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Histological analysis revealed two characteristic patterns: metastatic foci exhibiting an angiocentric pattern were designated \u2018perivascular proliferations\u2019; neoplastic cells infiltrating the brain parenchyma were designated \u2018invasive proliferations\u2019. Electron microscopic observation of perivascular proliferations showed that neoplastic cells were confined to the perivascular space. In invasive proliferations, however, fragments of collagen fibre were observed in the gaps between neoplastic cells, indicating that the neoplastic cells had disintegrated the pia\u2010glial membrane. We analysed the expressions of matrix metalloproteinase\u20102 (MMP\u20102) and MMP\u20109 by using both immunohistochemical analysis and real\u2010time polymerase chain reaction analysis. MMP\u20102 expression was significantly higher in invasive proliferations. MMP\u20109 expression was significantly higher in day 7, but there was no significant difference in day 11. The pia\u2010glial membrane and perivascular space are the barriers that neoplastic cells must overcome to infiltrate the brain. In conclusion, our findings suggest that brain metastasis requires two distinct processes.<\/jats:p>","DOI":"10.1111\/j.1365-2990.2007.00799.x","type":"journal-article","created":{"date-parts":[[2007,1,22]],"date-time":"2007-01-22T11:07:55Z","timestamp":1169464075000},"page":"288-298","source":"Crossref","is-referenced-by-count":17,"title":["A double three\u2010step theory of brain metastasis in mice: the role of the pia mater and matrix metalloproteinases"],"prefix":"10.1111","volume":"33","author":[{"given":"N.","family":"Saito","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T.","family":"Hatori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N.","family":"Murata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Z.\u2010A.","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F.","family":"Ishikawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Nonaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Iwabuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Samejima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2007,1,22]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910440131"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-005-8115-6"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1023\/B:CLIN.0000024761.00373.55"},{"key":"e_1_2_6_5_2","first-page":"95","article-title":"Regional growth of different human melanomas as metastases in the brain of nude mice","volume":"136","author":"Schackert G","year":"1990","journal-title":"Am J Pathol"},{"key":"e_1_2_6_6_2","first-page":"3478","article-title":"Site\u2010specific metastasis of mouse melanomas and a fibrosarcoma in the brain or meninges of syngeneic animals","volume":"48","author":"Schackert G","year":"1988","journal-title":"Cancer Res"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.1.217"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/62.6.655"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1011858925376"},{"key":"e_1_2_6_10_2","first-page":"5217","article-title":"Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models","volume":"56","author":"Ewend MG","year":"1996","journal-title":"Cancer Res"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-05-0082"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-005-7453-8"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-0311"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-4570"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cccn.2004.11.011"},{"key":"e_1_2_6_16_2","first-page":"717","article-title":"Expression spectra of matrix metalloproteinases in metastatic non\u2010small cell lung cancer","volume":"12","author":"Lin TS","year":"2004","journal-title":"Oncol Rep"},{"key":"e_1_2_6_17_2","first-page":"4028","article-title":"Expression of p53, bcl\u20102, E\u2010cadherin, matrix metalloproteinase\u20109, and tissue inhibitor of metalloproteinases\u20101 in paired primary tumors and brain metastasis","volume":"5","author":"Arnold SM","year":"1999","journal-title":"Clin Cancer Res"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1006421112839"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1679\/aohc.65.133"},{"key":"e_1_2_6_20_2","volume-title":"Color Atlas of Histology","author":"Gartner LP","year":"2001"},{"key":"e_1_2_6_21_2","volume-title":"Gray's Anatomy","author":"Williams PL","year":"1995"},{"key":"e_1_2_6_22_2","volume-title":"Basic Histology Text and Atlas","author":"Junqueura LC","year":"2005"},{"key":"e_1_2_6_23_2","first-page":"482","article-title":"A study on the microvasculature of the cerebral cortex. 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