Cytotoxic therapy for malignant gliomas is limited by poor delivery and drug resistance, and local therapy is ineffective in managing migratory cells. However, recent developments in malignant glioma therapy involve trials of cytostatic rather than conventional cytotoxic agents.
Methods:
The biology of the brain extracellular matrix, tumor invasion, and angiogenesis are reviewed, and the cytostatic agents that inhibit matrix metalloproteinases, angiogenesis, cell proliferation, and signal transduction are discussed, as well as studies of the angiogenic and migratory capacity of malignant brain tumors.
Results:
Two specific and interrelated areas, anti-invasion (migration) and anti-angiogenesis, are potential areas to develop new treatment strategies. Tumor invasion and angiogenesis are important components of the spread and biologic effects of malignant gliomas. Several proteinase inhibitors are in clinical trial, as well as anti-angiogenic agents and signal transduction cascade inhibitors.
Conclusions:
Biologic control of brain tumor cell populations may offer a new management approach to add to currently available management options for malignant brain tumors.
Get full access to this article
View all access options for this article.
References
1.
WingoP.A., TongT., BoldenS.. Cancer statistics, 1995.CA Cancer J Clin.1995; 45: 8–30.
2.
DesmeulesM., MikkelsenT., MaoY.. Increasing incidence of primary malignant brain tumors: influence of diagnostic methods.J Natl Cancer Inst.1992; 84: 442–445.
3.
KohnE.C., LiottaL.A.. Molecular insights into cancer invasion: strategies for prevention and intervention.Cancer Res.1995; 55: 1856–1862.
4.
SchipperH., GohC.R., WangT.L.. Shifting the cancer paradigm: must we kill to cure?J Clin Oncol.1995; 13; 801–807.
5.
SidranskyD., MikkelsenT., SchwechheimerK.. Clonal expansion of p53 mutant cells is associated with brain tumour progression.Nature.1992; 355: 846–847.
6.
SchererH.D.. Cerebral astrocytomas and their derivatives.Am J Cancer.1940; 1: 159–198.
7.
BurgerP.C., HeinzE.R., ShibataT.. Topographic anatomy and CT correlations in the untreated glioblastoma multiforme.J Neurosurg.1988; 68: 698–704.
8.
BurgerP.C., DuboisP.J., ScholdSJr. Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme.J Neurosurg.1983; 58: 159–169.
9.
KellyP.J., Daumas-DuportC., ScheithauerB.W.. Stereotactic histologic correlations of computed tomography- and magnetic resonance imaging-defined abnormalities patients with glial neoplasms.Mayo Clin Proc.1987; 62: 450–459.
10.
MikkelsenT., RosenblumM.L.. Tumor invasiveness. In: BergerM.S., WilsonC.B., eds. Textbook of Gliomas.Cambridge, Mass: WB Saunders Co; 1998. In press.
11.
MikkelsenT., EdvardsenK.. Invasiveness in nervous system tumors. In: BlackP., LoefflerJ.S., eds. Cancer of the Nervous System.Cambridge Mass: Blackwell Scientific Publications; 1998.
12.
AznavoorianS., MurphyA.N., Stetler-StevensonW.G.. Molecular aspects of tumor cell invasion and metastasis.Cancer.1993; 71: 1368–1383.
13.
RaoJ.S., SteckP.A., MohanamS.. Elevated levels of Mr 92,000 type IV collagenase in human brain tumors.Cancer Res.1993; 53: 2208–2211.
14.
McCormickD.. Secretion of cathepsin B by human gliomas in vitro.Neuropathol Appl Neurobiol.1993; 19: 146–151.
15.
RempelS.A., RosenblumM.L., MikkelsenT.. Cathepsin B expression and localization in glioma progression and invasion.Cancer Res.1994; 54: 6027–6031.
16.
SivaparvathiM., SawayaR., WangS.W.. Overexpression and localization of cathepsin B during the progression of human gliomas.Clin Exp Metastasis.1995; 13: 49–56.
17.
MikkelsenT., YanP.S., HoK.L.. Immunolocalization of cathepsin B in human glioma: implications for tumor invasion and angiogenesis.J Neurosurg.1995; 83: 285–290.
18.
MohanamS., SawayaR., McCutcheonI.. Modulation of in vitro invasion of human glioblastoma cells by urokinase-type plasminogen activator receptor antibody.Cancer Res.1993; 53: 4143–4147.
19.
YamamotoM., SawayaR., MohanamS.. Expression and localization of urokinase-type plasminogen activator in human astrocytomas in vivo.Cancer Res.1994; 54: 3656–3661.
