Summary
Background
Intratumoral hemorrhage, as one of the cerebrovascular complications in various tumor-related conditions, occurs mainly in malignant brain tumors. Recent studies have shown that the overexpression of vascular endothelial growth factor (VEGF) and metalloproteinase (MMP) may play a role for the loss of vascular integrity and the subsequent hemorrhage in several instances, in addition to their well-known properties in tumor development and metastasis.
Methods
To investigate the potential role of VEGF and MMP in hemorrhagic complication of metastatic brain tumor, we estimated the expression of VEGF, MMP-2 & -9 by immunohistochemical studies in pathological specimens of metastatic brain tumors obtained from 16 patients, 7 in hemorrhagic and 9 in non-hemorrhagic group. We also examined the expression of collagen type IV, CD34, Factor VIII in order to evaluate the status of tumor vasculature.
Results
Patients in hemorrhagic group showed a higher VEGF expression with neovascularization than those in non-hemorrhagic group. The basement membranes of newly formed vessels were disrupted in cases with high expression in both MMP-2 and -9. These results indicate that rapid growing nascent blood vessels, responding vigorously to VEGF, are concentrated around the hemorrhagic tumors. Besides, these results suggest a possibility that the basement membranes of these nascent vessels could be disrupted proteolytically by MMP.
Conclusion
We conclude that overexpression of VEGF and MMP may play a role in metastatic brain tumor-associated hemorrhage. Presumably, the underlying pathophysiological mechanisms are through rapid growth and breakdown of vessels around the tumors caused by overexpression of VEGF and MMP of tumor cells.
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References
M Salcman (1992) Intracranial hemorrhage caused by brain tumor HH Kaufman (Eds) Intracerebral Hematoma Raven Press New York 95–106
SY Cheng M Nagane HS Huang WK Cavenee (1997) ArticleTitleIntracerebral tumor-associated hemorrhage caused by overexpression of the vascular endothelial growth factor isoforms VEGF121 and VEGF165 but not VEGF189 Proc Natl Acad Sci USA 94 12081–12087 Occurrence Handle1:CAS:528:DyaK2sXntFSmtro%3D Occurrence Handle9342366
KP Claffey LF Brown LF Aguila Particledel K Tognazzi KT Yeo EJ Manseau HF Dvorak (1996) ArticleTitleExpression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis Cancer Res 56 172–181 Occurrence Handle1:CAS:528:DyaK28Xit1Cgsw%3D%3D Occurrence Handle8548760
T Oku JG Tjuvajev T Miyagawa T Sasajima A Joshi R Joshi R Finn KP Claffey RG Blasberg (1998) ArticleTitleTumor growth modulation by sense and antisense vascular endothelial growth factor gene expression: effects on angiogenesis, vascular permeability, blood volume, blood flow. Fluorodeoxyglucose uptake, and proliferation of human melanoma intracerebral xenografts Cancer Res 58 4185–4192 Occurrence Handle1:CAS:528:DyaK1cXmtlCksLg%3D Occurrence Handle9751633
R Cao A Eriksson H Kubo K Alitalo Y Cao J Thyberg (2004) ArticleTitleComparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogesis, lymphangiogenesis, vascular fenestration, and permeability Circ Res 94 664–670 Occurrence Handle1:CAS:528:DC%2BD2cXitVGlu7c%3D Occurrence Handle14739162
O Ishimoto Y Saijo K Narumi Y Kimura M Ebina N Matsubara N Asou Y Nakai T Nukiwa (2002) ArticleTitleHigh level of vascular endothelial growth factor in hemorrhagic pleural effusion of cancer Oncology 63 70–75 Occurrence Handle10.1159/000065723 Occurrence Handle1:CAS:528:DC%2BD38XmtlGiurc%3D Occurrence Handle12187074
JC Luo M Toyoda M Shibuya (1998) ArticleTitleDifferential inhibition of fluid accumulation and tumor growth in two mouse ascites tumors by an anti-vascular endothelial growth factor/permeability factor neutralizing antibody Cancer Res 58 2594–2600 Occurrence Handle1:CAS:528:DyaK1cXktVajtLg%3D Occurrence Handle9635584
S Wizigmann-Voos KH Plate (1996) ArticleTitlePathology, genetics and cell biology of hemangioblastomas Histol Histopathol 11 1049–1061 Occurrence Handle1:STN:280:ByiD1cvjtVc%3D Occurrence Handle8930647
