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Brain
metastases in melanoma: Roles of neurotrophins
Yvonne
Denkins, Jane Reiland, Madhuchhanda Roy, Neeta D. Sinnappah-Kang, Jennifer
Galjour, Brian P. Murry, Jason Blust, Rebecca Aucoin, Dario Marchetti
Department of Comparative
Biomedical Sciences, Louisiana State University School of Veterinary Medicine,
Baton Rouge, LA 70803, USA
Brain
metastasis, which occurs in 20% to 40% of all cancer patients, is an important
cause of neoplastic morbidity and mortality.
Successful invasion into the brain by tumor cells must include attachment to
microvessel endothelial cells, penetration through the blood-brain barrier, and,
of relevance, a response to brain survival and growth factors.
Neurotrophins (NTs) are important in brain-invasive steps.
Human melanoma cell lines express low-affinity NT receptor p75NTR in
relation to their brain-metastatic propensity with their invasive properties
being regulated by NGF, or nerve growth factor, the prototypic NT.
They also express functional TrkC, the putative receptor for the
invasion-promoting NT-3.
In brain-metastatic melanoma cells, NTs promote invasion by enhancing the
production of extracellular matrix (ECM)-degradative enzymes such as heparanase,
an enzyme capable of locally destroying both ECM and the basement membrane of
the blood-brain barrier.
Heparanase is an endo- β
- d -glucuronidase that cleaves heparan sulfate (HS) chains of ECM HS
proteoglycans, and it is a unique metastatic determinant because it is the
dominant mammalian HS degradative enzyme.
Brain-metastatic melanoma cells also produce autocrine/paracrine factors that
influence their growth, invasion, and survival in the brain.
Synthesis of these factors may serve to regulate NT production by brain cells
adjacent to the neoplastic invasion front, such as astrocytes.
Increased NT levels have been observed in tumor-adjacent tissues at the invasion
front of human brain melanoma.
Additionally, astrocytes may contribute to the brain-metastatic specificity of
melanoma cells by producing NT-regulated heparanase.
Trophic, autocrine, and paracrine growth factors may therefore determine whether
metastatic cells can successfully invade, colonize, and grow in the CNS.
© 2003 Duke
University Press
Source: http://konstanza.ingentaselect.com/vl=1635347/cl=66/nw=1/rpsv/cgi-bin/linker?ini=dup_no&reqidx=/cw/dup/15228517/v6n2/s9/p154
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