Skip to main content
SpringerLink
Log in

Aberrant Signalling Complexes in GBMs: Prognostic and Therapeutic Implications

  • Chapter
  • First Online:
Glioblastoma

  • 1813 Accesses

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumour and one of the most deadly forms of cancer. GBM can arise in previously healthy individuals (primary GBM) or result from the malignant transformation of lower-grade gliomas (secondary GBM). Primary and secondary GBMs display different molecular alterations, suggesting different signalling pathways in their development. The current knowledge in terms of signalling and molecular alterations typical of GBM is presented and discussed in this chapter. Briefly, the aberrant signalling pathways can be divided into those that affect growth factor signalling and those that deregulate the cell cycle pathways. The main growth factor alterations are those affecting PDGF, EGFR, VEGF, HGF/SF, integrins, MMPs/TIMPs, p21-RAS, PI3K-PTEN-AKT, JAK-STAT, and PKC. As for the cell cycle pathway alterations, some of the principal ones are those involving p53, Rb, and p16/cdk4/cyclinD/pRb. In addition, the mechanisms underlying some key GBM features such as angiogenesis and invasion deserve special attention considering the most recent therapeutic implications. A thorough presentation of the main undergoing and completed clinical trial with inhibitors of growth factors or aberrant pathways is provided in this chapter. Novel therapeutic agents include anti-PDGFR, anti-EGFR, anti-VEGF, anti-VEGFR, anti-SF/HGF molecules, inhibitors of integrins and metalloproteinases, and blocking agents of Ras, MTOR/PI3K, and PKC pathways. In the foreseeable future, patients with GBM will have a molecular characterization of their tumour and therapies might be tailored for each case.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Antoniades HN, Scher CD, Stiles CD (1979) Purification of human platelet-derived growth factor. Proc Natl Acad Sci USA 76(4):1809–1813

    Article  CAS  PubMed  Google Scholar 

  • Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, Rich JN (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66(16):7843–7848

    Article  CAS  PubMed  Google Scholar 

  • Bello L, Lucini V, Carrabba G, Giussani C, Machluf M, Pluderi M, Nikas D, Zhang J, Tomei G, Villani RM, Carroll RS, Bikfalvi A, Black PM (2001a) Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2. Cancer Res 61(24):8730–8736

    CAS  PubMed  Google Scholar 

  • Bello L, Francolini M, Marthyn P, Zhang J, Carroll RS, Nikas DC, Strasser JF, Villani R, Cheresh DA, Black PM (2001a) Alpha(v)beta3 and alpha(v)beta5 integrin expression in glioma periphery. Neurosurgery 49(2):380–389; discussion 390

    Google Scholar 

  • Bello L, Giussani C, Carrabba G, Pluderi M, Lucini V, Pannacci M, Caronzolo D, Tomei G, Villani R, Scaglione F, Carroll RS, Bikfalvi A (2002) Suppression of malignant glioma recurrence in a newly developed animal model by endogenous inhibitors. Clin Cancer Res 8(11):3539–3548

    CAS  PubMed  Google Scholar 

  • Bello L, Lucini V, Costa F, Pluderi M, Giussani C, Acerbi F, Carrabba G, Pannacci M, Caronzolo D, Grosso S, Shinkaruk S, Colleoni F, Canron X, Tomei G, Deleris G, Bikfalvi A (2004) Combinatorial administration of molecules that simultaneously inhibit angiogenesis and invasion leads to increased therapeutic efficacy in mouse models of malignant glioma. Clin Cancer Res 10(13):4527–4537

    Article  CAS  PubMed  Google Scholar 

  • Bergsten E, Uutela M, Li X, Pietras K, Ostman A, Heldin CH, Alitalo K, Eriksson U (2001) PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. Nat Cell Biol 3(5):512–516

    Article  CAS  PubMed  Google Scholar 

  • Berkman RA, Merrill MJ, Reinhold WC, Monacci WT, Saxena A, Clark WC, Robertson JT, Ali IU, Oldfield EH (1993) Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest 91(1):153–159

    Article  CAS  PubMed  Google Scholar 

  • Bigg HF, Shi YE, Liu YE, Steffensen B, Overall CM (1997) Specific, high affinity binding of tissue inhibitor of metalloproteinases-4 (TIMP-4) to the COOH-terminal hemopexin-like domain of human gelatinase A. TIMP-4 binds progelatinase A and the COOH-terminal domain in a similar manner to TIMP-2. J Biol Chem 272(24):15496–15500

    Google Scholar 

  • Binder DK, Berger MS (2002) Proteases and the biology of glioma invasion. J Neurooncol 56(2):149–158

    Article  PubMed  Google Scholar 

  • Bjerkvig R, Lund-Johansen M, Edvardsen K (1997) Tumor cell invasion and angiogenesis in the central nervous system. Curr Opin Oncol 9(3):223–229

    Article  CAS  PubMed  Google Scholar 

  • Blumberg PM (1991) Complexities of the protein kinase C pathway. Mol Carcinog 4(5):339–344

    Article  CAS  PubMed  Google Scholar 

  • Bos JL (1989) ras oncogenes in human cancer: A review. Cancer Res 49(17):4682–4689

    CAS  PubMed  Google Scholar 

  • Brandes AA, Ermani M, Turazzi S, Scelzi E, Berti F, Amista P, Rotilio A, Licata C, Fiorentino MV (1999) Procarbazine and high-dose tamoxifen as a second-line regimen in recurrent high-grade gliomas: A phase II study. J Clin Oncol 17(2):645–650

    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 1399

    Google Scholar 

  • Brooks PC (1996) Role of integrins in angiogenesis. Eur J Cancer 32A(14):2423–2429

    Article  CAS  PubMed  Google Scholar 

  • Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Stetler-Stevenson WG, Quigley JP, Cheresh DA (1996) Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 85(5):683–693

    Article  CAS  PubMed  Google Scholar 

  • Brooks PC, Silletti S, von Schalscha TL, Friedlander M, Cheresh DA (1998) Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell 92(3):391–400

    Article  CAS  PubMed  Google Scholar 

  • Bussolino F, Di Renzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L, Gaudino G, Tamagnone L, Coffer A, Comoglio PM (1992) Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 119(3):629–641

