p75 neurotrophin receptor functions as a survival receptor in brain-metastatic melanoma cells.
The p75 neurotrophin receptor (p75(NTR)), a common receptor for members of the neurotrophins (NT) family, was previously identified as a molecular determinant of brain metastasis. We have also reported that NT treatment of murine and human brain-metastatic melanoma cells affects their invasive capacities and increases the production of heparanase, an important and unique extracellular matrix (ECM) degradative enzyme. Neurotrophism can be a survival-support mechanism for brain-metastatic cells and a survival assay was devised to mimic the growth limiting conditions of rapidly expanding metastatic tumors prior to neoangiogenesis. We report that p75(NTR) promoted the survival of brain-metastatic melanoma cells but not melanocytes in stress cultures conditions. Secondly, melanoma cells fluorescently sorted for high p75(NTR) expression (p75(NTR-H) cells) had an up to a 15-fold greater survival than those sorted for low p75(NTR) expression (p75(NTR-L) cells). Thirdly, cells overexpressing p75(NTR) associated with the growth fraction and provided these cells with an inherent growth advantage. Finally, we observed an increased survival of sorted p75(NTR-L) cells, dependent upon treatment of NT members whose functional receptors are present on these cells. Together, these results delineate that p75(NTR)-mediated trophic support profoundly affects competitive melanoma-cell survival when the tumor cell microenvironment becomes growth limiting.
Marchetti
Dario
D
Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University at Baton Rouge, Baton Rouge, Louisiana 70803, USA. dmarchetti@vetmed.lsu.edu
Aucoin
Rebecca
R
Blust
Jason
J
Murry
Brian
B
Greiter-Wilke
Andrea
A
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000556:secondary; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005434:Flow Cytometry; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology*; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000099175:Heparanase
D005966:Glucuronidase; D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D000099175:Heparanase