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Para- and Autocrine Mediators in the Glioma Microenvironment

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Book cover Glioma Cell Biology

Abstract

Unregulated growth, apoptosis-resistance, invasion, strongly increased angiogenesis, and immunosuppression are hallmarks of gliomas. Drivers of these tumor-promoting processes are several auto- and paracrine factors, mostly bioactive peptides. Among them, distinct neuropeptides, chemokines, growth factors, and cytokines play a prominent role. Since receptors for neuropeptides are often overexpressed on glioma cells, derivatives are increasingly used for imaging/diagnosis and radiotherapy, whereas clinical significance of agonists or antagonists remains questionable. Chemokines and their receptors significantly contribute to tumor growth and progression by exerting not only chemotactic but also proliferative and anti-apoptotic effects. Next to these small peptides, a multitude of classical growth factors and their receptors with tyrosine kinase activity are driving players of glioma cell progression. Growth factor receptors on glioma cells are partly overexpressed or constitutively activated through mutations, and therefore appear prominent targets for anti-glioma therapies. Several cytokines are heavily produced by glioma cells and exhibit not only immune-modulatory functions, but favor glioma cell proliferation, maintenance for the stem cell character of glioma stem(-like) cells, and may attract stroma cells. Apart from peptides/proteins, some lipid and also nutrient factors are additional drivers of glioma progression. Thus, factors produced by glioma cells (or glioma stem-like cells) exert autocrine as well as paracrine actions on endothelial (angiogenesis factors), microglial, and other cells. Vice versa, blood-borne factors or those produced by the glioma microenvironment drive tumor progression in complex ways. Despite its complexity, this network of auto- and paracrine mediators provides excellent targets for glioma diagnosis, imaging, and therapies.

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Abbreviations

7TM receptor:

Seven transmembrane domain receptor

ADAM:

A disintegrin and metalloproteinase

bFGF:

Basic fibroblast growth factor

EGF:

Epidermal growth factor

FCS:

Fetal calf serum

GDNF:

Glial cell-derived neurotrophic factor

GSC:

Glioma stem(-like) cell

HGF/SF:

Hepatocyte growth factor/scatter factor

IGF:

Insulin-like growth factor

IL:

Interleukin

MAPK:

Mitogen-activated protein kinase

MMP:

Matrix metalloproteinase

PDGF:

Platelet-derived growth factor

PG:

Prostaglandin

PTN:

Pleiotrophin, heparin-binding brain mitogen, heparin-binding growth factor 8

RTK:

Receptor tyrosine kinase

Stat:

Signal transducer and activator of transcription, signal transduction and transcription

TAM:

Tumor-associated macrophage

TGF:

Transforming growth factor

TIL:

Tumor-infiltrating lymphocyte

VEGF:

Vascular endothelial cell growth factor

References

  • Abel S, Hundhausen C, Mentlein R, Schulte A, Berkhout TA, Broadway N et al (2004) The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10. J Immunol 172(10):6362–6372

    CAS  PubMed  Google Scholar 

  • Abounader R, Laterra J (2005) Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. Neuro Oncol 7(4):436–451

    CAS  PubMed Central  PubMed  Google Scholar 

  • Abounader R, Ranganathan S, Lal B, Fielding K, Book A, Dietz H et al (1999) Reversion of human glioblastoma malignancy by U1 small nuclear RNA/ribozyme targeting of scatter factor/hepatocyte growth factor and c-met expression. J Natl Cancer Inst 91(18):1548–1556

    CAS  PubMed  Google Scholar 

  • Adams S, Braidy N, Bessesde A, Brew BJ, Grant R, Teo C et al (2012) The kynurenine pathway in brain tumor pathogenesis. Cancer Res 72(22):5649–5657

    CAS  PubMed  Google Scholar 

  • Aldape KD, Ballman K, Furth A, Buckner JC, Giannini C, Burger PC et al (2004) Immunohistochemical detection of EGFRvIII in high malignancy grade astrocytomas and evaluation of prognostic significance. J Neuropathol Exp Neurol 63(7):700–707

    CAS  PubMed  Google Scholar 

  • Alentorn A, Marie Y, Carpentier C, Boisselier B, Giry M, Labussiere M et al (2012) Prevalence, clinico-pathological value, and co-occurrence of PDGFRA abnormalities in diffuse gliomas. Neuro Oncol 14(11):1393–1403

    CAS  PubMed Central  PubMed  Google Scholar 

  • Allen SJ, Crown SE, Handel TM (2007) Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol 25:787–820

    CAS  PubMed  Google Scholar 

  • Arcella A, Carpinelli G, Battaglia G, D’Onofrio M, Santoro F, Ngomba RT et al (2005) Pharmacological blockade of group II metabotropic glutamate receptors reduces the growth of glioma cells in vivo. Neuro Oncol 7(3):236–245

    CAS  PubMed Central  PubMed  Google Scholar 

  • Arrieta O, Pineda-Olvera B, Guevara-Salazar P, Hernandez-Pedro N, Morales-Espinosa D, Ceron-Lizarraga TL et al (2008) Expression of AT1 and AT2 angiotensin receptors in astrocytomas is associated with poor prognosis. Br J Cancer 99(1):160–166

    CAS  PubMed Central  PubMed  Google Scholar 

  • Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4(12):915–925

    CAS  PubMed  Google Scholar 

  • Black KL, Chen K, Becker DP, Merrill JE (1992) Inflammatory leukocytes associated with increased immunosuppression by glioblastoma. J Neurosurg 77(1):120–126