    Article  CAS  PubMed  Google Scholar 

  • Cai W, Chen X (2006) Anti-angiogenic cancer therapy based on integrin alphavbeta3 antagonism. Anticancer Agents Med Chem 6(5):407–428

    Article  CAS  PubMed  Google Scholar 

  • Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407(6801):249–257

    Article  CAS  PubMed  Google Scholar 

  • Chamberlain MC (2008) Bevacizumab plus irinotecan in recurrent glioblastoma. J Clin Oncol 26(6):1012–1013; author reply 1013

    Google Scholar 

  • Chang SM, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, Fink K, Robins HI, De Angelis L, Raizer J, Hess K, Aldape K, Lamborn KR, Kuhn J, Dancey J, Prados MD (2005) Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23(4):357–361

    Article  CAS  PubMed  Google Scholar 

  • Cheng SY, Huang HJ, Nagane M, Ji XD, Wang D, Shih CC, Arap W, Huang CM, Cavenee WK (1996) Suppression of glioblastoma angiogenicity and tumorigenicity by inhibition of endogenous expression of vascular endothelial growth factor. Proc Natl Acad Sci USA 93(16):8502–8507

    Article  CAS  PubMed  Google Scholar 

  • Choi C, Jeong E, Benveniste EN (2004) Caspase-1 mediates Fas-induced apoptosis and is up-regulated by interferon-gamma in human astrocytoma cells. J Neurooncol 67(1–2):167–176

    Article  PubMed  Google Scholar 

  • Clark EA, Leach KL, Trojanowski JQ, Lee VM (1991) Characterization and differential distribution of the three major human protein kinase C isozymes (PKC alpha, PKC beta, and PKC gamma) of the central nervous system in normal and Alzheimer’s disease brains. Lab Invest 64(1):35–44

    CAS  PubMed  Google Scholar 

  • Cloughesy TF, Wen PY, Robins HI, Chang SM, Groves MD, Fink KL, Junck L, Schiff D, Abrey L, Gilbert MR, Lieberman F, Kuhn J, DeAngelis LM, Mehta M, Raizer JJ, Yung WK, Aldape K, Wright J, Lamborn KR, Prados MD (2006) Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: A North American Brain Tumor Consortium Study. J Clin Oncol 24(22):3651–3656

    Article  CAS  PubMed  Google Scholar 

  • Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ (1996) Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem 271(2):736–741

    Article  CAS  PubMed  Google Scholar 

  • Collins VP (1995) Gene amplification in human gliomas. Glia 15(3):289–296

    Article  CAS  PubMed  Google Scholar 

  • Combs SE, Heeger S, Haselmann R, Edler L, Debus J, Schulz-Ertner D (2006) Treatment of primary glioblastoma multiforme with cetuximab, radiotherapy and temozolomide (GERT)--phase I/II trial: Study protocol. BMC Cancer 6:133

    Google Scholar 

  • Connolly DT (1991) Vascular permeability factor: A unique regulator of blood vessel function. J Cell Biochem 47(3):219–223

    Article  CAS  PubMed  Google Scholar 

  • Cooper CS, Park M, Blair DG, Tainsky MA, Huebner K, Croce CM, Vande Woude GF (1984) Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 311(5981):29–33

    Article  CAS  PubMed  Google Scholar 

  • Couldwell WT, Antel JP, Yong VW (1992) Protein kinase C activity correlates with the growth rate of malignant gliomas: Part II. Effects of glioma mitogens and modulators of protein kinase C. Neurosurgery 31(4):717–724; discussion 724.

    Google Scholar 

  • Criscuolo GR, Merrill MJ, Oldfield EH (1988) Further characterization of malignant glioma-derived vascular permeability factor. J Neurosurg 69(2):254–262

    Article  CAS  PubMed  Google Scholar 

  • Cullinan-Bove K, Koos RD (1993) Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: Rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth. Endocrinology 133(2):829–837

    Article  CAS  PubMed  Google Scholar 

  • Damert A, Machein M, Breier G, Fujita MQ, Hanahan D, Risau W, Plate KH (1997) Up-regulation of vascular endothelial growth factor expression in a rat glioma is conferred by two distinct hypoxia-driven mechanisms. Cancer Res 57(17):3860–3864

    CAS  PubMed  Google Scholar 

  • de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255(5047):989–991

    Article  PubMed  Google Scholar 

  • Dresemann G (2005) Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: A patient series. Ann Oncol 16(10):1702–1708

    Article  CAS  PubMed  Google Scholar 

  • Dvorak HF, Nagy JA, Feng D, Brown LF, Dvorak AM (1999) Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Curr Top Microbiol Immunol 237:97–132

    CAS  PubMed  Google Scholar 

  • Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG (2000) Heterogeneity of angiogenesis and blood vessel maturation in human tumors: Implications for antiangiogenic tumor therapies. Cancer Res 60(5):1388–1393

    CAS  PubMed  Google Scholar 

  • Ekman S, Thuresson ER, Heldin CH, Ronnstrand L (1999) Increased mitogenicity of an alphabeta heterodimeric PDGF receptor complex correlates with lack of RasGAP binding. Oncogene 18(15):2481–2488

    Article  CAS  PubMed  Google Scholar 

  • Ekstrand AJ, Longo N, Hamid ML, Olson JJ, Liu L, Collins VP, James CD (1994) Functional characterization of an EGF receptor with a truncated extracellular domain expressed in glioblastomas with EGFR gene amplification. Oncogene 9(8):2313–2320

    Google Scholar 

  • Eller JL, Longo SL, Kyle MM, Bassano D, Hicklin DJ, Canute GW (2005) Anti-epidermal growth factor receptor monoclonal antibody cetuximab augments radiation effects in glioblastoma multiforme in vitro and in vivo. Neurosurgery 56(1):155–162; discussion 162

    Google Scholar 

  • Esser S, Wolburg K, Wolburg H, Breier G, Kurzchalia T, Risau W (1998) Vascular endothelial growth factor induces endothelial fenestrations in vitro. J Cell Biol 140(4):947–959

    Article  CAS  PubMed  Google Scholar 

  • Feldkamp MM, Lala P, Lau N, Roncari L, Guha A (1999a) Expression of activated epidermal growth factor receptors, Ras-guanosine triphosphate, and mitogen-activated protein kinase in human glioblastoma multiforme specimens. Neurosurgery 45(6):1442–1453

