Mesenchymal Migration as a Therapeutic Target in Glioblastoma

Extensive infiltration of the surrounding healthy brain tissue is a cardinal feature of glioblastomas, highly lethal brain tumors. Deep infiltration by the glioblastoma cells renders complete surgical excision difficult and contemporary adjuvant therapies have had little impact on long-term survival. Thus, deep infiltration and resistance to irradiation and chemotherapy remain a major cause of patient mortality. Modern therapies specifically targeted to this unique aspect of glioblastoma cell biology hold significant promise to substantially improve survival rates for glioblastoma patients. In the present paper, we focus on the role of adhesion signaling molecules and the actin cytoskeleton in the mesenchymal mode of motility that characterizes invading glioblastoma cells. We then review current approaches to targeting these elements of the glioblastoma cell migration machinery and discuss other aspects of cell migration that may improve the treatment of infiltrating glioblastoma.

[1]  S. Dedhar,et al.  αv integrins regulate cell proliferation through integrin-linked kinase (ILK) in ovarian cancer cells , 2003, Oncogene.

[2]  Fan Wang,et al.  Integrin αvβ3-Targeted Radioimmunotherapy of Glioblastoma Multiforme , 2008, Clinical Cancer Research.

[3]  Keith Burridge,et al.  Recruitment of the Arp2/3 complex to vinculin , 2002, The Journal of cell biology.

[4]  D. Cheresh,et al.  Definition of two angiogenic pathways by distinct alpha v integrins. , 1995, Science.

[5]  K. Vuori,et al.  CAS/Crk Coupling Serves as a “Molecular Switch” for Induction of Cell Migration , 1998, The Journal of cell biology.

[6]  X. Bu,et al.  EFFECT OF THE ANGIOGENESIS INHIBITOR CILENGITIDE (EMD 121974) ON GLIOBLASTOMA GROWTH IN NUDE MICE , 2006, Neurosurgery.

[7]  D. Nelson,et al.  Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: results of three consecutive Radiation Therapy Oncology Group (RTOG) clinical trials. , 1993, International journal of radiation oncology, biology, physics.

[8]  D. Cheresh,et al.  Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells. , 1991, The Journal of clinical investigation.

[9]  K. Schlingensiepen,et al.  Effects of Transforming Growth Factor‐β1 on Collagen Synthesis, Integrin Expression, Adhesion an Invasion of Glioma Cells , 1995 .

[10]  M. Mrugala,et al.  Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. , 2009, Neurology.

[11]  W. F. Hillier Total Left Cerebral Hemispherectomy for Malignant Glioma , 1954, Neurology.

[12]  Kristiina Vuori,et al.  The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures , 2007, Molecular Cancer Therapeutics.

[13]  Andreas S. Beutler,et al.  Diffuse brain invasion of glioma cells requires β1 integrins , 1996 .

[14]  C. Bokemeyer,et al.  Cilengitide induces cellular detachment and apoptosis in endothelial and glioma cells mediated by inhibition of FAK/src/AKT pathway , 2008, Journal of experimental & clinical cancer research : CR.

[15]  D. Price,et al.  The motility of glioblastoma tumour cells is modulated by intracellular cofilin expression in a concentration-dependent manner. , 2005, Cell motility and the cytoskeleton.

[16]  Xinming Cai,et al.  Structural Basis for the Autoinhibition of Focal Adhesion Kinase , 2007, Cell.

[17]  Michael J. Fry,et al.  Phosphatidylinositol-3-OH kinase direct target of Ras , 1994, Nature.

[18]  D. Kaplan,et al.  SRC regulates actin dynamics and invasion of malignant glial cells in three dimensions. , 2004, Molecular cancer research : MCR.

[19]  G. O'Neill,et al.  Molecular basis for HEF1/NEDD9/Cas-L action as a multifunctional co-ordinator of invasion, apoptosis and cell cycle , 2007, Cell Biochemistry and Biophysics.

[20]  J. Thiery Epithelial–mesenchymal transitions in tumour progression , 2002, Nature Reviews Cancer.

[21]  Gabriel A Silva,et al.  Nanotechnology approaches to crossing the blood-brain barrier and drug delivery to the CNS , 2008, BMC Neuroscience.

[22]  Osamu Ohmori,et al.  A novel low‐molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth , 2007, Molecular carcinogenesis.

[23]  D. Louis,et al.  In situ analysis of integrin and growth factor receptor signaling pathways in human glioblastomas suggests overlapping relationships with focal adhesion kinase activation. , 2005, The American journal of pathology.