    CAS  PubMed  Google Scholar 

  • Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP et al (2009) IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat 30(1):7–11

    CAS  PubMed  Google Scholar 

  • Bodmer S, Strommer K, Frei K, Siepl C, de Tribolet N, Heid I et al (1989) Immunosuppression and transforming growth factor-beta in glioblastoma. Preferential production of transforming growth factor-beta 2. J Immunol 143(10):3222–3229

    CAS  PubMed  Google Scholar 

  • Bowers DC, Fan S, Walter KA, Abounader R, Williams JA, Rosen EM et al (2000) Scatter factor/hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase- and AKT-dependent pathways. Cancer Res 60(15):4277–4283

    CAS  PubMed  Google Scholar 

  • Brantley EC, Benveniste EN (2008) Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas. Mol Cancer Res 6(5):675–684

    CAS  PubMed  Google Scholar 

  • Brockmann MA, Ulbricht U, Gruner K, Fillbrandt R, Westphal M, Lamszus K (2003) Glioblastoma and cerebral microvascular endothelial cell migration in response to tumor-associated growth factors. Neurosurgery 52(6):1391–1399, discussion 9

    PubMed  Google Scholar 

  • Camp ER, Summy J, Bauer TW, Liu W, Gallick GE, Ellis LM (2005) Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res 11(1):397–405

    CAS  PubMed  Google Scholar 

  • Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068

    Google Scholar 

  • Cao B, Su Y, Oskarsson M, Zhao P, Kort EJ, Fisher RJ et al (2001) Neutralizing monoclonal antibodies to hepatocyte growth factor/scatter factor (HGF/SF) display antitumor activity in animal models. Proc Natl Acad Sci U S A 98(13):7443–7448

    CAS  PubMed Central  PubMed  Google Scholar 

  • Castelli MG, Chiabrando C, Fanelli R, Martelli L, Butti G, Gaetani P et al (1989) Prostaglandin and thromboxane synthesis by human intracranial tumors. Cancer Res 49(6):1505–1508

    CAS  PubMed  Google Scholar 

  • Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H (2011) The brain tumor microenvironment. Glia 59(8):1169–1180

    PubMed  Google Scholar 

  • Chen SH, Gillespie GY, Benveniste EN (2006) Divergent effects of oncostatin M on astroglioma cells: influence on cell proliferation, invasion, and expression of matrix metalloproteinases. Glia 53(2):191–200

    PubMed  Google Scholar 

  • Cordier D, Forrer F, Bruchertseifer F, Morgenstern A, Apostolidis C, Good S et al (2010) Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8, Met(O2)11]-substance P: a pilot trial. Eur J Nucl Med Mol Imaging 37(7):1335–1344

    CAS  PubMed  Google Scholar 

  • D’Onofrio M, Arcella A, Bruno V, Ngomba RT, Battaglia G, Lombari V et al (2003) Pharmacological blockade of mGlu2/3 metabotropic glutamate receptors reduces cell proliferation in cultured human glioma cells. J Neurochem 84(6):1288–1295

    PubMed  Google Scholar 

  • Day SE, Waziri A (2012) Clinical trials of small molecule inhibitors in high-grade glioma. Neurosurg Clin N Am 23(3):407–416

    PubMed  Google Scholar 

  • De Armas R, Durand K, Guillaudeau A, Weinbreck N, Robert S, Moreau JJ et al (2010) mRNA levels of enzymes and receptors implicated in arachidonic acid metabolism in gliomas. Clin Biochem 43(10–11):827–835

    PubMed  Google Scholar 

  • de Groot J, Sontheimer H (2011) Glutamate and the biology of gliomas. Glia 59(8):1181–1189

    PubMed Central  PubMed  Google Scholar 

  • Desbaillets I, Tada M, de Tribolet N, Diserens AC, Hamou MF, Van Meir EG (1994) Human astrocytomas and glioblastomas express monocyte chemoattractant protein-1 (MCP-1) in vivo and in vitro. Int J Cancer 58(2):240–247

    CAS  PubMed  Google Scholar 

  • Dong Y, Han Q, Zou Y, Deng Z, Lu X, Wang X et al (2012) Long-term exposure to imatinib reduced cancer stem cell ability through induction of cell differentiation via activation of MAPK signaling in glioblastoma cells. Mol Cell Biochem 370(1–2):89–102

    CAS  PubMed  Google Scholar 

  • Ehtesham M, Mapara KY, Stevenson CB, Thompson RC (2009) CXCR4 mediates the proliferation of glioblastoma progenitor cells. Cancer Lett 274(2):305–312

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ehtesham M, Thompson RC (2012) CXCR4-expressing glial precursor cells demonstrate enhanced migratory tropism for glioma. J Cancer Ther 3(6):1086–1091

    PubMed Central  PubMed  Google Scholar 

  • Ehtesham M, Winston JA, Kabos P, Thompson RC (2006) CXCR4 expression mediates glioma cell invasiveness. Oncogene 25(19):2801–2806

    CAS  PubMed  Google Scholar 

  • Ellert-Miklaszewska A, Ciechomska I, Kaminska B (2013) Cannabinoid signaling in glioma cells. Adv Exp Med Biol 986:209–220