    Article  CAS  PubMed  Google Scholar 

  • Feldkamp MM, Angelov L, Guha A (1999b) Neurofibromatosis type 1 peripheral nerve tumors: Aberrant activation of the Ras pathway. Surg Neurol 51(2):211–218

    Article  CAS  PubMed  Google Scholar 

  • Feldkamp MM, Lau N, Guha A (1999c) The farnesyltransferase inhibitor L-744, 832 inhibits the growth of astrocytomas through a combination of antiproliferative, antiangiogenic, and proapoptotic activities. Ann N Y Acad Sci 886:257–260

    Article  CAS  PubMed  Google Scholar 

  • Feldkamp MM, Lau N, Roncari L, Guha A (2001) Isotype-specific Ras.GTP-levels predict the efficacy of farnesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status. Cancer Res 61(11):4425–4431

    Google Scholar 

  • Fischer S, Wobben M, Marti HH, Renz D, Schaper W (2002) Hypoxia-induced hyperpermeability in brain microvessel endothelial cells involves VEGF-mediated changes in the expression of zonula occludens-1. Microvasc Res 63(1):70–80

    Article  CAS  PubMed  Google Scholar 

  • Forsyth PA, Laing TD, Gibson AW, Rewcastle NB, Brasher P, Sutherland G, Johnston RN, Edwards DR (1998) High levels of gelatinase-B and active gelatinase-A in metastatic glioblastoma. J Neurooncol 36(1):21–29

    Article  CAS  PubMed  Google Scholar 

  • Forsyth PA, Wong H, Laing TD, Rewcastle NB, Morris DG, Muzik H, Leco KJ, Johnston RN, Brasher PM, Sutherland G, Edwards DR (1999) Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas. Br J Cancer 79(11–12):1828–1835

    Article  CAS  PubMed  Google Scholar 

  • 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(9):4604–4613

    CAS  PubMed  Google Scholar 

  • Franceschi E, Cavallo G, Lonardi S, Magrini E, Tosoni A, Grosso D, Scopece L, Blatt V, Urbini B, Pession A, Tallini G, Crino L, Brandes AA (2007) Gefitinib in patients with progressive high-grade gliomas: A multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Br J Cancer 96(7):1047–1051

    Article  CAS  PubMed  Google Scholar 

  • Friedl P, Wolf K (2003) Tumour-cell invasion and migration: Diversity and escape mechanisms. Nat Rev Cancer 3(5):362–374

    Article  CAS  PubMed  Google Scholar 

  • Fulci G, Ishii N, Van Meir EG (1998) p53 and brain tumors: From gene mutations to gene therapy. Brain Pathol 8(4):599–613

    Article  CAS  PubMed  Google Scholar 

  • Furnari FB, Lin H, Huang HS, Cavenee WK (1997) Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. Proc Natl Acad Sci USA 94(23):12479–12484

    Article  CAS  PubMed  Google Scholar 

  • Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J, Peralba JM, Jenkins RB, Dakhil SR, Morton RF, Jaeckle KA, Scheithauer BW, Dancey J, Hidalgo M, Walsh DJ (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A North Central Cancer Treatment Group Study. J Clin Oncol 23(23):5294–5304

    Article  CAS  PubMed  Google Scholar 

  • Geng L, Shinohara ET, Kim D, Tan J, Osusky K, Shyr Y, Hallahan DE (2006) STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma. Int J Radiat Oncol Biol Phys 64(1):263–271

    PubMed  Google Scholar 

  • Giese A, Westphal M (1996) Glioma invasion in the central nervous system. Neurosurgery 39(2):235–250; discussion 250–252

    Google Scholar 

  • Giese A, Bjerkvig R, Berens ME, Westphal M (2003) Cost of migration: Invasion of malignant gliomas and implications for treatment. J Clin Oncol 21(8):1624–1636

    Article  CAS  PubMed  Google Scholar 

  • Gladson CL, Wilcox JN, Sanders L, Gillespie GY, Cheresh DA (1995) Cerebral microenvironment influences expression of the vitronectin gene in astrocytic tumors. J Cell Sci 108 (Pt 3):947–956

    Google Scholar 

  • Goldbrunner RH, Bendszus M, Wood J, Kiderlen M, Sasaki M, Tonn JC (2004) PTK787/ZK222584, an inhibitor of vascular endothelial growth factor receptor tyrosine kinases, decreases glioma growth and vascularization. Neurosurgery 55(2):426–432; discussion 432

    Google Scholar 

  • Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY (1993) Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: A model of glioblastoma multiforme pathophysiology. Mol Biol Cell 4(1):121–133

    CAS  PubMed  Google Scholar 

  • Golub TR, Barker GF, Lovett M, Gilliland DG (1994) Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 77(2):307–316

    Article  CAS  PubMed  Google Scholar 

  • Goudar RK, Shi Q, Hjelmeland MD, Keir ST, McLendon RE, Wikstrand CJ, Reese ED, Conrad CA, Traxler P, Lane HA, Reardon DA, Cavenee WK, Wang XF, Bigner DD, Friedman HS, Rich JN (2005) Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Mol Cancer Ther 4(1):101–112

    CAS  PubMed  Google Scholar 

  • Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379(6560):88–91

    Article  CAS  PubMed  Google Scholar 

  • Grant DS, Kleinman HK, Goldberg ID, Bhargava MM, Nickoloff BJ, Kinsella JL, Polverini P, Rosen EM (1993) Scatter factor induces blood vessel formation in vivo. Proc Natl Acad Sci USA 90(5):1937–1941

    Article  CAS  PubMed  Google Scholar 

  • Grimmond S, Lagercrantz J, Drinkwater C, Silins G, Townson S, Pollock P, Gotley D, Carson E, Rakar S, Nordenskjold M, Ward L, Hayward N, Weber G (1996) Cloning and characterization of a novel human gene related to vascular endothelial growth factor. Genome Res 6(2):124–131

    Article  CAS  PubMed  Google Scholar 

  • Groves MD, Puduvalli VK, Hess KR, Jaeckle KA, Peterson P, Yung WK, Levin VA (2002) Phase II trial of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme. J Clin Oncol 20(5):1383–1388

