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The role of neurotrophins in brain metastasis of malignant melanoma cells
Author(s) -
Nicolson G. L.
Publication year - 2004
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/j.0906-6705.2004.0212n.x
Subject(s) - neurotrophin , paracrine signalling , autocrine signalling , heparanase , biology , nerve growth factor , tropomyosin receptor kinase a , melanoma , cancer research , microbiology and biotechnology , receptor , heparan sulfate , cell , biochemistry
We have examined the role of neurotrophin receptors and neurotrophins in brain invasion and colonization of malignant melanoma cells. Using mouse and human melanoma variant cell sublines that have the capacity to form brain tumor colonies in nude mice, we studied the effects of neurotrophins and growth factors on malignant properties. The high brain‐colonizing melanoma lines were characterized by high expression of the low‐affinity nerve growth factor (NGF) receptor p75NTR, which forms transmembrane complexes containing the neurotrophin and its receptors, but they expressed very low amounts if any of the high‐affinity neurotrophin receptor trkA. In the presence of brain endothelial cell‐derived motility factors, NGF and other neurotrophins, such as neurotrophin‐3 (NT‐3), stimulate release of basement membrane degradative enzymes and significantly increase the invasion of endothelial cell extracellular matrix and Matigel‐coated filters. Enzymes such as the collagenase‐degrading enzyme MMP‐2 and heparan sulfate‐degrading enzyme heparanase are increased in their synthesis and release from the high brain‐colonizing but not by other melanoma variant lines by NGF or NT‐3. The increase in heparanase can be blocked by antisense resulting in decreased invasion and capacity to colonize brain. Neurotrophins also stimulate the synthesis and release of autocrine growth factors by brain‐colonizing melanoma cells. Brain‐colonizing melanoma cells also respond to paracrine growth factors in the brain, and one of the important paracrine growth factors in brain metastasis has been identified as a transferrin. Examination of the invasion front in brains colonized by the brain‐colonizing melanoma cells revealed high concentrations of NGF and other neurotrophins (NT‐3) at the interface between melanoma cells and adjoining normal brain tissue (with extensive gliosis) that gradually diminished with distance from the invasion front. Using immunohistochemical techniques to detect neurotrophins, uninvolved brain tissue (adult animals) possessed very low or undetectable concentrations of these neurotrophins. Trophic factors, autocrine factors, paracrine growth factors and other factors may determine whether metastatic melanoma cells can successfully invade, colonize and grow in the CNS.