: a clinicopathological study of 23 cases with special emphasis on proliferative markers and expression of p53 and retinoblastoma gene proteins. Pathology 36:139–144PubMedCrossRefGoogle Scholar
  115. 115.
    Solinas G, Germano G, Mantovani A, Allavena P (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86:1065–1073PubMedCrossRefGoogle Scholar
  116. 116.
    Sorokin L (2010) The impact of the extracellular matrix on inflammation. Nat Rev Immunol 10:712–723PubMedCrossRefGoogle Scholar
  117. 117.
    Spindler V, Schlegel N, Waschke J (2010) Role of GTPases in control of microvascular permeability. Cardiovasc Res 87:243–253PubMedCrossRefGoogle Scholar
  118. 118.
    Strukova S (2006) Blood coagulation-dependent inflammation. Coagulation-dependent inflammation and inflammation-dependent thrombosis. Front Biosci 11:59–80PubMedCrossRefGoogle Scholar
  119. 119.
    Suzuki Y, Deitch EA, Mishima S, Duran WN, Xu DZ (2000) Endotoxin-induced mesenteric microvascular changes involve iNOS-derived nitric oxide: results from a study using iNOS knock out mice. Shock 13:397–403PubMedCrossRefGoogle Scholar
  120. 120.
    Tanimoto T, Jin ZG, Berk BC (2002) Transactivation of vascular endothelial growth factor (VEGF) receptor Flk-1/KDR is involved in sphingosine 1-phosphate-stimulated phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS). J Biol Chem 277:42997–43001PubMedCrossRefGoogle Scholar
  121. 121.
    Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B, Asadi S, Vasiadi M, Weng Z, Miniati A et al (2012) Mast cells and inflammation. Biochim Biophys Acta 1822:21–33. doi: 10.1016/j.bbadis.2010.1012.1014 PubMedCrossRefGoogle Scholar
  122. 122.
    Touzot M, Soulillou JP, Dantal J (2012) Mechanistic target of rapamycin inhibitors in solid organ transplantation: from benchside to clinical use. Curr Opin Organ Transplant 17:626–633PubMedCrossRefGoogle Scholar
  123. 123.
    Tucker M, Goldstein A, Dean M, Knudson A (2000) National Cancer Institute workshop report: the phakomatoses revisited. J Natl Cancer Inst 92:530–533PubMedCrossRefGoogle Scholar
  124. 124.
    Uesaka T, Shono T, Suzuki SO, Nakamizo A, Niiro H, Mizoguchi M, Iwaki T, Sasaki T (2007) Expression of VEGF and its receptor genes in intracranial schwannomas. J Neuro-Oncol 83:259–266CrossRefGoogle Scholar
  125. 125.
    Ulloa-Gutierrez R, Dobson S, Forbes J (2005) Group a streptococcal subdural empyema as a complication of varicella. Pediatrics 115:e112–e114PubMedCrossRefGoogle Scholar
  126. 126.
    Waschke J, Curry FE, Adamson RH, Drenckhahn D (2005) Regulation of actin dynamics is critical for endothelial barrier functions. Am J Physiol Heart Circ Physiol 288:H1296–H1305PubMedCrossRefGoogle Scholar
  127. 127.
    Weichhart T, Hengstschlager M, Linke M (2015) Regulation of innate immune cell function by mTOR. Nat Rev Immunol 15:599–614PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Wennerberg K, Rossman KL, Der CJ (2005) The Ras superfamily at a glance. J Cell Sci 118:843–846PubMedCrossRefGoogle Scholar
  129. 129.
    Zamora R, Vodovotz Y, Billiar TR (2000) Inducible nitric oxide synthase and inflammatory diseases. Mol Med 6:347–373PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Zeng Z, Sarbassov dos D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C, Giles FJ, Sabatini DM, Andreeff M, Konopleva M (2007) Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109:3509–3512PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Zhang B, Zou J, Rensing NR, Yang M, Wong M (2015) Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex. Neurobiol Dis 80:70–79PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Zhu L, Yang T, Li L, Sun L, Hou Y, Hu X, Zhang L, Tian H, Zhao Q, Peng J et al (2014) TSC1 controls macrophage polarization to prevent inflammatory disease. Nat Commun 5Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Department of Surgery, Division of Neurosurgery, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  2. 2.Department of Neurology/Epilepsy CentreUniversity of ErlangenErlangenGermany

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