[24]  Timothy A. Springer,et al.  Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1) , 1987, Cell.

[25]  A. Ridley Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. , 2006, Trends in cell biology.

[26]  K. Kinzler,et al.  Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[27]  K. Rottner,et al.  Interplay between Rac and Rho in the control of substrate contact dynamics , 1999, Current Biology.

[28]  A. Baron,et al.  Assessment of the biological and pharmacological effects of the alpha nu beta3 and alpha nu beta5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[29]  V. Tse,et al.  Recurrent glioblastoma multiforme: a review of natural history and management options. , 2006, Neurosurgical focus.

[30]  B. Felding-Habermann,et al.  Activation of tumor cell integrin αvβ3 controls angiogenesis and metastatic growth in the brain , 2009, Proceedings of the National Academy of Sciences.

[31]  F. McCormick,et al.  Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. , 1997, Science.

[32]  A. Puisieux,et al.  Metastasis: a question of life or death , 2006, Nature Reviews Cancer.

[33]  Peter J. Parker,et al.  The activation of phosphatidylinositol 3-kinase by Ras , 1994, Current Biology.

[34]  Jill M. Stukel,et al.  Two-step synthesis of multivalent cancer-targeting constructs. , 2010, Biomacromolecules.

[35]  P. Pellicena,et al.  Src Phosphorylates Cas on Tyrosine 253 to Promote Migration of Transformed Cells* , 2003, Journal of Biological Chemistry.

[36]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[37]  P. Kleihues,et al.  Primary and secondary glioblastomas: from concept to clinical diagnosis. , 1999, Neuro-oncology.

[38]  Nicole S. Bryce,et al.  Specification of actin filament function and molecular composition by tropomyosin isoforms. , 2003, Molecular biology of the cell.

[39]  Michael E. Berens,et al.  Molecular Mechanisms of Glioma Cell Migration and Invasion , 2004, Journal of Neuro-Oncology.

[40]  John Condeelis,et al.  The cofilin pathway in breast cancer invasion and metastasis , 2007, Nature Reviews Cancer.

[41]  P. Friedl,et al.  Proteolytic and non-proteolytic migration of tumour cells and leucocytes. , 2003, Biochemical Society symposium.

[42]  J. Groot,et al.  Improving the prognosis for patients with glioblastoma: the rationale for targeting Src , 2009, Journal of Neuro-Oncology.

[43]  M. Westphal,et al.  Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. , 2000, Neoplasia.

[44]  Yi Zheng,et al.  Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[45]  A. Donson,et al.  MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma , 2007, Pediatric blood & cancer.

[46]  J. Parsons,et al.  pp125FAK-dependent tyrosine phosphorylation of paxillin creates a high-affinity binding site for Crk , 1995, Molecular and cellular biology.

[47]  J. Parsons,et al.  Inhibition of cell spreading by expression of the C-terminal domain of focal adhesion kinase (FAK) is rescued by coexpression of Src or catalytically inactive FAK: a role for paxillin tyrosine phosphorylation , 1997, Molecular and cellular biology.

[48]  Faith Davis,et al.  Brain tumor survival: Results from the National Cancer Data Base , 1998, Journal of Neuro-Oncology.

[49]  L. Shaw,et al.  RAFTK/Pyk2 tyrosine kinase mediates the association of p190 RhoGAP with RasGAP and is involved in breast cancer cell invasion , 2000, Oncogene.

[50]  G. Semenza,et al.  Molecular Events Implicated in Brain Tumor Angiogenesis and Invasion , 2000, Pediatric Neurosurgery.

[51]  J. Schneider-Mergener,et al.  Subsets of the Major Tyrosine Phosphorylation Sites in Crk-associated Substrate (CAS) Are Sufficient to Promote Cell Migration* , 2004, Journal of Biological Chemistry.

[52]  T. Mikkelsen,et al.  Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  R. Mamillapalli,et al.  Genetic deletion of the Pten tumor suppressor gene promotes cell motility by activation of Rac1 and Cdc42 GTPases , 2000, Current Biology.

[54]  Paul S Mischel,et al.  Fyn and SRC are effectors of oncogenic epidermal growth factor receptor signaling in glioblastoma patients. , 2009, Cancer research.

[55]  C. Beaudry,et al.  Migrating glioma cells activate the PI3-K pathway and display decreased susceptibility to apoptosis , 2003, Journal of Cell Science.

