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The aim of the study was to evaluate the contribution of such interactions to the formation of brain metastasis in nude mice xenografted with human melanoma cells. An insight into these interactions is an essential prerequisite for the development of effective targeted therapy for melanoma brain metastasis. We assessed the effects of soluble factors present in supernatants of short\u2010term cultures of normal mouse brain (referred here after as brain\u2010derived soluble factors) on several characteristics linked to melanoma brain metastasis. It was found that brain\u2010derived soluble factors affect differentially cutaneous and brain\u2010metastasizing melanoma cells variants <jats:italic>in vitro<\/jats:italic>. Such factors enhanced the viability of cutaneous melanoma cells but caused an S phase arrest followed by apoptosis of brain\u2010metastasizing cells. Brain\u2010derived soluble factors enhanced migration of melanoma cells metastasizing to the brain, but did not affect the migration of the cutaneous variants. Such factors upregulated the expression of the chemokine receptor CCR4 in both cutaneous and brain\u2010metastasizing melanoma cells. It is not unlikely that CCR4 ligands expressed in the brain interact with the CCR4\u2010expressing melanoma cells thereby directing them to the brain. Brain\u2010derived soluble factors enhanced the transmigration, across human brain endothelial cells of cutaneous but not of brain\u2010metastasizing melanoma variants. This activity could promote the capacity of the cutaneous cells to metastasize to the brain.<\/jats:p>","DOI":"10.1002\/ijc.27552","type":"journal-article","created":{"date-parts":[[2012,3,24]],"date-time":"2012-03-24T10:50:48Z","timestamp":1332586248000},"page":"2509-2518","source":"Crossref","is-referenced-by-count":28,"title":["The metastatic microenvironment: Brain\u2010derived soluble factors alter the malignant phenotype of cutaneous and brain\u2010metastasizing melanoma cells"],"prefix":"10.1002","volume":"131","author":[{"given":"Anat","family":"Klein","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Orit","family":"Sagi\u2010Assif","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sivan","family":"Izraely","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsipi","family":"Meshel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Metsada","family":"Pasmanik\u2010Chor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Nahmias","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre\u2010Olivier","family":"Couraud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neta","family":"Erez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dave S.B.","family":"Hoon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isaac P.","family":"Witz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,4,12]]},"reference":[{"key":"e_1_2_5_2_2","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2003.013623"},{"key":"e_1_2_5_3_2","doi-asserted-by":"publisher","DOI":"10.1215\/S115285170300067X"},{"key":"e_1_2_5_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-002-0870-6"},{"key":"e_1_2_5_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2004.05.001"},{"key":"e_1_2_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-230X(08)00007-9"},{"key":"e_1_2_5_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/35065016"},{"key":"e_1_2_5_8_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1747.2002.01725.x"},{"key":"e_1_2_5_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2009.12.003"},{"key":"e_1_2_5_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-59537-0_1"},{"key":"e_1_2_5_11_2","article-title":"The metastatic microenvironment. brain residing melanoma metastasis and dormant micro\u2010metastasis","author":"Izraely S","journal-title":"Int J Cancer"},{"key":"e_1_2_5_12_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-3458fje"},{"key":"e_1_2_5_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/biostatistics\/4.2.249"},{"key":"e_1_2_5_14_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1636908"},{"key":"e_1_2_5_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0026-2862(77)90141-8"},{"key":"e_1_2_5_16_2","first-page":"467","article-title":"How is blood vessel growth regulated in normal and neoplastic tissue? 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