RS Schehr (1996) ArticleTitleNew treatments for acute stroke Nat Biotechnol 14 1549–1554 Occurrence Handle10.1038/nbt1196-1549 Occurrence Handle1:CAS:528:DyaK28XmsFyntr4%3D Occurrence Handle9634819
Z Kovacs K Ikezaki K Samoto T Inamura M Fukui (1996) ArticleTitleVEGF and flt: Expression time kinetics in rat brain infarct Stroke 27 1865–1872 Occurrence Handle1:CAS:528:DyaK28XmsVamsbY%3D Occurrence Handle8841346
LM Coussens B Fingleton LM Matrisian (2002) ArticleTitleMatrix metalloproteinase inhibitors and cancer: trials and tribulations Science 295 2387–2392 Occurrence Handle10.1126/science.1067100 Occurrence Handle1:CAS:528:DC%2BD38XisFSmtb0%3D Occurrence Handle11923519
JA Curci D Mao DG Bohner BT Allen BG Rubin JM Reilly GA Sicard RW Thompson (2000) ArticleTitlePreoperative treatment with doxycycline reduces aortic wall expression and activation of matrix metalloproteinases in patients with abdominal aortic aneurysms J Vasc Surg 31 325–342 Occurrence Handle10.1016/S0741-5214(00)90163-0 Occurrence Handle1:STN:280:DC%2BD3c7jtVCmuw%3D%3D Occurrence Handle10664501
P Gaetani R Rodriguezy Baena F Tartara AL Messina F Tancioni R Schiavo V Grazioli (1999) ArticleTitleMetalloproteases and intracranial vascular lesions Neurol Res 21 385–390 Occurrence Handle1:CAS:528:DyaK1MXkslOntLY%3D Occurrence Handle10406011
S Goodall M Crowther DM Hemingway PR Bell MM Thompson (2001) ArticleTitlebiquitous elevation of matrix metalloproteinase-2 expression in the vasculature of patients with abdominal aneurysms Circulation 104 304–309 Occurrence Handle1:CAS:528:DC%2BD3MXlslOmtLw%3D Occurrence Handle11457749
SC Kim M Singh J Huang CJ Prestigiacomo CJ Winfree RA Solomon ES Connolly SuffixJr (1997) ArticleTitleMatrix metalloproteinase-9 in cerebral aneurysms Neurosurgery 41 642–666 Occurrence Handle1:STN:280:ByiH2Mjgtl0%3D Occurrence Handle9310982
JB Knox GK Sukhova AD Whittemore P Libby (1997) ArticleTitleEvidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases Circulation 95 205–212 Occurrence Handle1:STN:280:ByiC2cjms1I%3D Occurrence Handle8994438
DR Todor I Lewis G Bruno D Chyatte (1998) ArticleTitleIdentification of a serum gelatinase associated with the occurrence of cerebral aneurysms as pro-matrix metalloproteinase-2 Stroke 29 1580–1583 Occurrence Handle1:CAS:528:DyaK1cXlsVOmur4%3D Occurrence Handle9707196
T Hashimoto G Wen MT Lawton NJ Boudreau AW Bollen GY Yang NM Barbaro RT Higashida CF Dowd VV Halbach WL Young (2003) ArticleTitleUniversity of California, San Francisco BAVM Study Group: abnormal expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in brain arteriovenous malformations Stroke 34 925–931 Occurrence Handle10.1161/01.STR.0000061888.71524.DF Occurrence Handle1:CAS:528:DC%2BD3sXitlyrtro%3D Occurrence Handle12649522
M Asahi K Asahi JC Jung GJ Zoppo Particledel ME Fini EH Lo (2000) ArticleTitleRole of matrix metalloproteinase 9 after focal cerbral ischemia: effects of gene knockout and enzyme inhibition with BB-94 J Cereb Blood Flow Metab 20 1681–1689 Occurrence Handle1:CAS:528:DC%2BD3cXptVegur4%3D Occurrence Handle11129784
AW Clark CA Krekoski SS Bou KR Chapman DR Edwards (1997) ArticleTitleIncreased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia Neurosci Lett 238 53–56 Occurrence Handle10.1016/S0304-3940(97)00859-8 Occurrence Handle1:CAS:528:DyaK2sXotVyhtbk%3D Occurrence Handle9464653
JH Heo J Lucero T Abumiya JA Koziol BR Copeland GJ Zoppo Particledel (1999) ArticleTitleMatrix metalloproteinases increase very early during experimental focal cerebral ischemia J Cereb Blood Flow Metab 19 624–633 Occurrence Handle1:CAS:528:DC%2BD3cXksVCqt74%3D Occurrence Handle10366192
J Montaner J Alvarez-Sabin C Molina A Angles S Abilleira J Arenillas MA Gonzalez J Monasterio (2001) ArticleTitleMatrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment Stroke 32 1759–1766 Occurrence Handle1:CAS:528:DC%2BD3MXms1ehtLg%3D Occurrence Handle11486102