    Article  CAS  PubMed  Google Scholar 

  • Grugel S, Finkenzeller G, Weindel K, Barleon B, Marme D (1995) Both v-Ha-Ras and v-Raf stimulate expression of the vascular endothelial growth factor in NIH 3T3 cells. J Biol Chem 270(43):25915–25919

    Article  CAS  PubMed  Google Scholar 

  • Guha A (1991) Platelet-derived growth factor: A general review with emphasis on astrocytomas. Pediatr Neurosurg 17(1):14–20

    Article  PubMed  Google Scholar 

  • Guha A, Dashner K, Black PM, Wagner JA, Stiles CD (1995) Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. Int J Cancer 60(2):168–173

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364

    Article  CAS  PubMed  Google Scholar 

  • Harada H, Nakagawa K, Iwata S, Saito M, Kumon Y, Sakaki S, Sato K, Hamada K (1999) Restoration of wild-type p16 down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human gliomas. Cancer Res 59(15):3783–3789

    CAS  PubMed  Google Scholar 

  • Hashizume H, Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156(4):1363–1380

    CAS  PubMed  Google Scholar 

  • Hattori K, Dias S, Heissig B, Hackett NR, Lyden D, Tateno M, Hicklin DJ, Zhu Z, Witte L, Crystal RG, Moore MA, Rafii S (2001) Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med 193(9):1005–1014

    Article  CAS  PubMed  Google Scholar 

  • Hatva E, Kaipainen A, Mentula P, Jaaskelainen J, Paetau A, Haltia M, Alitalo K (1995) Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. Am J Pathol 146(2):368–378

    CAS  PubMed  Google Scholar 

  • Haupt Y, Maya R, Kazaz A, Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387(6630):296–299

    Article  CAS  PubMed  Google Scholar 

  • Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79(4):1283–1316

    CAS  PubMed  Google Scholar 

  • Heldin CH, Ostman A, Ronnstrand L (1998) Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta 1378(1):F79–F113

    CAS  PubMed  Google Scholar 

  • Heldin CH, Eriksson U, Ostman A (2002) New members of the platelet-derived growth factor family of mitogens. Arch Biochem Biophys 398(2):284–290

    Article  CAS  PubMed  Google Scholar 

  • Helmlinger G, Endo M, Ferrara N, Hlatky L, Jain RK (2000) Formation of endothelial cell networks. Nature 405(6783):139–141

    Article  CAS  PubMed  Google Scholar 

  • Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B, Nister M (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 

  • Hiratsuka S, Maru Y, Okada A, Seiki M, Noda T, Shibuya M (2001) Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res 61(3):1207–1213

    CAS  PubMed  Google Scholar 

  • Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, Torchilin VP, Jain RK (1998) Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment. Proc Natl Acad Sci USA 95(8):4607–4612

    Article  CAS  PubMed  Google Scholar 

  • Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, Boland P, Leidich R, Hylton D, Burova E, Ioffe E, Huang T, Radziejewski C, Bailey K, Fandl JP, Daly T, Wiegand SJ, Yancopoulos GD, Rudge JS (2002) VEGF-Trap: A VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 99(17):11393–11398

    Article  CAS  PubMed  Google Scholar 

  • Holland EC (2001) Gliomagenesis: Genetic alterations and mouse models. Nat Rev Genet 2(2):120–129

    Article  CAS  Google Scholar 

  • Honegger P (1986) Protein kinase C-activating tumor promoters enhance the differentiation of astrocytes in aggregating fetal brain cell cultures. J Neurochem 46(5):1561–1566

    Article  CAS  PubMed  Google Scholar 

  • Huang S, Houghton PJ (2003) Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol 3(4):371–377

    Article  CAS  PubMed  Google Scholar 

  • Hui AM, Zhang W, Chen W, Xi D, Purow B, Friedman GC, Fine HA (2004) Agents with selective estrogen receptor (ER) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells. Cancer Res 64(24):9115–9123

    Article  CAS  PubMed  Google Scholar 

  • Humphrey PA, Wong AJ, Vogelstein B, Zalutsky MR, Fuller GN, Archer GE, Friedman HS, Kwatra MM, Bigner SH, Bigner DD (1990) Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci USA 87(11):4207–4211

    Article  CAS  PubMed  Google Scholar 

  • Hynes RO (1992) Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 69(1):11–25

    Article  CAS  PubMed  Google Scholar 

  • Ikeda E, Achen MG, Breier G, Risau W (1995) Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem 270(34):19761–19766

    Article  CAS  PubMed  Google Scholar 

  • James GL, Goldstein JL, Brown MS, Rawson TE, Somers TC, McDowell RS, Crowley CW, Lucas BK, Levinson AD, Marsters JC Jr (1993) Benzodiazepine peptidomimetics: Potent inhibitors of Ras farnesylation in animal cells. Science 260(5116):1937–1942

    Article  CAS  PubMed  Google Scholar 

  • Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K (1996) A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. Embo J 15(7):1751

    CAS  PubMed  Google Scholar 

  • Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246(4935):1309–1312

    Article  CAS  PubMed  Google Scholar 

  • Kieser A, Weich HA, Brandner G, Marme D, Kolch W (1994) Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9(3):963–969

    CAS  PubMed  Google Scholar 

  • Kilic T, Alberta JA, Zdunek PR, Acar M, Iannarelli P, O’Reilly T, Buchdunger E, Black PM, Stiles CD (2000) Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class. Cancer Res 60(18):5143–5150

    CAS  PubMed  Google Scholar 

  • Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362(6423):841–844

    Article  CAS  PubMed  Google Scholar 

  • Kirsch M, Strasser J, Allende R, Bello L, Zhang J, Black PM (1998) Angiostatin suppresses malignant glioma growth in vivo. Cancer Res 58(20):4654–4659

    CAS  PubMed  Google Scholar 

  • Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW (2002) Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285(1–2):1–24

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Ku DD, Zaleski JK, Liu S, Brock TA (1993) Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. Am J Physiol 265(2 Pt 2):H586–H592