BoikeG., LahT., SloaneB.F.. A possible role for cysteine proteinase and its inhibitors in motility of malignant melanoma and other tumour cells.Melanoma Res.1991; 1: 333–340.
FolkmanJ.. The role of angiogenesis in tumor growth.Semin Cancer Biol.1992; 3: 65–71.
25.
BouckM.. Tumor angiogenesis: the role of oncogenes and tumor suppressor genes.Cancer Cells.1990; 2: 179–185.
26.
FolkmanJ., KlagsbrunM.. Vascular physiology: a family of angiogenic peptides.Nature.1987; 329: 671–672.
27.
GaylisF.D., KeerH.N., WilsonM.J.. Plasminogen activators in human prostate cancer cell lines and tumors: correlation with the aggressive phenotype.J Urol.1989; 142: 193–198.
28.
KepplerD., SameniM., MoinK.. Tumor progression and angiogenesis: cathepsin B and C.Biochem Cell Biol.1996; 74: 799–810.
29.
RosenbergG.A.. Matrix metalloproteinases in brain injury.J Neurotrauma.1995; 12: 833–842.
30.
Stetler-StevensonW.G., AznavoorianS., LiottaL.A.. Tumor cell interactions with the extracellular matrix during invasion and metastasis.Annu Rev Cell Biol.1993; 9: 541–573.
31.
SatoH., TakinoT., OkadaY.. A matrix metalloproteinase expressed on the surface of invasive tumour cells.Nature.1994; 370: 61–65.
32.
NakanoA., TaniE., MiyazakiK.. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human gliomas.J Neurosurg.1995; 83: 298–307.
33.
StronginA.Y., CollierI., BannikovG.. Mechanism of cell surface activation of 72-kDa type IV collagenase: isolation of the activated form of the membrane metalloproteinase.J Biol Chem.1995; 270: 5331–5338.
34.
AmbergerV.R., PaganettiP.A., SeulbergerH.. Characterization of a membrane-bound metalloendoproteinase of rat C6 glioblastoma cells.Cancer Res.1994; 54: 4017–4025.
35.
AbeT., MoriT., KohnoK.. Expression of 72 kDa type IV collagenase and invasion activity of human glioma cells.Clin Exp Metastasis.1994; 12: 296–304.
36.
CostelloP.C., Del MaestroR.F., Stetler-StevensonW.G.. Gelatinase A expression in human malignant gliomas.Ann N Y Acad Sci.1994; 732: 450–452.
37.
NakanoA., TaniE., MiyazakiK.. Expressions of matrilysin and stromelysin in human glioma cells.Biochem Biophys Res Commun.1993; 192: 999–1003.
38.
ReithA., RucklidgeG.J.. Invasion of brain tissue by primary glioma: evidence for the involvement of urokinase-type plasminogen activator as an activator of type IV collagenase.Biochem Biophys Res Commun.1992; 186: 348–354.
39.
RucklidgeG.J., Lund-JohansenM., MilneG.. Isolation and characterization of a metalloproteinase secreted by rat glioma cells in serum-free culture.Biochem Biophys Res Commun.1990; 172: 544–550.
40.
Lund-JohansenM., RucklidgeG.J., MilneG.. A metalloproteinase, capable of destroying cultured brain tissue isolated from rat glioma cells.Anticancer Res.1991; 11: 1001–1006.
41.
NakagawaT., KubotaT., KabutoM.. Production of matrix metalloproteinases and tissue inhibitor of metalloproteinases-1 by human brain tumors.J Neurosurg.1994; 81: 69–77.
42.
BandaM.J., HowardE.W., HerronG.S.. Secreted inhibitors of metalloproteinases (IMPs) that are distinct from TIMP.Matrix Suppl.1992; 1: 294–298.
43.
KhokhaR., WaterhouseP., YagelS.. Antisense RNA-induced reduction in murine TIMP levels confers oncogenicity on Swiss 3T3 cells.Science.1989; 243: 947–950.
44.
DeClerckY.A., YeanT.D., ChanD.. Inhibition of tumor invasion of smooth muscle cell layers by recombinant human metalloproteinase inhibitor.Cancer Res.1991; 51: 2151–2157.
45.
DeClerckY.A., PerezN., ShimadaH.. Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases.Cancer Res.1992; 52: 701–708.
46.
KleinerDEJr, UnsworthE.J., KrutzschH.C.. Higher-order complex formation between the 72-kilodalton type IV collagenase and tissue inhibitor of metalloproteinases-2.Biochemistry.1992; 31: 1665–1672.