    CAS  PubMed  Google Scholar 

  • Feindt J, Becker I, Blomer U, Hugo HH, Mehdorn HM, Krisch B et al (1995) Expression of somatostatin receptor subtypes in cultured astrocytes and gliomas. J Neurochem 65(5):1997–2005

    CAS  PubMed  Google Scholar 

  • Feng Y, Broder CC, Kennedy PE, Berger EA (1996) HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272(5263):872–877

    CAS  PubMed  Google Scholar 

  • Fleming TP, Saxena A, Clark WC, Robertson JT, Oldfield EH, Aaronson SA et al (1992) Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res 52(16):4550–4553

    CAS  PubMed  Google Scholar 

  • Forstreuter F, Lucius R, Mentlein R (2002) Vascular endothelial growth factor induces chemotaxis and proliferation of microglial cells. J Neuroimmunol 132(1–2):93–98

    CAS  PubMed  Google Scholar 

  • Galve-Roperh I, Sanchez C, Cortes ML, Gomez del Pulgar T, Izquierdo M, Guzman M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6(3):313–319

    CAS  PubMed  Google Scholar 

  • Garton KJ, Gough PJ, Blobel CP, Murphy G, Greaves DR, Dempsey PJ et al (2001) Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J Biol Chem 276(41):37993–38001

    CAS  PubMed  Google Scholar 

  • Gomes RN, Colquhoun A (2012) E series prostaglandins alter the proliferative, apoptotic and migratory properties of T98G human glioma cells in vitro. Lipids Health Dis 11(1):171

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gough PJ, Garton KJ, Wille PT, Rychlewski M, Dempsey PJ, Raines EW (2004) A disintegrin and metalloproteinase 10-mediated cleavage and shedding regulates the cell surface expression of CXC chemokine ligand 16. J Immunol 172(6):3678–3685

    CAS  PubMed  Google Scholar 

  • Gupta SK, Lysko PG, Pillarisetti K, Ohlstein E, Stadel JM (1998) Chemokine receptors in human endothelial cells. Functional expression of CXCR4 and its transcriptional regulation by inflammatory cytokines. J Biol Chem 273(7):4282–4287

    CAS  PubMed  Google Scholar 

  • Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK et al (1998) Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci U S A 95(18):10896–10901

    CAS  PubMed Central  PubMed  Google Scholar 

  • Haskell CA, Cleary MD, Charo IF (1999) Molecular uncoupling of fractalkine-mediated cell adhesion and signal transduction. Rapid flow arrest of CX3CR1-expressing cells is independent of G-protein activation. J Biol Chem 274(15):10053–10058

    CAS  PubMed  Google Scholar 

  • Hatanpaa KJ, Burma S, Zhao D, Habib AA (2010) Epidermal growth factor receptor in glioma: signal transduction, neuropathology, imaging, and radioresistance. Neoplasia 12(9):675–684

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hattermann K, Held-Feindt J, Lucius R, Muerkoster SS, Penfold ME, Schall TJ et al (2010) The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res 70(8):3299–3308

    CAS  PubMed  Google Scholar 

  • Hattermann K, Mentlein R (2013) An infernal trio: the chemokine CXCL12 and its receptors CXCR4 and CXCR7 in tumor biology. Ann Anat 195(2):103–110

    CAS  PubMed  Google Scholar 

  • Hattermann K, Mentlein R, Held-Feindt J (2012) CXCL12 mediates apoptosis resistance in rat C6 glioma cells. Oncol Rep 27(5):1348–1352

    CAS  PubMed  Google Scholar 

  • Hau P, Jachimczak P, Schlaier J, Bogdahn U (2011) TGF-beta2 signaling in high-grade gliomas. Curr Pharm Biotechnol 12(12):2150–2157

    CAS  PubMed  Google Scholar 

  • Hede SM, Hansson I, Afink GB, Eriksson A, Nazarenko I, Andrae J et al (2009) GFAP promoter driven transgenic expression of PDGFB in the mouse brain leads to glioblastoma in a Trp53 null background. Glia 57(11):1143–1153

    PubMed  Google Scholar 

  • Held-Feindt J, Dörner L, Sahan G, Mehdorn HM, Mentlein R (2006) Cannabinoid receptors in human astroglial tumors. J Neurochem 98(3):886–893

    CAS  PubMed  Google Scholar 

  • Held-Feindt J, Hattermann K, Muerkoster SS, Wedderkopp H, Knerlich-Lukoschus F, Ungefroren H et al (2010) CX3CR1 promotes recruitment of human glioma-infiltrating microglia/macrophages (GIMs). Exp Cell Res 316(9):1553–1566

    CAS  PubMed  Google Scholar 

  • Held-Feindt J, Lutjohann B, Ungefroren H, Mehdorn HM, Mentlein R (2003) Interaction of transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF) in human glioma cells. J Neurooncol 63(2):117–127

    PubMed  Google Scholar 

  • Heldin CH, Westermark B (1984) Growth factors: mechanism of action and relation to oncogenes. Cell 37(1):9–20

    CAS  PubMed  Google Scholar 

  • Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B et al (1992) Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res 52(11):3213–3219

    CAS  PubMed  Google Scholar 

  • Hoelzinger DB, Demuth T, Berens ME (2007) Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. J Natl Cancer Inst 99(21):1583–1593

    CAS  PubMed  Google Scholar 

  • Ikushima H, Todo T, Ino Y, Takahashi M, Miyazawa K, Miyazono K (2009) Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 5(5):504–514