    CAS  PubMed  Google Scholar 

  • Kunkel P, Muller S, Schirmacher P, Stavrou D, Fillbrandt R, Westphal M, Lamszus K (2001) Expression and localization of scatter factor/hepatocyte growth factor in human astrocytomas. Neuro Oncol 3(2):82–88

    CAS  PubMed  Google Scholar 

  • Lal A, Glazer CA, Martinson HM, Friedman HS, Archer GE, Sampson JH, Riggins GJ (2002) Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion. Cancer Res 62(12):3335–3339

    CAS  PubMed  Google Scholar 

  • Lamszus K, Jin L, Fuchs A, Shi E, Chowdhury S, Yao Y, Polverini PJ, Laterra J, Goldberg ID, Rosen EM (1997) Scatter factor stimulates tumor growth and tumor angiogenesis in human breast cancers in the mammary fat pads of nude mice. Lab Invest 76(3):339–353

    CAS  PubMed  Google Scholar 

  • Lamszus K, Heese O, Westphal M (2004) Angiogenesis-related growth factors in brain tumors. Cancer Treat Res 117:169–190

    CAS  PubMed  Google Scholar 

  • LaRochelle WJ, Jeffers M, McDonald WF, Chillakuru RA, Giese NA, Lokker NA, Sullivan C, Boldog FL, Yang M, Vernet C, Burgess CE, Fernandes E, Deegler LL, Rittman B, Shimkets J, Shimkets RA, Rothberg JM, Lichenstein HS (2001) PDGF-D, a new protease-activated growth factor. Nat Cell Biol 3(5):517–521

    Article  CAS  PubMed  Google Scholar 

  • Laterra J, Nam M, Rosen E, Rao JS, Lamszus K, Goldberg ID, Johnston P (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 DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246(4935):1306–1309

    Article  CAS  PubMed  Google Scholar 

  • Levy AP, Levy NS, Goldberg MA (1996) Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem 271(5):2746–2753

    Article  CAS  PubMed  Google Scholar 

  • Li J, Perrella MA, Tsai JC, Yet SF, Hsieh CM, Yoshizumi M, Patterson C, Endege WO, Zhou F, Lee ME (1995) Induction of vascular endothelial growth factor gene expression by interleukin-1 beta in rat aortic smooth muscle cells. J Biol Chem 270(1):308–312

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Millikan RC, Carozza S, Newman B, Liu E, Davis R, Miike R, Wrensch M (1998) p53 mutations in malignant gliomas. Cancer Epidemiol Biomarkers Prev 7(4):303–308

    CAS  PubMed  Google Scholar 

  • Li X, Ponten A, Aase K, Karlsson L, Abramsson A, Uutela M, Backstrom G, Hellstrom M, Bostrom H, Li H, Soriano P, Betsholtz C, Heldin CH, Alitalo K, Ostman A, Eriksson U (2000) PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor. Nat Cell Biol 2(5):302–309

    Article  CAS  PubMed  Google Scholar 

  • Libermann TA, Razon N, Bartal AD, Yarden Y, Schlessinger J, Soreq H (1984) Expression of epidermal growth factor receptors in human brain tumors. Cancer Res 44(2):753–760

    CAS  PubMed  Google Scholar 

  • Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schlessinger J (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 31(5998):144–147

    Article  Google Scholar 

  • Liotta LA, Steeg PS, Stetler-Stevenson WG (1991) Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation. Cell 64(2):327–336

    Article  CAS  PubMed  Google Scholar 

  • Louis DN, Gusella JF (1995) A tiger behind many doors: Multiple genetic pathways to malignant glioma. Trends Genet 11(10):412–415

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Luna EJ, Hitt AL (1992) Cytoskeleton–plasma membrane interactions. Science 258(5084):955–964

    Article  CAS  PubMed  Google Scholar 

  • Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA, Hooper A, Priller J, De Klerck B, Compernolle V, Daci E, Bohlen P, Dewerchin M, Herbert JM, Fava R, Matthys P, Carmeliet G, Collen D, Dvorak HF, Hicklin DJ, Carmeliet P (2002) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8(8):831–840

    CAS  PubMed  Google Scholar 

  • Machein MR, Kullmer J, Ronicke V, Machein U, Krieg M, Damert A, Breier G, Risau W, Plate KH (1999a) Differential downregulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells. Neuropathol Appl Neurobiol 25(2):104–112

    Article  CAS  PubMed  Google Scholar 

  • Machein MR, Kullmer J, Fiebich BL, Plate KH, Warnke PC (1999a) Vascular endothelial growth factor expression, vascular volume, and, capillary permeability in human brain tumors. Neurosurgery 44(4):732–740; discussion 740–741

    Google Scholar 

  • Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG (1991) Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 88(20):9267–9271

    Article  CAS  PubMed  Google Scholar 

  • Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA (2001) Malignant glioma: Genetics and biology of a grave matter. Genes Dev 15(11):1311–1333

    Article  CAS  PubMed  Google Scholar 

  • Maity A, Pore N, Lee J, Solomon D, O’Rourke DM (2000) Epidermal growth factor receptor transcriptionally up-regulates vascular endothelial growth factor expression in human glioblastoma cells via a pathway involving phosphatidylinositol 3’-kinase and distinct from that induced by hypoxia. Cancer Res 60(20):5879–5886

    CAS  PubMed  Google Scholar 

  • Martens T, Schmidt NO, Eckerich C, Fillbrandt R, Merchant M, Schwall R, Westphal M, Lamszus K (2006) A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo. Clin Cancer Res 12(20 Pt 1):6144–6152

    Article  CAS  PubMed  Google Scholar 

  • Martin KH, Slack JK, Boerner SA, Martin CC, Parsons JT (2002) Integrin connections map: To infinity and beyond. Science 296(5573):1652–1653

    Article  CAS  PubMed  Google Scholar 

  • Maxwell M, Naber SP, Wolfe HJ, Galanopoulos T, Hedley-Whyte ET, Black PM, Antoniades HN (1990) Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance. J Clin Invest 86(1):131–140

    Article  CAS  PubMed  Google Scholar 

  • Mazure NM, Chen EY, Yeh P, Laderoute KR, Giaccia AJ (1996) Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression. Cancer Res 56(15):3436–3440