[56]  David M Sabatini,et al.  An expanding role for mTOR in cancer. , 2005, Trends in molecular medicine.

[57]  Y. Yonekawa,et al.  Amplification and Overexpression of MDM2 in Primary (de novo) Glioblastomas , 1997, Journal of neuropathology and experimental neurology.

[58]  J. Condeelis,et al.  Phospholipase C and cofilin are required for carcinoma cell directionality in response to EGF stimulation , 2004, The Journal of cell biology.

[59]  Christopher Beadle,et al.  The role of myosin II in glioma invasion of the brain. , 2008, Molecular biology of the cell.

[60]  W. Pardridge Drug Targeting to the Brain , 2007, Pharmaceutical Research.

[61]  B. Vanhaesebroeck,et al.  The PI3K-PDK1 connection: more than just a road to PKB. , 2000, The Biochemical journal.

[62]  M. Westphal,et al.  Glioma cell adhesion and migration on human brain sections. , 1998, Anticancer research.

[63]  C. Turner,et al.  Characterization of Tyrosine Phosphorylation of Paxillin in Vitro by Focal Adhesion Kinase (*) , 1995, The Journal of Biological Chemistry.

[64]  Donna J. Webb,et al.  FAK–Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly , 2004, Nature Cell Biology.

[65]  Jeremy Fairbank,et al.  Historical Perspective , 1987, Do We Really Understand Quantum Mechanics?.

[66]  M. Berens,et al.  Molecular targets of glioma invasion , 2007, Cellular and Molecular Life Sciences.

[67]  Pierre-Marie Martin,et al.  Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[68]  Liz Y. Han,et al.  Therapeutic efficacy of a novel focal adhesion kinase inhibitor TAE226 in ovarian carcinoma. , 2007, Cancer research.

[69]  G. Alghisi,et al.  Vascular integrins in tumor angiogenesis: mediators and therapeutic targets. , 2006, Endothelium : journal of endothelial cell research.

[70]  Sábata S Constancio,et al.  Crk-Associated Substrate Tyrosine Phosphorylation Sites Are Critical for Invasion and Metastasis of Src-Transformed Cells , 2005, Molecular Cancer Research.

[71]  T. Hunter,et al.  Evidence for in vivo phosphorylation of the Grb2 SH2-domain binding site on focal adhesion kinase by Src-family protein-tyrosine kinases , 1996, Molecular and cellular biology.

[72]  Cramer Lp Organization and polarity of actin filament networks in cells: implications for the mechanism of myosin-based cell motility. , 1999 .

[73]  W. Cance,et al.  Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. , 1995, Cancer research.

[74]  E. Golemis,et al.  HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells , 2007, Oncogene.

[75]  Y. Okada,et al.  Membrane Type 1 Matrix Metalloproteinase Digests Interstitial Collagens and Other Extracellular Matrix Macromolecules* , 1997, The Journal of Biological Chemistry.

[76]  M. Frame,et al.  The catalytic activity of Src is dispensable for translocation to focal adhesions but controls the turnover of these structures during cell motility , 1998, The EMBO journal.

[77]  Anastasia Khvorova,et al.  Identification of genes that regulate epithelial cell migration using an siRNA screening approach , 2008, Nature Cell Biology.

[78]  Horst Kessler,et al.  N-methylated cyclic RGD peptides as highly active and selective αvβ3 integrin antagonists , 1999 .

[79]  Erkki Ruoslahti,et al.  Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule , 1984, Nature.

[80]  D. Lauffenburger,et al.  Cell Migration: A Physically Integrated Molecular Process , 1996, Cell.

[81]  P. Friedl,et al.  Tumour-cell invasion and migration: diversity and escape mechanisms , 2003, Nature Reviews Cancer.

[82]  T. MacDonald,et al.  Pediatric High-grade Glioma: Molecular Genetic Clues for Innovative Therapeutic Approaches , 2005, Journal of Neuro-Oncology.

[83]  K. Pantel,et al.  Phenotypic characteristics of cell lines derived from disseminated cancer cells in bone marrow of patients with solid epithelial tumors: establishment of working models for human micrometastases. , 1999, Cancer research.

[84]  K. Stein,et al.  Temozolomide for high grade glioma. , 2008, The Cochrane database of systematic reviews.

[85]  W. Cai,et al.  Integrin αvβ3 Antagonists for Anti-Angiogenic Cancer Treatment , 2007 .