    CAS  PubMed  Google Scholar 

  • Inda MM, Bonavia R, Mukasa A, Narita Y, Sah DW, Vandenberg S et al (2010) Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev 24(16):1731–1745

    CAS  PubMed Central  PubMed  Google Scholar 

  • Izumoto S, Arita N, Ohnishi T, Hiraga S, Taki T, Tomita N et al (1997) Microsatellite instability and mutated type II transforming growth factor-beta receptor gene in gliomas. Cancer Lett 112(2):251–256

    CAS  PubMed  Google Scholar 

  • Jenny B, Harrison JA, Baetens D, Tille JC, Burkhardt K, Mottaz H et al (2006) Expression and localization of VEGF-C and VEGFR-3 in glioblastomas and haemangioblastomas. J Pathol 209(1):34–43

    CAS  PubMed  Google Scholar 

  • Joseph JV, Balasubramaniyan V, Walenkamp A, Kruyt FA (2013) TGF-beta as a therapeutic target in high grade gliomas – promises and challenges. Biochem Pharmacol 85(4):478–485

    CAS  PubMed  Google Scholar 

  • Joshi AD, Loilome W, Siu IM, Tyler B, Gallia GL, Riggins GJ (2012) Evaluation of tyrosine kinase inhibitor combinations for glioblastoma therapy. PLoS One 7(10):e44372

    CAS  PubMed Central  PubMed  Google Scholar 

  • Juillerat-Jeanneret L, Celerier J, Chapuis Bernasconi C, Nguyen G, Wostl W, Maerki HP et al (2004) Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma. Br J Cancer 90(5):1059–1068

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kapitonov D, Allegood JC, Mitchell C, Hait NC, Almenara JA, Adams JK et al (2009) Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts. Cancer Res 69(17):6915–6923

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kerber M, Reiss Y, Wickersheim A, Jugold M, Kiessling F, Heil M et al (2008) Flt-1 signaling in macrophages promotes glioma growth in vivo. Cancer Res 68(18):7342–7351

    CAS  PubMed  Google Scholar 

  • Knerlich-Lukoschus F, Noack M, von der Ropp-Brenner B, Lucius R, Mehdorn HM, Held-Feindt J (2011) Spinal cord injuries induce changes in CB1 cannabinoid receptor and C-C chemokine expression in brain areas underlying circuitry of chronic pain conditions. J Neurotrauma 28(4):619–634

    PubMed  Google Scholar 

  • Koka V, Potti A, Forseen SE, Pervez H, Fraiman GN, Koch M et al (2003) Role of Her-2/neu overexpression and clinical determinants of early mortality in glioblastoma multiforme. Am J Clin Oncol 26(4):332–335

    PubMed  Google Scholar 

  • Koochekpour S, Jeffers M, Rulong S, Taylor G, Klineberg E, Hudson EA et al (1997) Met and hepatocyte growth factor/scatter factor expression in human gliomas. Cancer Res 57(23):5391–5398

    CAS  PubMed  Google Scholar 

  • Koochekpour S, Merzak A, Pilkington GJ (1996) Vascular endothelial growth factor production is stimulated by gangliosides and TGF-beta isoforms in human glioma cells in vitro. Cancer Lett 102(1–2):209–215

    CAS  PubMed  Google Scholar 

  • Krisch B, Mentlein R (1994) Neuropeptide receptors and astrocytes. Int Rev Cytol 148:119–169

    CAS  PubMed  Google Scholar 

  • Ku MC, Wolf SA, Respondek D, Matyash V, Pohlmann A, Waiczies S et al (2013) GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis. Acta Neuropathol 125(4):609–620

    CAS  PubMed  Google Scholar 

  • Laterra J, Nam M, Rosen E, Rao JS, Lamszus K, Goldberg ID et al (1997) Scatter factor/hepatocyte growth factor gene transfer enhances glioma growth and angiogenesis in vivo. Lab Invest 76(4):565–577

    CAS  PubMed  Google Scholar 

  • Leung SY, Wong MP, Chung LP, Chan AS, Yuen ST (1997) Monocyte chemoattractant protein-1 expression and macrophage infiltration in gliomas. Acta Neuropathol 93(5):518–527

    CAS  PubMed  Google Scholar 

  • Li W, Graeber MB (2012) The molecular profile of microglia under the influence of glioma. Neuro Oncol 14(8):958–978

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lilja A, Nordborg C, Brun A, Salford LG, Aman P (2001) Expression of the IL-6 family cytokines in human brain tumors. Int J Oncol 19(3):495–499

    CAS  PubMed  Google Scholar 

  • Liu C, Luo D, Streit WJ, Harrison JK (2008) CX3CL1 and CX3CR1 in the GL261 murine model of glioma: CX3CR1 deficiency does not impact tumor growth or infiltration of microglia and lymphocytes. J Neuroimmunol 198(1–2):98–105

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liu G, Ying H, Zeng G, Wheeler CJ, Black KL, Yu JS (2004) HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res 64(14):4980–4986

    CAS  PubMed  Google Scholar 

  • Liu XS, Zhang ZG, Zhang RL, Gregg SR, Wang L, Yier T et al (2007) Chemokine ligand 2 (CCL2) induces migration and differentiation of subventricular zone cells after stroke. J Neurosci Res 85(10):2120–2125