47.
GrignonD.J., SakrW., TothM.. High levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) expression are associated with poor outcome in invasive bladder cancer.Cancer Res.1996; 56: 1654–1659.
48.
DaviesB., WaxmanJ., WasanH.. Levels of matrix metalloproteinases in bladder cancer correlate with tumor grade and invasion.Cancer Res.1993; 53: 5365–5369.
49.
EdvardsenK., ChenW., RucklidgeG.. Transmembrane neural cell-adhesion molecule (NCAM), but not glycosyl-phosphatidylinositol-anchored NCAM, down regulates secretion of matrix metalloproteinases.Proc Natl Acad Sci U S A.1993; 90: 11463–11467.
50.
WerbZ., HembryR.M., MurphyG.. Commitment to expression of the metalloendopeptidases, collagenase and stromelysin: relationship of inducing events to changes in cytoskeletal architecture.J Cell Biol.1986; 102: 697–702.
51.
WerbZ., TrembleP.M., BehrendtsenO.. Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression.J Cell Biol.1989; 109: 877–889.
52.
SeftorR.E., SeftorE.A., GehlsenK.R.. Proc Natl Acad Sci U S A.1992; 89: 1557–1561.
53.
O'GradyP., LijnenH.R., DuffyM.J.. Multiple forms of plasminogen activator in human breast tumors.Cancer Res.1985; 45: 6216–6218.
54.
VerspagetH.W., SierC.F.M., GaneshS.. Prognostic value of plasminogen activators and their inhibitors in colorectal cancer.Eur J Cancer.1995; 31A: 1105–1109.
55.
MarkusG., TakitaH., CamioloS.M.. Content and characterization of plasminogen activators in human lung tumors and normal lung tissue.Cancer Res.1980; 40: 841–848.
56.
LundL.R., RomerJ., RonneE.. Urokinase-receptor biosynthesis, mRNA level and gene transcription are increased by transforming growth factor beta 1 in human A549 lung carcinoma cells.EMBO J.1991; 10: 3399–3407.
57.
NielsenL.S., KellermanG.M., BehrendtN.. A 55,000-60,000 Mr receptor protein for urokinase-type plasminogen activator: identification in human tumor cell lines and partial purification.J Biol Chem.1988; 263: 2358–2363.
58.
BehrendtN., RonneE., DanoK.. The structure and function of the urokinase receptor, a membrane protein governing plasminogen activation on the cell surface.Biol Chem Hoppe Seyler.1995; 376: 269–279.
59.
CamioloS.M., ThorsenS., AstrupT.. Fibrinogenolysis and fibrinolysis with tissue plasminogen activator, urokinase, streptokinase-activated human globulin, and plasmin.Proc Soc Exp Biol Med.1971; 138: 277–280.
60.
WallenP.. Activation of plasminogen with urokinase and tissue activator. In: PaoletttiR., SherryS., eds. Thrombosis and Urokinase.London: Academic Press;1977: 91–102.
61.
SawayaR., RamoO.J., ShiM.L.. Biological significance of tissue plasminogen activator content in brain tumors.J Neurosurg.1991; 74: 480–486.
62.
PollanenJ., SakselaO., SalonenE.M.. Distinct localizations of urokinase-type plasminogen activator and its type 1 inhibitor under cultured human fibroblasts and sarcoma cells.J Cell Biol.1987; 104: 1085–1096.
63.
KobayashiH., SchmittM., GoretzkiL.. Cathepsin B efficiently activates the soluble and the tumor cell receptor-bound form of the proenzyme urokinase-type plasminogen activator (Pro-uPA).J Biol Chem.1991; 266: 5147–5152.
64.
MignattiP., RobbinsE., RifkinD.B.. Tumor invasion through the human amniotic membrane: requirement for a proteinase cascade.Cell.1986; 47: 487–498.
65.
ReichR., ThompsonE.W., IwamotoY.. Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells.Cancer Res.1988; 48: 3307–3312.
66.
BykowskaK., RijkenD.C., CollenD.. Purification and characterization of the plasminogen activator secreted by a rat brain tumor cell line in culture.Thromb Haemost.1981; 46: 642–644.
67.
KeohaneM.E., HallS.W., VandenBergS.R.. Secretion of alpha 2-macroglobulin, alpha 2-antiplasmin, and plasminogen activator inhibitor-1 by glioblastoma multiforme in primary organ culture.J Neurosurg.1990; 73: 234–241.
68.