[86]  R. Kessin,et al.  Dictyostelium: Cell Motility and the Cytoskeleton , 2001 .

[87]  Christoph Ballestrem,et al.  Vinculin controls focal adhesion formation by direct interactions with talin and actin , 2007, The Journal of cell biology.

[88]  Shile Huang,et al.  Rapamycin inhibits F-actin reorganization and phosphorylation of focal adhesion proteins , 2008, Oncogene.

[89]  Jochen Herms,et al.  Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral angiogenesis , 2009, Glia.

[90]  Kenneth M. Yamada,et al.  Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. , 1999, Cancer research.

[91]  T. Mikkelsen,et al.  Cilengitide: an integrin-targeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme. , 2008, Expert opinion on investigational drugs.

[92]  C. Bokemeyer,et al.  TAE226-mediated inhibition of focal adhesion kinase interferes with tumor angiogenesis and vasculogenesis , 2010, Investigational New Drugs.

[93]  Jyrki Heino,et al.  Cellular receptors of extracellular matrix molecules. , 2009, Current pharmaceutical design.

[94]  J. Olson,et al.  Benefit of temozolomide compared to procarbazine in treatment of glioblastoma multiforme at first relapse: effect on neurological functioning, performance status, and health related quality of life. , 2005, Cancer investigation.

[95]  D. Schlaepfer,et al.  Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. , 1999, Journal of cell science.

[96]  D. Louis The p53 Gene and Protein in Human Brain Tumors , 1994, Journal of neuropathology and experimental neurology.

[97]  W. Vandertop,et al.  Genetic profiling of a distant second glioblastoma multiforme after radiotherapy: Recurrence or second primary tumor? , 2006, Journal of neurosurgery.

[98]  C. Gladson,et al.  FAK signaling in anaplastic astrocytoma and glioblastoma tumors. , 2003, Cancer journal.

[99]  R. Pazdur,et al.  U.S. Food and Drug Administration Drug Approval Summary: conversion of imatinib mesylate (STI571; Gleevec) tablets from accelerated approval to full approval. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[100]  P. Friedl Prespecification and plasticity: shifting mechanisms of cell migration. , 2004, Current opinion in cell biology.

[101]  E. Sahai,et al.  Rac Activation and Inactivation Control Plasticity of Tumor Cell Movement , 2008, Cell.

[102]  Gareth E. Jones,et al.  Focal adhesion kinase controls actin assembly via a FERM-mediated interaction with the Arp2/3 complex , 2007, Nature Cell Biology.

[103]  K. Kaibuchi,et al.  Rho-Kinase–Mediated Contraction of Isolated Stress Fibers , 2001, The Journal of cell biology.

[104]  Alan Hall,et al.  Rho GTPases Control Polarity, Protrusion, and Adhesion during Cell Movement , 1999, The Journal of cell biology.

[105]  G. E. Jones,et al.  Rho family proteins and cell migration. , 1999, Biochemical Society symposium.

[106]  G. O'Neill,et al.  Specialisation of the tropomyosin composition of actin filaments provides new potential targets for chemotherapy. , 2006, Current cancer drug targets.

[107]  Tony Hunter,et al.  Multiple Grb2-Mediated Integrin-Stimulated Signaling Pathways to ERK2/Mitogen-Activated Protein Kinase: Summation of Both c-Src- and Focal Adhesion Kinase-Initiated Tyrosine Phosphorylation Events , 1998, Molecular and Cellular Biology.

[108]  A. Ridley Rho GTPases and cell migration. , 2001, Journal of cell science.

[109]  Victoria Sanz-Moreno,et al.  Rho-GTPase signaling drives melanoma cell plasticity , 2009, Cell cycle.

[110]  S. Itzkovitz,et al.  Functional atlas of the integrin adhesome , 2007, Nature Cell Biology.

[111]  J. Gunnersen,et al.  Growth and migration markers of rat C6 glioma cells identified by serial analysis of gene expression , 2000, Glia.

[112]  G. O'Neill,et al.  Integrin signalling: a new Cas(t) of characters enters the stage. , 2000, Trends in cell biology.

[113]  D. Zagzag,et al.  Angiogenesis in Gliomas: Biology and Molecular Pathophysiology , 2005, Brain pathology.

[114]  K. Weinberg,et al.  αv‐Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin , 2002, International journal of cancer.

[115]  T. Svitkina,et al.  Myosin II filament assemblies in the active lamella of fibroblasts: their morphogenesis and role in the formation of actin filament bundles , 1995, The Journal of cell biology.