    CAS  PubMed  Google Scholar 

  • Lu DY, Leung YM, Cheung CW, Chen YR, Wong KL (2010) Glial cell line-derived neurotrophic factor induces cell migration and matrix metalloproteinase-13 expression in glioma cells. Biochem Pharmacol 80(8):1201–1209

    CAS  PubMed  Google Scholar 

  • Lu J, Ksendzovsky A, Yang C, Mehta GU, Yong RL, Weil RJ et al (2012) CNTF receptor subunit alpha as a marker for glioma tumor-initiating cells and tumor grade: laboratory investigation. J Neurosurg 117(6):1022–1031

    CAS  PubMed  Google Scholar 

  • Lucius R, Mentlein R (1991) Degradation of the neuropeptide somatostatin by cultivated neuronal and glial cells. J Biol Chem 266(28):18907–18913

    CAS  PubMed  Google Scholar 

  • Lucius R, Sievers J, Mentlein R (1995) Enkephalin metabolism by microglial aminopeptidase N (CD13). J Neurochem 64(4):1841–1847

    CAS  PubMed  Google Scholar 

  • Ludwig A, Mentlein R (2008) Glial cross-talk by transmembrane chemokines CX3CL1 and CXCL16. J Neuroimmunol 198(1–2):92–97

    CAS  PubMed  Google Scholar 

  • Ludwig A, Schiemann F, Mentlein R, Lindner B, Brandt E (2002) Dipeptidyl peptidase IV (CD26) on T cells cleaves the CXC chemokine CXCL11 (I-TAC) and abolishes the stimulating but not the desensitizing potential of the chemokine. J Leukoc Biol 72(1):183–191

    CAS  PubMed  Google Scholar 

  • Ludwig A, Schulte A, Schnack C, Hundhausen C, Reiss K, Brodway N et al (2005) Enhanced expression and shedding of the transmembrane chemokine CXCL16 by reactive astrocytes and glioma cells. J Neurochem 93(5):1293–1303

    CAS  PubMed  Google Scholar 

  • Luyken C, Hildebrandt G, Scheidhauer K, Krisch B, Schicha H, Klug N (1994) 111Indium (DTPA-octreotide) scintigraphy in patients with cerebral gliomas. Acta Neurochir (Wien) 127(1–2):60–64

    CAS  Google Scholar 

  • Magge SN, Malik SZ, Royo NC, Chen HI, Yu L, Snyder EY et al (2009) Role of monocyte chemoattractant protein-1 (MCP-1/CCL2) in migration of neural progenitor cells toward glial tumors. J Neurosci Res 87(7):1547–1555

    CAS  PubMed  Google Scholar 

  • Matsumoto K, Nakamura T (2003) NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics. Cancer Sci 94(4):321–327

    CAS  PubMed  Google Scholar 

  • Mentlein R (2004) Cell-surface peptidases. Int Rev Cytol 235:165–213

    CAS  PubMed  Google Scholar 

  • Mentlein R (2007) Targeting pleiotropin to treat osteoarthritis. Expert Opin Ther Targets 11(7):861–867

    CAS  PubMed  Google Scholar 

  • Mentlein R, Eichler O, Forstreuter F, Held-Feindt J (2001) Somatostatin inhibits the production of vascular endothelial growth factor in human glioma cells. Int J Cancer 92(4):545–550

    CAS  PubMed  Google Scholar 

  • Mentlein R, Forstreuter F, Mehdorn HM, Held-Feindt J (2004) Functional significance of vascular endothelial growth factor receptor expression on human glioma cells. J Neurooncol 67(1–2):9–18

    PubMed  Google Scholar 

  • Mentlein R, Hattermann K, Held-Feindt J (2012) Lost in disruption: role of proteases in glioma invasion and progression. Biochim Biophys Acta 1825(2):178–185

    CAS  PubMed  Google Scholar 

  • Mentlein R, Hattermann K, Held-Feindt J (2013) Migration, metastasis and more: the role of chemokines in the proliferation, spreading and metastasis of tumors. In: Resende R, Ulrich H (eds) Trends in stem cell proliferation and cancer research. Springer, Vienna, pp. 339–358

    Google Scholar 

  • Mentlein R, Held-Feindt J (2002) Pleiotrophin, an angiogenic and mitogenic growth factor, is expressed in human gliomas. J Neurochem 83(4):747–753

    CAS  PubMed  Google Scholar 

  • Mentlein R, Held-Feindt J (2003) Angiogenesis factors in gliomas: a new key to tumour therapy? Naturwissenschaften 90(9):385–394

    CAS  PubMed  Google Scholar 

  • Merlo A, Hausmann O, Wasner M, Steiner P, Otte A, Jermann E et al (1999) Locoregional regulatory peptide receptor targeting with the diffusible somatostatin analogue 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC): a pilot study in human gliomas. Clin Cancer Res 5(5):1025–1033

    CAS  PubMed  Google Scholar 

  • Merzak A, McCrea S, Koocheckpour S, Pilkington GJ (1994) Control of human glioma cell growth, migration and invasion in vitro by transforming growth factor beta 1. Br J Cancer 70(2):199–203

    CAS  PubMed Central  PubMed  Google Scholar 

  • Michieli P, Mazzone M, Basilico C, Cavassa S, Sottile A, Naldini L et al (2004) Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell 6(1):61–73

    CAS  PubMed  Google Scholar 

  • Miller RJ, Rostene W, Apartis E, Banisadr G, Biber K, Milligan ED et al (2008) Chemokine action in the nervous system. J Neurosci 28(46):11792–11795