    CAS  PubMed  Google Scholar 

  • Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353(19):2012–2024

    Article  CAS  PubMed  Google Scholar 

  • Meyer M, Clauss M, Lepple-Wienhues A, Waltenberger J, Augustin HG, Ziche M, Lanz C, Buttner M, Rziha HJ, Dehio C (1999) A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. Embo J 18(2):363–374

    Article  CAS  PubMed  Google Scholar 

  • Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NP, Risau W, Ullrich A (1993) High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72(6):835–846

    Article  CAS  PubMed  Google Scholar 

  • Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A (1994) Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367(6463):576–579

    Article  CAS  PubMed  Google Scholar 

  • Millauer B, Longhi MP, Plate KH, Shawver LK, Risau W, Ullrich A, Strawn LM (1996) Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res 56(7):1615–1620

    CAS  PubMed  Google Scholar 

  • Miyamoto S, Teramoto H, Gutkind JS, Yamada KM (1996) Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: Roles of integrin aggregation and occupancy of receptors. J Cell Biol 135(6 Pt 1):1633–1642

    Article  CAS  PubMed  Google Scholar 

  • Mohanam S, Wang SW, Rayford A, Yamamoto M, Sawaya R, Nakajima M, Liotta LA, Nicolson GL, Stetler-Stevenson WG, Rao JS (1995) Expression of tissue inhibitors of metalloproteinases: Negative regulators of human glioblastoma invasion in vivo. Clin Exp Metastasis 13(1):57–62

    Article  CAS  PubMed  Google Scholar 

  • Momota H, Nerio E, Holland EC (2005) Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res 65(16):7429–7435

    Article  CAS  PubMed  Google Scholar 

  • Moriyama T, Kataoka H, Hamasuna R, Yokogami K, Uehara H, Kawano H, Goya T, Tsubouchi H, Koono M, Wakisaka S (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

    Article  CAS  PubMed  Google Scholar 

  • Moscatello DK, Holgado-Madruga M, Emlet DR, Montgomery RB, Wong AJ (1998) Constitutive activation of phosphatidylinositol 3-kinase by a naturally occurring mutant epidermal growth factor receptor. J Biol Chem 273(1):200–206

    Article  CAS  PubMed  Google Scholar 

  • Mukhopadhyay D, Tsiokas L, Zhou XM, Foster D, Brugge JS, Sukhatme VP (1995) Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature 375(6532):577–581

    Article  CAS  PubMed  Google Scholar 

  • Nabeshima K, Shimao Y, Sato S, Kataoka H, Moriyama T, Kawano H, Wakisaka S, Koono M (1997) Expression of c-Met correlates with grade of malignancy in human astrocytic tumours: An immunohistochemical study. Histopathology 31(5):436–443

    Article  CAS  PubMed  Google Scholar 

  • Nabors LB, Mikkelsen T, Rosenfeld SS, Hochberg F, Akella NS, Fisher JD, Cloud GA, Zhang Y, Carson K, Wittemer SM, Colevas AD, Grossman SA (2007) Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol 25(13):1651–1657

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Teramoto H, Ichihara A (1986) Purification and characterization of a growth factor from rat platelets for mature parenchymal hepatocytes in primary cultures. Proc Natl Acad Sci USA 83(17):6489–6493

    Article  CAS  PubMed  Google Scholar 

  • Nicholas MK, Lukas RV, Jafri NF, Faoro L, Salgia R (2006) Epidermal growth factor receptor – mediated signal transduction in the development and therapy of gliomas. Clin Cancer Res 12(24):7261–7270

    Article  CAS  PubMed  Google Scholar 

  • Nishizuka Y (1992) Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258(5082):607–614

    Article  CAS  PubMed  Google Scholar 

  • Nister M, Libermann TA, Betsholtz C, Pettersson M, Claesson-Welsh L, Heldin CH, Schlessinger J, Westermark B (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 

  • Nyberg P, Xie L, Kalluri R (2005) Endogenous inhibitors of angiogenesis. Cancer Res 65(10):3967–3979

    Article  CAS  PubMed  Google Scholar 

  • Olofsson B, Pajusola K, Kaipainen A, von Euler G, Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K, Eriksson U (1996) Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93(6):2576–2581

    Article  CAS  PubMed  Google Scholar 

  • Ono Y, Tamiya T, Ichikawa T, Kunishio K, Matsumoto K, Furuta T, Ohmoto T, Ueki K, Louis DN (1996) Malignant astrocytomas with homozygous CDKN2/p16 gene deletions have higher Ki-67 proliferation indices. J Neuropathol Exp Neurol 55(10):1026–1031

    CAS  PubMed  Google Scholar 

  • O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 88(2):277–285

    Article  PubMed  Google Scholar 

  • Overall CM, King AE, Sam DK, Ong AD, Lau TT, Wallon UM, DeClerck YA, Atherstone J (1999) Identification of the tissue inhibitor of metalloproteinases-2 (TIMP-2) binding site on the hemopexin carboxyl domain of human gelatinase A by site-directed mutagenesis. The hierarchical role in binding TIMP-2 of the unique cationic clusters of hemopexin modules III and IV. J Biol Chem 274(7):4421–4429.

    Google Scholar 

  • Paulus W, Tonn JC (1994) Basement membrane invasion of glioma cells mediated by integrin receptors. J Neurosurg 80(3):515–519

    Article  CAS  PubMed  Google Scholar 

  • Paulus W, Tonn JC (1995) Interactions of glioma cells and extracellular matrix. J Neurooncol 24(1):87–91

    Article  CAS  PubMed  Google Scholar 

  • Paulus W, Baur I, Schuppan D, Roggendorf W (1993) Characterization of integrin receptors in normal and neoplastic human brain. Am J Pathol 143(1):154–163

    CAS  PubMed  Google Scholar 

  • Paulus W, Baur I, Beutler AS, Reeves SA (1996) Diffuse brain invasion of glioma cells requires beta 1 integrins. Lab Invest 75(6):819–826

    CAS  PubMed  Google Scholar 

  • Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Grignani F, Pawson T, Pelicci PG (1992) A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 70(1):93–104

    Article  CAS  PubMed  Google Scholar 

  • Pepper MS, Ferrara N, Orci L, Montesano R (1991) Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun 181(2):902–906