[116]  Koji Yoshimoto,et al.  Distinct transcription profiles of primary and secondary glioblastoma subgroups. , 2006, Cancer research.

[117]  M. Mareel,et al.  The lipid phosphatase activity of PTEN is critical for stabilizing intercellular junctions and reverting invasiveness , 2001, The Journal of cell biology.

[118]  S. Aizawa,et al.  Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice , 1995, Nature.

[119]  T. Lafortune,et al.  Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma , 2009, Molecular Cancer Therapeutics.

[120]  S. Akiyama,et al.  A Novel Protease-docking Function of Integrin at Invadopodia* , 1999, The Journal of Biological Chemistry.

[121]  Santosh Kesari,et al.  Malignant gliomas in adults. , 2008, The New England journal of medicine.

[122]  J. Hickman,et al.  Blockade of αvβ3 and αvβ5 integrins by RGD mimetics induces anoikis and not integrin-mediated death in human endothelial cells , 2006 .

[123]  R. Pazdur,et al.  Food and Drug Administration Drug Approval Summary: Temozolomide Plus Radiation Therapy for the Treatment of Newly Diagnosed Glioblastoma Multiforme , 2005, Clinical Cancer Research.

[124]  H. Kessler,et al.  Targeting RGD recognizing integrins: drug development, biomaterial research, tumor imaging and targeting. , 2006, Current pharmaceutical design.

[125]  D. Moreau,et al.  Original triazine inductor of new specific molecular targets, with antitumor activity against nonsmall cell lung cancer , 2008, International journal of cancer.

[126]  Richard LeBlanc,et al.  Suppression of Rac activity induces apoptosis of human glioma cells but not normal human astrocytes. , 2002, Cancer research.

[127]  D. Osoba,et al.  A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse , 2000, British Journal of Cancer.

[128]  S. Blystone,et al.  Purified Integrin Adhesion Complexes Exhibit Actin-Polymerization Activity , 2006, Current Biology.

[129]  J. Saras,et al.  Rho GTPases have diverse effects on the organization of the actin filament system. , 2004, The Biochemical journal.

[130]  M. Wolfe,et al.  Selective amyloid-β lowering agents , 2008, BMC Neuroscience.

[131]  P. D’Eustachio,et al.  Cellular functions of TC10, a Rho family GTPase: regulation of morphology, signal transduction and cell growth , 1999, Oncogene.

[132]  D. Louis,et al.  The retinoblastoma gene is involved in malignant progression of astrocytomas , 1994, Annals of neurology.

[133]  R. Klemke,et al.  Regulation of Cell Contraction and Membrane Ruffling by Distinct Signals in Migratory Cells , 1999, The Journal of cell biology.

[134]  P. Carmeliet,et al.  Angiogenesis in cancer and other diseases , 2000, Nature.

[135]  J. Thiery,et al.  Reversible transition towards a fibroblastic phenotype in a rat carcinoma cell line , 1989, International journal of cancer. Supplement = Journal international du cancer. Supplement.

[136]  S. Almo,et al.  Cellular localization of activated N-WASP using a conformation-sensitive antibody. , 2004, Cell motility and the cytoskeleton.

[137]  C. Marosi,et al.  Survival and prognostic factors of patients with unresectable glioblastoma multiforme , 2003, Anti-cancer drugs.

[138]  J. Condeelis,et al.  Cofilin takes the lead , 2005, Journal of Cell Science.

[139]  Anne J. Ridley,et al.  The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors , 1992, Cell.

[140]  M. Westphal,et al.  Migration of human glioma cells on myelin. , 1996, Neurosurgery.

[141]  G. O'Neill,et al.  The coordination between actin filaments and adhesion in mesenchymal migration , 2009, Cell adhesion & migration.

[142]  L. Chin,et al.  Malignant astrocytic glioma: genetics, biology, and paths to treatment. , 2007, Genes & development.

[143]  J. Heino,et al.  Evolution of collagen-based adhesion systems. , 2009, The international journal of biochemistry & cell biology.

[144]  Z. Kam,et al.  Early molecular events in the assembly of matrix adhesions at the leading edge of migrating cells , 2003, Journal of Cell Science.

[145]  S. Hanks,et al.  Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases , 1995, Molecular and cellular biology.

[146]  C. James,et al.  Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. , 2000, Cancer research.

