Expression of the neurotrophin receptor TrkA down-regulates expression and function of angiogenic stimulators in SH-SY5Y neuroblastoma cells.

Angiogenesis is essential for tumor growth and metastasis and depends on the production of angiogenic factors. Mechanisms regulating the expression of angiogenic factors in tumor cells are largely unknown. High expression of the neurotrophin receptor TrkA in neuroblastomas (NBs) is associated with a favorable prognosis, whereas TrkB is mainly expressed on aggressive, MYCN-amplified NBs. To investigate the biological effects of TrkA and TrkB expression on angiogenesis in NB, we examined the expression of angiogenic factors in the human NB cell line SY5Y and its TrkA and TrkB transfectants. In comparison with parental SY5Y cells, mRNA and protein levels of the examined angiogenic factors were significantly reduced in SY5Y-TrkA cells, whereas SY5Y-TrkB cells did not demonstrate a significant change. Conditioned medium of TrkB transfectants and parental SY5Y cells induced endothelial cell proliferation and migration, but this effect was completely absent in SY5Y-TrkA cells. TrkA expression also resulted in severely impaired tumorigenicity in a mouse xenograft model and was associated with reduced angiogenic factor expression and vascularization of tumors, as determined by immunohistochemistry and an in vivo Matrigel assay. TrkA expression inhibits angiogenesis and tumor growth in SY5Y NB cells by down-regulation of angiogenic factors, whereas expression of TrkB does not down-regulate the production of these angiogenic factors. The biologically different behavior of TrkA- and TrkB-expressing NBs may be explained in part by their effects on angiogenesis.