    Article  CAS  PubMed  Google Scholar 

  • Pertovaara L, Kaipainen A, Mustonen T, Orpana A, Ferrara N, Saksela O, Alitalo K (1994) Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem 269(9):6271–6274

    CAS  PubMed  Google Scholar 

  • Plate KH, Breier G, Farrell CL, Risau W (1992a) Platelet-derived growth factor receptor-beta is induced during tumor development and upregulated during tumor progression in endothelial cells in human gliomas. Lab Invest 67(4):529–534

    CAS  PubMed  Google Scholar 

  • Plate KH, Breier G, Weich HA, Risau W (1992b) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359(6398):845–848

    Article  CAS  PubMed  Google Scholar 

  • Plate KH, Breier G, Millauer B, Ullrich A, Risau W (1993) Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res 53(23):5822–5827

    CAS  PubMed  Google Scholar 

  • Plate KH, Breier G, Weich HA, Mennel HD, Risau W (1994) Vascular endothelial growth factor and glioma angiogenesis: Coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. Int J Cancer 59(4):520–529

    Article  CAS  PubMed  Google Scholar 

  • Pore N, Liu S, Haas-Kogan DA, O’Rourke DM, Maity A (2003) PTEN mutation and epidermal growth factor receptor activation regulate vascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter. Cancer Res 63(1):236–241

    CAS  PubMed  Google Scholar 

  • Prados MD, Lamborn KR, Chang S, Burton E, Butowski N, Malec M, Kapadia A, Rabbitt J, Page MS, Fedoroff A, Xie D, Kelley SK (2006) Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro Oncol 8(1):67–78

    Article  CAS  PubMed  Google Scholar 

  • Raizer JJ, Abrey LE, Wen P et al (2004) A phase II trial of erlotinib (OSI-774) in patients with recurrent malignant glioma not on EIAEDs. J Clin Oncol 22:107s

    Google Scholar 

  • Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, Kerbel RS (1995) Mutant ras oncogenes upregulate VEGF/VPF expression: Implications for induction and inhibition of tumor angiogenesis. Cancer Res 55(20):4575–4580

    CAS  PubMed  Google Scholar 

  • Rasheed BK, Wiltshire RN, Bigner SH, Bigner DD (1999) Molecular pathogenesis of malignant gliomas. Curr Opin Oncol 11(3):162–167

    Article  CAS  PubMed  Google Scholar 

  • Reardon DA, Egorin MJ, Quinn JA, Rich JN, Gururangan S, Vredenburgh JJ, Desjardins A, Sathornsumetee S, Provenzale JM, Herndon JE 2nd, Dowell JM, Badruddoja MA, McLendon RE, Lagattuta TF, Kicielinski KP, Dresemann G, Sampson JH, Friedman AH, Salvado AJ, Friedman HS (2005) Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 23(36):9359–9368

    Article  CAS  PubMed  Google Scholar 

  • Reardon DA, Desjardins A, Vredenburgh JJ, Sathornsumetee S, Rich JN, Quinn JA, Lagattuta TF, Egorin MJ, Gururangan S, McLendon R, Herndon Ii JE, Friedman AH, Salvado AJ, Friedman HS (2008) Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: Phase 1 trial in adults with malignant glioma. Neuro Oncol 10:330–340

    Google Scholar 

  • Reifenberger G, Reifenberger J, Ichimura K, Meltzer PS, Collins VP (1994) Amplification of multiple genes from chromosomal region 12q13–14 in human malignant gliomas: Preliminary mapping of the amplicons shows preferential involvement of CDK4, SAS, and MDM2. Cancer Res 54(16):4299–4303

    CAS  PubMed  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105–111

    Article  CAS  PubMed  Google Scholar 

  • Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, Wikstrand CJ, Van Duyn LB, Dancey JE, McLendon RE, Kao JC, Stenzel TT, Ahmed Rasheed BK, Tourt-Uhlig SE, Herndon JE 2nd, Vredenburgh JJ, Sampson JH, Friedman AH, Bigner DD, Friedman HS (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22(1):133–142

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Sathornsumetee S, Hjelmeland AB, Keir ST, McLendon RE, Batt D, Ramsey T, Yusuff N, Rasheed BK, Kieran MW, Laforme A, Bigner DD, Friedman HS, Rich JN (2006) AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma. Cancer Res 66(17):8722–8730

    Article  CAS  PubMed  Google Scholar 

  • Sato N, Beitz JG, Kato J, Yamamoto M, Clark JW, Calabresi P, Raymond A, Frackelton AR Jr (1993) Platelet-derived growth factor indirectly stimulates angiogenesis in vitro. Am J Pathol 142(4):1119–1130

    CAS  PubMed  Google Scholar 

  • Schaefer LK, Ren Z, Fuller GN, Schaefer TS (2002) Constitutive activation of Stat3alpha in brain tumors: Localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2). Oncogene 21(13):2058–2065

    Article  CAS  PubMed  Google Scholar 

  • Schmidt NO, Westphal M, Hagel C, Ergun S, Stavrou D, Rosen EM, Lamszus K (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

    Article  CAS  PubMed  Google Scholar 

  • Schulenburg A, Ulrich-Pur H, Thurnher D, Erovic B, Florian S, Sperr WR, Kalhs P, Marian B, Wrba F, Zielinski CC, Valent P (2006) Neoplastic stem cells: A novel therapeutic target in clinical oncology. Cancer 107(10):2512–2520

    Article  CAS  PubMed  Google Scholar 

  • Schwartz MA (2001) Integrin signaling revisited. Trends Cell Biol 11(12):466–470

    Article  CAS  PubMed  Google Scholar 

  • Seetharam L, Gotoh N, Maru Y, Neufeld G, Yamaguchi S, Shibuya M (1995) A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene 10(1):135–147

    CAS  PubMed  Google Scholar 

  • Senger DR, Connolly DT, Van de Water L, Feder J, Dvorak HF (1990) Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res 50(6):1774–1778

    CAS  PubMed  Google Scholar 

  • Senger DR, Van de Water L, Brown LF, Nagy JA, Yeo KT, Yeo TK, Berse B, Jackman RW, Dvorak AM, Dvorak HF (1993) Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev 12(3–4):303–324