[147]  H. Wheeler,et al.  Loss of prostaglandin D2 synthase: a key molecular event in the transition of a low-grade astrocytoma to an anaplastic astrocytoma , 2008, Molecular Cancer Therapeutics.

[148]  J W Smith,et al.  Integrin activation controls metastasis in human breast cancer. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[149]  E. Adamson,et al.  Rescue of the mutant phenotype by reexpression of full-length vinculin in null F9 cells; effects on cell locomotion by domain deleted vinculin. , 1998, Journal of cell science.

[150]  C. Lipinski,et al.  Extended survival of Pyk2 or FAK deficient orthotopic glioma xenografts , 2008, Journal of Neuro-Oncology.

[151]  E. Tracey,et al.  Cancer in New South Wales Incidence and Mortality 2000 featuring projections of selected sites to 2010 , 2002 .

[152]  Lucienne Juillerat-Jeanneret,et al.  The targeted delivery of cancer drugs across the blood-brain barrier: chemical modifications of drugs or drug-nanoparticles? , 2008, Drug discovery today.

[153]  Jill M. Stukel,et al.  Targeted drug delivery for treatment and imaging of glioblastoma multiforme , 2009, Expert opinion on drug delivery.

[154]  E. Ruoslahti,et al.  Control of adhesion-dependent cell survival by focal adhesion kinase , 1996, The Journal of cell biology.

[155]  I. Pollack,et al.  Expression of p53 and prognosis in children with malignant gliomas. , 2002, The New England journal of medicine.

[156]  Daniel L. Gustafson,et al.  Assessment of the biological and pharmacological effects of the ανβ3 and ανβ5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors , 2007 .

[157]  K. Burridge,et al.  Focal adhesions, contractility, and signaling. , 1996, Annual review of cell and developmental biology.

[158]  C. Damsky,et al.  FAK integrates growth-factor and integrin signals to promote cell migration , 2000, Nature Cell Biology.

[159]  M. Westphal,et al.  Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2. , 2001, Cancer research.

[160]  R. Stupp,et al.  Cilengitide modulates attachment and viability of human glioma cells, but not sensitivity to irradiation or temozolomide in vitro. , 2009, Neuro-oncology.

[161]  Kathleen R. Lamborn,et al.  Cilengitide Targeting of αvβ3 Integrin Receptor Synergizes with Radioimmunotherapy to Increase Efficacy and Apoptosis in Breast Cancer Xenografts , 2002 .

[162]  R. Milo,et al.  A paxillin tyrosine phosphorylation switch regulates the assembly and form of cell-matrix adhesions , 2006, Journal of Cell Science.

[163]  C. Tepper,et al.  The Src Inhibitor AZD0530 Blocks Invasion and May Act as a Radiosensitizer in Lung Cancer Cells , 2009, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[164]  H. Wheeler,et al.  Variation of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in serial samples in glioblastoma , 2008, Journal of Neuro-Oncology.

[165]  R. Ezzell,et al.  Targeted disruption of vinculin genes in F9 and embryonic stem cells changes cell morphology, adhesion, and locomotion. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[166]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[167]  D. Yamazaki,et al.  Involvement of Rac and Rho signaling in cancer cell motility in 3D substrates. , 2009, Oncogene.

[168]  David S. Miller,et al.  Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy , 2008, Pharmacological Reviews.

[169]  C. Der,et al.  Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K , 1997, Nature.

[170]  W. Cavenee,et al.  A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[171]  Timothy Y. Huang,et al.  Cofilin phosphatases and regulation of actin dynamics. , 2006, Current opinion in cell biology.

[172]  T. Byzova,et al.  Mechanisms of Integrin–Vascular Endothelial Growth Factor Receptor Cross-Activation in Angiogenesis , 2007, Circulation research.

[173]  O. Destaing,et al.  Actin machinery and mechanosensitivity in invadopodia, podosomes and focal adhesions , 2009, Journal of Cell Science.

[174]  G. Reifenberger,et al.  CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. , 1994, Cancer research.

[175]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[176]  Y. Yonekawa,et al.  Incidence and timing of p53 mutations during astrocytoma progression in patients with multiple biopsies. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[177]  Hong Wu,et al.  Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[178]  L. Cramer Organization and polarity of actin filament networks in cells: implications for the mechanism of myosin-based cell motility. , 1999, Biochemical Society symposium.

[179]  P. Kleihues,et al.  Genetic pathways to primary and secondary glioblastoma. , 2007, The American journal of pathology.