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mishima K, Higashiyama S, Asai A, Yamaoka K, Nagashima Y, Taniguchi N et al (1998) Heparin-binding epidermal growth factor-like growth factor stimulates mitogenic signaling and is highly expressed in human malignant gliomas. Acta Neuropathol 96(4):322–328

    CAS  PubMed  Google Scholar 

  • Montana V, Sontheimer H (2011) Bradykinin promotes the chemotactic invasion of primary brain tumors. J Neurosci 31(13):4858–4867

    CAS  PubMed Central  PubMed  Google Scholar 

  • Moriyama T, Kataoka H, Hamasuna R, Yokogami K, Uehara H, Kawano H et al (1998) Up-regulation of vascular endothelial growth factor induced by hepatocyte growth factor/scatter factor stimulation in human glioma cells. Biochem Biophys Res Commun 249(1):73–77

    CAS  PubMed  Google Scholar 

  • Moroz MA, Huang R, Kochetkov T, Shi W, Thaler H, de Stanchina E et al (2011) Comparison of corticotropin-releasing factor, dexamethasone, and temozolomide: treatment efficacy and toxicity in U87 and C6 intracranial gliomas. Clin Cancer Res 17(10):3282–3292

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mortier A, Gouwy M, Van Damme J, Proost P (2011) Effect of posttranslational processing on the in vitro and in vivo activity of chemokines. Exp Cell Res 317(5):642–654

    CAS  PubMed  Google Scholar 

  • Mukasa A, Wykosky J, Ligon KL, Chin L, Cavenee WK, Furnari F (2010) Mutant EGFR is required for maintenance of glioma growth in vivo, and its ablation leads to escape from receptor dependence. Proc Natl Acad Sci U S A 107(6):2616–2621

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nagasawa T, Kikutani H, Kishimoto T (1994) Molecular cloning and structure of a pre-B-cell growth-stimulating factor. Proc Natl Acad Sci U S A 91(6):2305–2309

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nakada M, Kita D, Teng L, Pyko IV, Watanabe T, Hayashi Y et al (2013) Receptor tyrosine kinases: principles and functions in glioma invasion. Adv Exp Med Biol 986:143–170

    CAS  PubMed  Google Scholar 

  • Nazarenko I, Hede SM, He X, Hedren A, Thompson J, Lindstrom MS et al (2012) PDGF and PDGF receptors in glioma. Ups J Med Sci 117(2):99–112

    PubMed Central  PubMed  Google Scholar 

  • Nazarenko I, Hedren A, Sjodin H, Orrego A, Andrae J, Afink GB et al (2011) Brain abnormalities and glioma-like lesions in mice overexpressing the long isoform of PDGF-A in astrocytic cells. PLoS One 6(4):e18303

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nister M, Libermann TA, Betsholtz C, Pettersson M, Claesson-Welsh L, Heldin CH et al (1988) Expression of messenger RNAs for platelet-derived growth factor and transforming growth factor-alpha and their receptors in human malignant glioma cell lines. Cancer Res 48(14):3910–3918

    CAS  PubMed  Google Scholar 

  • Oikonomou E, Buchfelder M, Adams EF (2008) Cholecystokinin (CCK) and CCK receptor expression by human gliomas: evidence for an autocrine/paracrine stimulatory loop. Neuropeptides 42(3):255–265

    CAS  PubMed  Google Scholar 

  • Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S et al (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478(7368):197–203

    CAS  PubMed  Google Scholar 

  • Ozawa T, Brennan CW, Wang L, Squatrito M, Sasayama T, Nakada M et al (2010) PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas. Genes Dev 24(19):2205–2218

    CAS  PubMed Central  PubMed  Google Scholar 

  • Paulsson J, Lindh MB, Jarvius M, Puputti M, Nister M, Nupponen NN et al (2011) Prognostic but not predictive role of platelet-derived growth factor receptors in patients with recurrent glioblastoma. Int J Cancer 128(8):1981–1988

    CAS  PubMed  Google Scholar 

  • Penuelas S, Anido J, Prieto-Sanchez RM, Folch G, Barba I, Cuartas I et al (2009) TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15(4):315–327

    CAS  PubMed  Google Scholar 

  • Pinski J, Schally AV, Halmos G, Szepeshazi K, Groot K (1994) Somatostatin analogues and bombesin/gastrin-releasing peptide antagonist RC-3095 inhibit the growth of human glioblastomas in vitro and in vivo. Cancer Res 54(22):5895–5901

    CAS  PubMed  Google Scholar 

  • Platten M, Kretz A, Naumann U, Aulwurm S, Egashira K, Isenmann S et al (2003) Monocyte chemoattractant protein-1 increases microglial infiltration and aggressiveness of gliomas. Ann Neurol 54(3):388–392

    CAS  PubMed  Google Scholar 

  • Potti A, Forseen SE, Koka VK, Pervez H, Koch M, Fraiman G et al (2004) Determination of HER-2/neu overexpression and clinical predictors of survival in a cohort of 347 patients with primary malignant brain tumors. Cancer Invest 22(4):537–544

    CAS  PubMed  Google Scholar 

  • Pozsgai E, Schally AV, Halmos G, Rick F, Bellyei S (2010) The inhibitory effect of a novel cytotoxic somatostatin analogue AN-162 on experimental glioblastoma. Horm Metab Res 42(11):781–786