CaccamoD.V., KeohaneM.E., McKeeverP.E.. Plasminogen activators and inhibitors in gliomas: an immunohistochemical study.Mod Pathol.1994; 7: 99–104.
69.
LandauB.J., KwaanH.C., VerrosiaE.N.. Elevated levels of urokinase-type plasminogen activator and plasminogen activator inhibitor type- in malignant human brain tumors.Cancer Res.1994; 54: 1105–1108.
70.
YamamotoM., SawayaR., MohanamS.. Expression and localization of urokinase-type plasminogen activator receptor in human gliomas.Cancer Res.1994; 54: 5016–5020.
71.
FranksA.J., EllisE.. Immunohistochemical localisation of tissue plasminogen activator in human brain tumours.Br J Cancer.1989; 59: 462–466.
72.
SawayaR., HighsmithR.. Plasminogen activator activity and molecular weight patterns in human brain tumors.J Neurosurg.1988; 68: 73–79.
73.
SawayaR., ZuccarelloM., HighsmithR.. Alpha-1-antitrypsin in human brain tumors.J Neurosurg.1987; 67: 258–262.
74.
BerquinI.M., SloaneB.F.. Cathepsin B expression in human tumors. In: SuzukiK., BondJ., eds. Intracellular Protein Catabolism.New York, NY: Plenum Press;1996: 281–294.
75.
SloaneB.F., MoinK., SameniM.. Membrane association of cathepsin B can be induced by transfection of human breast epithelial cells with c-Ha-ras oncogene.J Cell Sci.1994; 107: 373–384.
76.
CorticchiatoO., CajotJ.F., AbrahamsonM.. Cystatin C and cathepsin B in human colon carcinoma: expression by cell lines and matrix degradation.Int J Cancer.1992; 52: 645–652.
77.
BramhallS.R.. The matrix metalloproteinases and their inhibitors in pancreatic cancer: from molecular science to a clinical application.Int J Pancreatol.1997; 21: 1–12.
78.
MiyajiK., TaniE., ShindoH.. Effect of tyrphostin on cell growth and tyrosine kinase activity of epidermal growth factor receptor in human gliomas.J Neurosurg.1994; 81: 411–419.
79.
HanY., CadayC.G., NandaA.. Tyrphostin AG 1478 preferentially inhibits human glioma cells expressing truncated rather than wild-type epidermal growth factor receptors.Cancer Res.1996; 56: 3859–3861.
80.
KimK.J., LiB., WinerJ.. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.Nature.1993; 362: 841–844.
81.
Stetler-StevensonW.G., KrutzschH.C., WacherM.P.. The activation of human type IV collagenase proenzyme: sequence identification of the major converstion product following organomercurial activation.J Biol Chem.1989; 264: 1353–1356.
82.
DaviesB., BrownP.D., EastN.. A synthetic matrix metalloproteinase inhibitor decreases tumor burden and prolongs survival of mice bearing human ovarian carcinoma xenografts.Cancer Res.1993; 53: 2087–2091.
83.
TarabolettiG., GarofaloA., BelottiD.. Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases.J Natl Cancer Inst.1995; 87: 293–298.
84.
WangX., FuX., BrownP.D.. Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice.Cancer Res.1994; 54: 4726–4728.
85.
FolkmanJ.. Seminars in Medicine of the Beth Israel Hospital, Boston, Mass: clinical applications of research on angiogenesis.N Engl J Med.1995; 333: 1757–1763.
86.
TakiT., OhnishiT., AritaN.. Anti-proliferative effects of TNP-470 on human malignant glioma in vivo: potent inhibition of tumor angiogenesis.J Neurooncol.1994; 19: 251–258.
87.
YamaokaM., YamamotoT., MasakiT.. Inhibition of tumor growth and metastasis of rodent tumors by the angiogenesis inhibitor O (chloroacetyl-carbamoyl) fumagillol (TNP-470; AGM-1470).Cancer Res.1993; 53: 4262–4267.
88.
YazakiT., TakamiyaY., CostelloP.C.. Inhibition of angiogenesis and growth of human non-malignant and malignant meningiomas by TNP-470.J Neurooncol.1995; 23: 23–29.
89.
D'AmatoR.J., LoughnanM.S., FlynnE.. Thalidomide is an inhibitor of angiogenesis.Proc Natl Acad Sci U S A.1994; 91: 4082–4085.
90.
SchwartzG.K., JiangJ., KelsenD.. Protein kinase C: a novel target for inhibiting gastric cancer cell invasion.J Natl Cancer Inst.1993; 85: 402–407.
91.