J Montaner J Alvarez-Sabin CA Molina A Angles S Abilleira J Arenillas J Monasterio (2001) ArticleTitleMatrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke Stroke 32 2762–2767 Occurrence Handle1:CAS:528:DC%2BD38XivFSqtA%3D%3D Occurrence Handle11739970
GA Rosenberg M Navratil F Barone G Feuerstein (1996) ArticleTitleProteolytic cascade enzymes increase in focal cerebral ischemia in rat J Cereb Blood Flow Metab 16 360–366 Occurrence Handle1:CAS:528:DyaK28XivFWgtb0%3D Occurrence Handle8621740
EN Baramova JD Shannon JB Bjarnason JW Fox (1989) ArticleTitleDegradation of extracellular matrix proteins by hemorrhagic metalloproteinases Arch Biochem Biophys Nov 15 IssueID275 63–71
E Bello-Reuss K Holubec S Rajaraman (2001) ArticleTitleAngiogenesis in autosomal-dominant polycystic kidney disease Kidney Int 60 37–45 Occurrence Handle10.1046/j.1523-1755.2001.00768.x Occurrence Handle1:STN:280:DC%2BD3Mzmt1yjtA%3D%3D Occurrence Handle11422734
K Mayerhofer P Lozanov K Bodner B Bodner-Adler N Mayerhofer-Gallenbacher G Hudelist K Czerwenka (2003) ArticleTitleImmunohistochemical analysis of a primary ovarian leiomyosarcoma. Case report Anticancer Res 23 3433–3436 Occurrence Handle12926085
D Kondziolka M Bernstein L Resch CH Tator JF Fleming RG Vanderlinden H Schutz (1987) ArticleTitleSignificance of hemorrhage into brain tumors: clinicopathological study J Neurosurg 67 852–857 Occurrence Handle1:STN:280:BieD287mtVA%3D Occurrence Handle3316531
IJ Fidler S Yano RD Zhang T Fujimaki CD Bucana (2002) ArticleTitleThe seed and soil hypithesis: vasculization and brain metastases Lancet Oncol 3 53–57 Occurrence Handle10.1016/S1470-2045(01)00622-2 Occurrence Handle1:CAS:528:DC%2BD38Xhtleitb0%3D Occurrence Handle11905606
N Ferrara WJ Henzel (1989) ArticleTitlePituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells Biochem Biophys Res Commun 161 851–859 Occurrence Handle10.1016/0006-291X(89)92678-8 Occurrence Handle1:CAS:528:DyaL1MXkslWhtbY%3D Occurrence Handle2735925
R Kumar J Yoneda CD Bucana IJ Fidler (1998) ArticleTitleRegulation of distinct steps of angiogenesis by different angiogenic molecules Int J Oncol 12 749–757 Occurrence Handle1:CAS:528:DyaK1cXitlejtrs%3D Occurrence Handle9499433
MS Pepper N Ferrara L Orci R Montesano (1991) ArticleTitleVascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells Biochem Biophys Res Commun 181 902–906 Occurrence Handle10.1016/0006-291X(91)91276-I Occurrence Handle1:CAS:528:DyaK38XhtVSjt7w%3D Occurrence Handle1755866
EN Unemori N Ferrara EA Bauer EP Amento (1992) ArticleTitleVascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells J Cell Physiol 153 557–562 Occurrence Handle10.1002/jcp.1041530317 Occurrence Handle1:CAS:528:DyaK3sXhs12msA%3D%3D Occurrence Handle1447317
LP Aiello RL Avery PG Arrigg BA Keyt HD Jampel ST Shah LR Pasquale H Thieme MA Iwamoto JE Park HV Nguyen LM Aiello N Ferrara GL King (1994) ArticleTitleVascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders N Engl J Med 331 1480–1487 Occurrence Handle10.1056/NEJM199412013312203 Occurrence Handle1:STN:280:ByqD2MbisFY%3D Occurrence Handle7526212
S Mun-Bryce GA Rosenberg (1998) ArticleTitleMatrix metalloproteinases in cerebrovascular disease J Cereb Blood Flow Metab 18 1163–1172 Occurrence Handle1:CAS:528:DyaK1cXnsFSru7w%3D Occurrence Handle9809504
GA Rosenberg (1995) ArticleTitleMatrix metalloproteinases in brain injury J Neurotrauma 12 833–842 Occurrence Handle1:STN:280:BymC2Mfkt10%3D Occurrence Handle8594211
WJ Lamoreaux ME Fitzgerald A Reiner KA Hasty ST Charles (1998) ArticleTitleVascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro Microvasc Res 55 29–42 Occurrence Handle10.1006/mvre.1997.2056 Occurrence Handle1:CAS:528:DyaK1cXhsF2nt7s%3D Occurrence Handle9473407
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Jung, S., Moon, KS., Jung, TY. et al. Possible Pathophysiological Role of Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloproteinases (MMPs) in Metastatic Brain Tumor-associated Intracerebral Hemorrhage. J Neurooncol 76, 257–263 (2006). https://doi.org/10.1007/s11060-005-6876-z
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DOI: https://doi.org/10.1007/s11060-005-6876-z