    CAS  PubMed  Google Scholar 

  • Prickett TD, Samuels Y (2012) Molecular pathways: dysregulated glutamatergic signaling pathways in cancer. Clin Cancer Res 18(16):4240–4246

    CAS  PubMed Central  PubMed  Google Scholar 

  • Puri N, Khramtsov A, Ahmed S, Nallasura V, Hetzel JT, Jagadeeswaran R et al (2007) A selective small molecule inhibitor of c-Met, PHA665752, inhibits tumorigenicity and angiogenesis in mouse lung cancer xenografts. Cancer Res 67(8):3529–3534

    CAS  PubMed  Google Scholar 

  • Rafei M, Deng J, Boivin MN, Williams P, Matulis SM, Yuan S et al (2011) A MCP1 fusokine with CCR2-specific tumoricidal activity. Mol Cancer 10:121

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rajagopal S, Kim J, Ahn S, Craig S, Lam CM, Gerard NP et al (2010) Beta-arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7. Proc Natl Acad Sci U S A 107(2):628–632

    PubMed Central  PubMed  Google Scholar 

  • Ransohoff RM (2009) Chemokines and chemokine receptors: standing at the crossroads of immunobiology and neurobiology. Immunity 31(5):711–721

    CAS  PubMed Central  PubMed  Google Scholar 

  • Re DB, Przedborski S (2006) Fractalkine: moving from chemotaxis to neuroprotection. Nat Neurosci 9(7):859–861

    PubMed  Google Scholar 

  • Reiss K, Mentlein R, Sievers J, Hartmann D (2002) Stromal cell-derived factor 1 is secreted by meningeal cells and acts as chemotactic factor on neuronal stem cells of the cerebellar external granular layer. Neuroscience 115(1):295–305

    CAS  PubMed  Google Scholar 

  • Rempel SA, Dudas S, Ge S, Gutierrez JA (2000) Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res 6(1):102–111

    CAS  PubMed  Google Scholar 

  • Rodero M, Marie Y, Coudert M, Blondet E, Mokhtari K, Rousseau A et al (2008) Polymorphism in the microglial cell-mobilizing CX3CR1 gene is associated with survival in patients with glioblastoma. J Clin Oncol 26(36):5957–5964

    PubMed  Google Scholar 

  • Rosen EM, Laterra J, Joseph A, Jin L, Fuchs A, Way D et al (1996) Scatter factor expression and regulation in human glial tumors. Int J Cancer 67(2):248–255

    CAS  PubMed  Google Scholar 

  • Rot A (2010) Chemokine patterning by glycosaminoglycans and interceptors. Front Biosci 15:645–660

    CAS  Google Scholar 

  • Saidi A, Hagedorn M, Allain N, Verpelli C, Sala C, Bello L et al (2009) Combined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness. Int J Cancer 125(5):1054–1064

    CAS  PubMed  Google Scholar 

  • Schmidt NO, Westphal M, Hagel C, Ergun S, Stavrou D, Rosen EM et al (1999) Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int J Cancer 84(1):10–18

    CAS  PubMed  Google Scholar 

  • Sciaccaluga M, Fioretti B, Catacuzzeno L, Pagani F, Bertollini C, Rosito M et al (2010) CXCL12-induced glioblastoma cell migration requires intermediate conductance Ca2+-activated K+ channel activity. Am J Physiol Cell Physiol 299(1):C175–C184

    CAS  PubMed  Google Scholar 

  • Semple BD, Kossmann T, Morganti-Kossmann MC (2010) Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J Cereb Blood Flow Metab 30(3):459–473

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sherry MM, Reeves A, Wu JK, Cochran BH (2009) STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 27(10):2383–2392

    CAS  PubMed  Google Scholar 

  • Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R et al (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318(5848):287–290

    CAS  PubMed  Google Scholar 

  • Strauss LG, Koczan D, Seiz M, Tuettenberg J, Schmieder K, Pan L et al (2012) Correlation of the Ga-68-bombesin analog Ga-68-BZH3 with receptors expression in gliomas as measured by quantitative dynamic positron emission tomography (dPET) and gene arrays. Mol Imaging Biol 14(3):376–383

    PubMed  Google Scholar 

  • Stylianou DC, Auf der Maur A, Kodack DP, Henke RT, Hohn S, Toretsky JA et al (2009) Effect of single-chain antibody targeting of the ligand-binding domain in the anaplastic lymphoma kinase receptor. Oncogene 28(37):3296–3306

    CAS  PubMed  Google Scholar 

  • Swiatek-Machado K, Kaminska B (2013) STAT signaling in glioma cells. Adv Exp Med Biol 986:189–208

    CAS  PubMed  Google Scholar 

  • Tang P, Steck PA, Yung WK (1997) The autocrine loop of TGF-alpha/EGFR and brain tumors. J Neurooncol 35(3):303–314

    CAS  PubMed  Google Scholar 

  • Tchirkov A, Rolhion C, Bertrand S, Dore JF, Dubost JJ, Verrelle P (2001) IL-6 gene amplification and expression in human glioblastomas. Br J Cancer 85(4):518–522

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ulbricht U, Eckerich C, Fillbrandt R, Westphal M, Lamszus K (2006) RNA interference targeting protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta suppresses glioblastoma growth in vitro and in vivo. J Neurochem 98(5):1497–1506