[180]  Douglas C. Miller,et al.  Preferential Inactivation of the p53 Tumor Suppressor Pathway and Lack of EGFR Amplification Distinguish de novo High Grade Pediatric Astrocytomas from de novo Adult Astrocytomas , 2000, Brain pathology.

[181]  V. Golubovskaya,et al.  TAE226 Inhibits Human Neuroblastoma Cell Survival , 2008, Cancer investigation.

[182]  W. Paulus,et al.  Diffuse brain invasion of glioma cells requires beta 1 integrins. , 1996, Laboratory investigation; a journal of technical methods and pathology.

[183]  P. Black,et al.  αvβ3 and αvβ5 Integrin Expression in Glioma Periphery , 2001 .

[184]  K. Rottner,et al.  Live imaging of glioblastoma cells in brain tissue shows requirement of actin bundles for migration. , 2006, Neuron glia biology.

[185]  M. Vogelbaum,et al.  Novel drug delivery strategies in neuro-oncology , 2009, Neurotherapeutics.

[186]  J. Guan,et al.  Stimulation of cell migration by overexpression of focal adhesion kinase and its association with Src and Fyn. , 1996, Journal of cell science.

[187]  M. Martel,et al.  Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study. , 1999, International journal of radiation oncology, biology, physics.

[188]  B. Scheithauer,et al.  The 2007 WHO classification of tumours of the central nervous system , 2007, Acta Neuropathologica.

[189]  J. Taylor,et al.  An SH3 domain-containing GTPase-activating protein for Rho and Cdc42 associates with focal adhesion kinase , 1996, Molecular and cellular biology.

[190]  G. O'Neill,et al.  Tropomyosins as interpreters of the signalling environment to regulate the local cytoskeleton. , 2008, Seminars in cancer biology.

[191]  B. Felding-Habermann,et al.  Integrin adhesion receptors in tumor metastasis , 2004, Clinical & Experimental Metastasis.

[192]  G. Borisy,et al.  Cell Migration: Integrating Signals from Front to Back , 2003, Science.

[193]  Kenneth M. Yamada,et al.  Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. , 1998, Science.

[194]  D. Webb,et al.  Differential Dynamics of α5 Integrin, Paxillin, and α-Actinin during Formation and Disassembly of Adhesions in Migrating Cells , 2001, The Journal of cell biology.

[195]  C. Gladson Expression of Integrin avß3 in Small Blood Vessels of Glioblastoma Tumors , 1996 .

[196]  Daniel J Brat,et al.  Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. , 2004, The international journal of biochemistry & cell biology.

[197]  J. Houghton,et al.  Tumor microenvironment: The role of the tumor stroma in cancer , 2007, Journal of cellular biochemistry.

[198]  S. Hanks,et al.  Mechanisms of CAS Substrate Domain Tyrosine Phosphorylation by FAK and Src , 2001, Molecular and Cellular Biology.

[199]  W. K. Alfred Yung,et al.  Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers , 1997, Nature Genetics.

[200]  J. S. Rao,et al.  Molecular mechanisms of glioma invasiveness: the role of proteases , 2003, Nature Reviews Cancer.

[201]  D. Hallahan,et al.  SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation. , 2006, International journal of radiation oncology, biology, physics.

[202]  R. Klemke,et al.  Purification of pseudopodia from polarized cells reveals redistribution and activation of Rac through assembly of a CAS/Crk scaffold , 2002, The Journal of cell biology.

[203]  R. DePinho,et al.  Malignant glioma: genetics and biology of a grave matter. , 2001, Genes & development.

[204]  A. Unterberg,et al.  Uniform MDM2 overexpression in a panel of glioblastoma multiforme cell lines with divergent EGFR and p53 expression status. , 2006, Anticancer research.

[205]  T. Mikkelsen,et al.  Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[206]  C. Nobes,et al.  Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia , 1995, Cell.

[207]  K. Pienta,et al.  Cell adhesion and chemotaxis in prostate cancer metastasis to bone: a minireview , 2000, Prostate Cancer and Prostatic Diseases.

[208]  David A. Cheresh,et al.  Definition of Two Angiogenic Pathways by Distinct αv Integrins , 1995, Science.

[209]  R. Stupp,et al.  Integrin inhibitors reaching the clinic. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[210]  H. Vogel,et al.  αvβ3 Integrin in central nervous system tumors , 2005 .

[211]  J. Guan,et al.  Phosphorylation of Tyrosine 397 in Focal Adhesion Kinase Is Required for Binding Phosphatidylinositol 3-Kinase* , 1996, The Journal of Biological Chemistry.

