Neurotrophins and their receptors stimulate melanoma cell proliferation and migration.
Melanoma is a highly aggressive skin tumor that originates in the epidermis from melanocytes. As melanocytes share with the nervous system a common neuroectodermal origin and express all neurotrophins (NTs), we evaluated the expression and function of NTs and their receptors in melanoma. We report that primary and metastatic melanoma cell lines synthesize and secrete all NTs. Moreover, melanoma cells express the low-affinity (p75NTR) and the high-affinity tyrosine kinase NT receptors (Trk). The inhibition of Trk receptors by either K252a or Trk/Fc chimeras prevents proliferation, indicating that autocrine NTs are responsible for this effect. NT-3, NT-4, and nerve growth factor (NGF) induce cell migration, with a stronger effect on metastatic cell lines. Transfection with p75NTR small interfering RNA (p75NTRsiRNA) or treatment with K252a inhibits NT-induced melanoma cell migration, indicating that both the low- and high-affinity NT receptors mediate this effect. All melanoma cell lines express the p75NTR coreceptor sortilin by which proNGF stimulates migration in melanoma cells, but not in cells transfected with p75NTRsiRNA. These results indicate that NTs, through their receptors, play a critical role in the progression of melanoma.
Truzzi
Francesca
F
Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy.
Marconi
Alessandra
A
Lotti
Roberta
R
Dallaglio
Katiuscia
K
French
Lars E
LE
Hempstead
Barbara L
BL
Pincelli
Carlo
C
D033942:Adaptor Proteins, Vesicular Transport; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D014162:Transfection; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D008562:Membrane Glycoproteins; D020932:Nerve Growth Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor; D000099183:Sortilin; C049985:staurosporine aglycone; C073922:neurotrophin 4