© 2004 by Society
© 2004 by the Society forNeuro-Oncology
Brain metastases in melanoma: Roles of neurotrophins
Department of Comparative Biomedical Sciences, Louisiana StateUniversity School of Veterinary Medicine, Baton Rouge, LA 70803,USA
2 Address correspondence to Dario Marchetti, Department of ComparativeBiomedical Sciences, School of Veterinary Medicine, Skip Bertman Drive, Room2522, Louisiana State University-Baton Rouge, Baton Rouge, LA 70803, USA(dmarchetti{at}vetmed.lsu.edu).
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Abstract |
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Brain metastasis, which occurs in 20% to 40% of all cancer patients, is animportant cause of neoplastic morbidity and mortality. Successful invasioninto the brain by tumor cells must include attachment to microvesselendothelial cells, penetration through the blood-brain barrier, and, ofrelevance, a response to brain survival and growth factors. Neurotrophins(NTs) are important in brain-invasive steps. Human melanoma cell lines expresslow-affinity NT receptor p75NTR in relation to theirbrain-metastatic propensity with their invasive properties being regulated byNGF, or nerve growth factor, the prototypic NT. They also express functionalTrkC, the putative receptor for the invasion-promoting NT-3. Inbrain-metastatic melanoma cells, NTs promote invasion by enhancing theproduction of extracellular matrix (ECM)-degradative enzymes such asheparanase, an enzyme capable of locally destroying both ECM and the basementmembrane of the blood-brain barrier. Heparanase is anendo-β-D-glucuronidase that cleaves heparan sulfate (HS)chains of ECM HS proteoglycans, and it is a unique metastatic determinantbecause it is the dominant mammalian HS degradative enzyme. Brain-metastaticmelanoma cells also produce autocrine/paracrine factors that influence theirgrowth, invasion, and survival in the brain. Synthesis of these factors mayserve to regulate NT production by brain cells adjacent to the neoplasticinvasion front, such as astrocytes. Increased NT levels have been observed intumor-adjacent tissues at the invasion front of human brain melanoma.Additionally, astrocytes may contribute to the brain-metastatic specificity ofmelanoma cells by producing NT-regulated heparanase. Trophic, autocrine, andparacrine growth factors may therefore determine whether metastatic cells cansuccessfully invade, colonize, and grow in the CNS.
Received November 18, 2003; Accepted December 11, 2003
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