[212]  S. Hanks,et al.  Identification of p130Cas as a Mediator of Focal Adhesion Kinase–promoted Cell Migration , 1998, The Journal of cell biology.

[213]  N. Carragher,et al.  Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530 , 2009, Molecular oncology.

[214]  K. Hahn,et al.  Localized Rac activation dynamics visualized in living cells. , 2000, Science.

[215]  L. Grochow,et al.  Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[216]  T. Hunter,et al.  Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase , 1994, Nature.

[217]  J. Bruce,et al.  Somatic mutations of PTEN in glioblastoma multiforme. , 1997, Cancer research.

[218]  S. Horvath,et al.  Antitumor Activity of Rapamycin in a Phase I Trial for Patients with Recurrent PTEN-Deficient Glioblastoma , 2008, PLoS medicine.

[219]  Peter Friedl,et al.  Cell migration strategies in 3‐D extracellular matrix: Differences in morphology, cell matrix interactions, and integrin function , 1998, Microscopy research and technique.

[220]  G. O'Neill,et al.  Tropomyosin Isoform Expression Regulates the Transition of Adhesions To Determine Cell Speed and Direction , 2009, Molecular and Cellular Biology.

[221]  E Biganzoli,et al.  Vascular integrin alpha(v)beta3: a new prognostic indicator in breast cancer. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[222]  Y. Yonekawa,et al.  Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C --> A:T mutations of the TP53 tumor suppressor gene. , 2001, Carcinogenesis.

[223]  H. Mellor,et al.  The novel Rho-family GTPase Rif regulates coordinated actin-based membrane rearrangements , 2000, Current Biology.

[224]  J. Norman,et al.  αvβ3 and α5β1 integrin recycling pathways dictate downstream Rho kinase signaling to regulate persistent cell migration , 2007, The Journal of cell biology.

[225]  R. Hynes A reevaluation of integrins as regulators of angiogenesis , 2002, Nature Medicine.

[226]  Andrew D Norden,et al.  Therapeutic strategies for inhibiting invasion in glioblastoma , 2009, Expert review of neurotherapeutics.

[227]  H. Kessler,et al.  Ligands for Mapping a v 3 -Integrin Expression in Vivo , 2009 .

[228]  Giuseppe Trapani,et al.  New strategies to deliver anticancer drugs to brain tumors , 2009, Expert opinion on drug delivery.

[229]  David A. Cheresh,et al.  Role of integrins in cell invasion and migration , 2002, Nature Reviews Cancer.

[230]  J. Debus,et al.  Inhibition of αvβ3 Integrin Survival Signaling Enhances Antiangiogenic and Antitumor Effects of Radiotherapy , 2005, Clinical Cancer Research.

[231]  V. Brunton,et al.  Src and focal adhesion kinase as therapeutic targets in cancer. , 2008, Current opinion in pharmacology.

[232]  B. Scheithauer,et al.  Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[233]  Charlie Teo,et al.  IQGAP1 and IGFBP2: Valuable Biomarkers for Determining Prognosis in Glioma Patients , 2007, Journal of neuropathology and experimental neurology.

[234]  M. Kirschner,et al.  The Interaction between N-WASP and the Arp2/3 Complex Links Cdc42-Dependent Signals to Actin Assembly , 1999, Cell.

[235]  W. Brück,et al.  Expression of tyrosine kinases FAK and Pyk2 in 331 human astrocytomas , 2004, Acta Neuropathologica.

[236]  W. Song,et al.  v-Crk regulates membrane dynamics and Rac activation , 2008, Cell adhesion & migration.

[237]  P. Keng,et al.  Inhibition of invasiveness of human lung cancer cell line H1299 by over‐expression of cofilin , 2005, Cell biology international.

[238]  J. Stull,et al.  Dedicated Myosin Light Chain Kinases with Diverse Cellular Functions* , 2001, The Journal of Biological Chemistry.

[239]  C. James,et al.  Clonal genomic alterations in glioma malignancy stages. , 1988, Cancer research.

[240]  C. Sawyers,et al.  The phosphatidylinositol 3-Kinase–AKT pathway in human cancer , 2002, Nature Reviews Cancer.

[241]  K. Kaibuchi,et al.  Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. , 2001, Trends in pharmacological sciences.

[242]  Michael D Schaller,et al.  The interplay between Src and integrins in normal and tumor biology , 2004, Oncogene.