    Article  CAS  PubMed  Google Scholar 

  • Shamah SM, Stiles CD, Guha A (1993) Dominant-negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells. Mol Cell Biol 13(12):7203–7212

    CAS  PubMed  Google Scholar 

  • Shaw RJ, Cantley LC (2006) Ras, PI(3) K and mTOR signalling controls tumour cell growth. Nature 441(7092):424–430

    Article  CAS  PubMed  Google Scholar 

  • Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359(6398):843–845

    Article  CAS  PubMed  Google Scholar 

  • Siemeister G, Weindel K, Mohrs K, Barleon B, Martiny-Baron G, Marme D (1996) Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res 56(10):2299–2301

    CAS  PubMed  Google Scholar 

  • Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401

    Article  CAS  PubMed  Google Scholar 

  • Song JH, Song DK, Pyrzynska B, Petruk KC, Van Meir EG, Hao C (2003) TRAIL triggers apoptosis in human malignant glioma cells through extrinsic and intrinsic pathways. Brain Pathol 13(4):539–553

    Article  CAS  PubMed  Google Scholar 

  • Spence AM, Peterson RA, Scharnhorst JD, Silbergeld DL, Rostomily RC (2004) Phase II study of concurrent continuous Temozolomide (TMZ) and Tamoxifen (TMX) for recurrent malignant astrocytic gliomas. J Neurooncol 70(1):91–95

    Article  PubMed  Google Scholar 

  • Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95(1):29–39

    Article  CAS  PubMed  Google Scholar 

  • Stavri GT, Zachary IC, Baskerville PA, Martin JF, Erusalimsky JD (1995) Basic fibroblast growth factor upregulates the expression of vascular endothelial growth factor in vascular smooth muscle cells. Synergistic interaction with hypoxia. Circulation 92(1):11–14

    Google Scholar 

  • Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15(4):356–362

    Google Scholar 

  • Stein I, Neeman M, Shweiki D, Itin A, Keshet E (1995) Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes. Mol Cell Biol 15(10):5363–5368

    CAS  PubMed  Google Scholar 

  • Stoker M, Gherardi E, Perryman M, Gray J (1987) Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 327(6119):239–242

    Article  CAS  PubMed  Google Scholar 

  • Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, Stegh AH, Bradner JE, Ligon KL, Brennan C, Chin L, DePinho RA (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318(5848):287–290

    Article  CAS  PubMed  Google Scholar 

  • Strawn LM, McMahon G, App H, Schreck R, Kuchler WR, Longhi MP, Hui TH, Tang C, Levitzki A, Gazit A, Chen I, Keri G, Orfi L, Risau W, Flamme I, Ullrich A, Hirth KP, Shawver LK (1996) Flk-1 as a target for tumor growth inhibition. Cancer Res 56(15):3540–3545

    CAS  PubMed  Google Scholar 

  • Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996

    Article  CAS  PubMed  Google Scholar 

  • Stupp R, Hegi ME, Gilbert MR, Chakravarti A (2007) Chemoradiotherapy in malignant glioma: Standard of care and future directions. J Clin Oncol 25(26):4127–4136

    Article  CAS  PubMed  Google Scholar 

  • Tsai JC, Goldman CK, Gillespie GY (1995) Vascular endothelial growth factor in human glioma cell lines: Induced secretion by EGF, PDGF-BB, and bFGF. J Neurosurg 82(5):864–873

    Article  CAS  PubMed  Google Scholar 

  • Uhm JH, Dooley NP, Villemure JG, Yong VW (1997) Mechanisms of glioma invasion: Role of matrix-metalloproteinases. Can J Neurol Sci 24(1):3–15

    CAS  PubMed  Google Scholar 

  • Unemori EN, Ferrara N, Bauer EA, Amento EP (1992) Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 153(3):557–562

    Article  CAS  PubMed  Google Scholar 

  • Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30):4722–4729

    Article  CAS  PubMed  Google Scholar 

  • Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH (1994) Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269(43):26988–26995

    CAS  PubMed  Google Scholar 

  • Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H (1996) Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 6(3):217–223; discussion 23–24

    Google Scholar 

  • Wen PY, Yung WK, Lamborn KR, Dahia PL, Wang Y, Peng B, Abrey LE, Raizer J, Cloughesy TF, Fink K, Gilbert M, Chang S, Junck L, Schiff D, Lieberman F, Fine HA, Mehta M, Robins HI, DeAngelis LM, Groves MD, Puduvalli VK, Levin V, Conrad C, Maher EA, Aldape K, Hayes M, Letvak L, Egorin MJ, Capdeville R, Kaplan R, Murgo AJ, Stiles C, Prados MD (2006) Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99–08. Clin Cancer Res 12(16):4899–4907

    Article  CAS  PubMed  Google Scholar 

  • Wong ET, Brem S (2007) Taming glioblastoma: Targeting angiogenesis. J Clin Oncol 25(30):4705–4706

    Article  CAS  PubMed  Google Scholar 

  • Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B (1987) Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 84(19):6899–6903

    Article  CAS  PubMed  Google Scholar 

  • Yamada Y, Nezu J, Shimane M, Hirata Y (1997) Molecular cloning of a novel vascular endothelial growth factor, VEGF-D. Genomics 42(3):483–488

    Article  CAS  PubMed  Google Scholar 

  • Yarden Y (2001) The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur J Cancer 37 Suppl 4:S3–S8

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Neurosurgery, The Toronto Hospital – Western Division, Suite 2-415 McLaughlin Pavilion, 399 Bathurst Street, Toronto, ON, Canada, M5T 2S8

    Abhijit Guha

Authors
  1. Giorgio Carrabba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Debabrata Mukhopadhyay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abhijit Guha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abhijit Guha .

Editor information

Editors and Affiliations

  1. Dept. Neurosciences, Medical University of South Carolina, Jonathan Lucas St. 96 , Charleston, 29425, U.S.A.

    Swapan K. Ray

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag New York

About this chapter

Cite this chapter

Carrabba, G., Mukhopadhyay, D., Guha, A. (2010). Aberrant Signalling Complexes in GBMs: Prognostic and Therapeutic Implications. In: Ray, S. (eds) Glioblastoma. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0410-2_5

Download citation

Publish with us

Policies and ethics

Search

Navigation