    CAS  PubMed  Google Scholar 

  • Van Brocklyn JR, Jackson CA, Pearl DK, Kotur MS, Snyder PJ, Prior TW (2005) Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol 64(8):695–705

    PubMed  Google Scholar 

  • Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang H, Lathia JD, Wu Q, Wang J, Li Z, Heddleston JM et al (2009) Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth. Stem Cells 27(10):2393–2404

    CAS  PubMed Central  PubMed  Google Scholar 

  • Weissenberger J, Loeffler S, Kappeler A, Kopf M, Lukes A, Afanasieva TA et al (2004) IL-6 is required for glioma development in a mouse model. Oncogene 23(19):3308–3316

    CAS  PubMed  Google Scholar 

  • Widera D, Holtkamp W, Entschladen F, Niggemann B, Zanker K, Kaltschmidt B et al (2004) MCP-1 induces migration of adult neural stem cells. Eur J Cell Biol 83(8):381–387

    CAS  PubMed  Google Scholar 

  • Wiesenhofer B, Stockhammer G, Kostron H, Maier H, Hinterhuber H, Humpel C (2000) Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-alpha 1) are strongly expressed in human gliomas. Acta Neuropathol 99(2):131–137

    CAS  PubMed  Google Scholar 

  • Wrann M, Bodmer S, de Martin R, Siepl C, Hofer-Warbinek R, Frei K et al (1987) T cell suppressor factor from human glioblastoma cells is a 12.5-kd protein closely related to transforming growth factor-beta. EMBO J 6(6):1633–1636

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wu X, Han L, Zhang X, Li L, Jiang C, Qiu Y et al (2012) Alteration of endocannabinoid system in human gliomas. J Neurochem 120(5):842–849

    CAS  PubMed  Google Scholar 

  • Yamada N, Kato M, Yamashita H, Nister M, Miyazono K, Heldin CH et al (1995) Enhanced expression of transforming growth factor-beta and its type-I and type-II receptors in human glioblastoma. Int J Cancer 62(4):386–392

    CAS  PubMed  Google Scholar 

  • Yamagami S, Tokuda Y, Ishii K, Tanaka H, Endo N (1994) cDNA cloning and functional expression of a human monocyte chemoattractant protein 1 receptor. Biochem Biophys Res Commun 202(2):1156–1162

    CAS  PubMed  Google Scholar 

  • Yang SX, Chen JH, Jiang XF, Wang QL, Chen ZQ, Zhao W et al (2005) Activation of chemokine receptor CXCR4 in malignant glioma cells promotes the production of vascular endothelial growth factor. Biochem Biophys Res Commun 335(2):523–528

    CAS  PubMed  Google Scholar 

  • Yoshimura T, Robinson EA, Tanaka S, Appella E, Kuratsu J, Leonard EJ (1989) Purification and amino acid analysis of two human glioma-derived monocyte chemoattractants. J Exp Med 169(4):1449–1459

    CAS  PubMed  Google Scholar 

  • Young N, Pearl DK, Van Brocklyn JR (2009) Sphingosine-1-phosphate regulates glioblastoma cell invasiveness through the urokinase plasminogen activator system and CCN1/Cyr61. Mol Cancer Res 7(1):23–32

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang J, Sarkar S, Yong VW (2005) The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase. Carcinogenesis 26(12):2069–2077

    CAS  PubMed  Google Scholar 

  • Zhu VF, Yang J, Lebrun DG, Li M (2012) Understanding the role of cytokines in Glioblastoma Multiforme pathogenesis. Cancer Lett 316(2):139–150

    CAS  PubMed  Google Scholar 

  • Zhu X, Fujita M, Snyder LA, Okada H (2011) Systemic delivery of neutralizing antibody targeting CCL2 for glioma therapy. J Neurooncol 104(1):83–92

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zujovic V, Benavides J, Vige X, Carter C, Taupin V (2000) Fractalkine modulates TNF-alpha secretion and neurotoxicity induced by microglial activation. Glia 29(4):305–315

    CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Clemens Franke for careful drawing figures. The own experimental work cited in the text is based on long collaborations and the great support of a team of engaged coworkers. Of these, which we cannot all mention, but we would like to thank especially our ambitious technicians Judith Becker, Martina Burmester, Sonja Dahle, Dagmar Freier, Miriam Lemmer and Ursula Prange and our colleagues Prof. Dr. Dr. Janka Held-Feindt and Prof. Dr. H. Maximilian Mehdorn from the Department of Neurosurgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany. RM is also particularity indebted to his deceased colleague Prof. Dr. Brigitte Krisch, who introduced him into the fields of neuropeptides and brain morphology. The authors declare that they have no competing interests. Due to space constraints, we apologize to colleagues in the field for not citing their relevant studies.

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  1. Department of Anatomy, University of Kiel, Olshausenstraße 40, 24098, Kiel, Germany

    Kirsten Hattermann & Rolf Mentlein

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  1. Kirsten Hattermann
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Correspondence to Rolf Mentlein .

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  1. Biochemistry and Experimental Oncology, Charles University Prague 1st Faculty of Medicine, Prague, Czech Republic

    Aleksi Sedo

  2. Anatomisches Institut, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

    Rolf Mentlein

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Hattermann, K., Mentlein, R. (2014). Para- and Autocrine Mediators in the Glioma Microenvironment. In: Sedo, A., Mentlein, R. (eds) Glioma Cell Biology. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1431-5_6

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