CouldwellW.T., HintonD.R., SurnockA.A.. Treatment of recurrent malignant gliomas with chronic high dose tamoxifen.Clin Cancer Res.1996; 2: 619–622.
92.
LevitzkiA., GazitA.. Tyrosine kinase inhibition: an approach to drug development.Science.1995; 267: 1782–1788.
93.
O'ReillyM.S., BoehmT., ShingY.. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.Cell.1997; 88: 277–285.
94.
O'ReillyM.S., HolmgrenL., ShingY.. A novel angiogenesis inhibitor that mediates the suppression of metastases by Lewis lung carcinoma.Cell.1994; 79: 315–328.
95.
O'ReillyM.S., HolmgrenL., ChenC.. Angiostatin induces and sustains dormancy of human primary tumors in mice.Nat Med.1996; 2: 689–692.
96.
BerridgeM.J.. Calcium signalling and cell proliferation.Bioessays.1995; 17: 491–500.
97.
AaronsonS.A.. Growth factors and cancer.Science.1991; 254: 1146–1153.
98.
ColeK., KohnE.. Calcium-mediated signal transduction: biology, biochemistry, and therapy.Cancer Metastasis Rev.1994; 13: 31–44.
99.
IrvineR.F.. Inositol phosphates and Ca2+ entry: toward a proliferation or a simplification?FASEB J.1992; 6: 3085–3091.
100.
SavareseD.M.F., RussellJ.T., FatatisA.. Type IV collagen stimulates an increase in intracellular calcium: potential role in tumor cell motility.J Biol Chem.1992; 267: 21928–21935.
101.
KohnE.C., FelderC.C., JacobsW.. Structure-function analysis of signal and growth inhibition by carboxyamido-triazole, CAI.Cancer Res.1994; 54: 935–942.
102.
PelletierA.J., BodaryS.C., LevinsonA.D.. Signal transduction by the platelet integrin alpha IIb beta 3: induction of calcium oscillations required for protein-tyrosine phosphorylation and ligand-induced spreading of stably transfected cells.Mol Biol Cell.1992; 3: 989–998.
103.
JanneyP.A.. Phosphoinositides and calcium as regulators of cellular actin assembly and disassembly.Ann Rev Phys.1994; 56: 169–191.
104.
LeeY.S., SayeedM.M., WursterR.D.. Inhibition of human brain tumor cell growth by a receptor-operated Ca2+ channel blocker.Cancer Lett.1993; 72: 77–81.
105.
KohnE.C., LiottaL.A.. L65l582: a novel antiproliferative and antimetastasis agent.J Natl Cancer Inst.1990; 82: 54–60.
106.
KohnE.C., SandeenM.A., LiottaL.A.. In vivo efficacy of a novel inhibitor of selected signal transduction pathways including calcium, arachidonate, and inositol phosphates.Cancer Res.1992; 52: 3208–3212.
107.
FelderC.C., MaA.L., LiottaL.A.. The antiproliferative and antimetastatic compound L651582, inhibits muscarinic acetylcholine receptor-stimulated calcium influx and arachidonic acid release.J Pharmacol Exp Ther.1991; 257: 967–971.
108.
KohnE.C., FelderC.C., JacobsW.. Stucture function analysis of signal and growth inhibition by carboxyamido-triazole, CAI.Cancer Res.1994; 54: 935–942.
109.
AlessandroR., MasieroL., LiottaL.A.. The role of calcium in the regulation of invasion and angiogenesis.In Vivo.1996; 10: 153–160.
110.
JacobsW., MikkelsenT., SmithR.. Inhibitory effects of CAI in glioblastoma growth and invasion.J Neurooncol.1997; 32: 93–101.
111.
FiggW.D., ColeK.A., ReedE.. Pharmacokinetics of orally administered carboxyamido-triazole (CAI), an inhibitor of calcium-mediated signal transduction.Clin Cancer Res.1995; 1: 797–803.
112.
KohnE.C., AlessandroR., SpoonsterJ.. Angiogenesis: role of calcium-mediated signal transduction.Proc Natl Acad Sci U S A.1995; 92: 1307–1311.
113.
KohnE.C., ReedE., SarosyG.. Clinical investigation of a cytostatic calcium influx inhibitor in patients with refractory cancers.Cancer Res.1996; 56: 569–573.
114.
KohnE.C., FiggW.D., SarosyG.A.. Phase I trial of micronized formulation carboxyamidotriazole in patients with refractory solid tumors: pharmacokinetics, clinical outcome, and comparison of formulations.J Clin Oncol.1997; 15: 1985–1993.
