Tropomyosin-related
kinase B (TrkB) plays an important role in
tumor progression in various kinds of
cancers; however, little is known about
biological significance of TrkB in human
lung cancer, especially large cell neuroendocrine
carcinoma (LCNEC). We hereby investigated the expressions of TrkB and its
ligand brain-derived neurotrophic factor (
BDNF) in clinical specimens and their influences on phenotypes of invasiveness and tumorigenicity for LCNEC. The expressions of TrkB and
BDNF analyzed by immunohistochemistry for patients samples with
lung cancer (n=104) were significantly higher in
neuroendocrine tumor (NET) compared with non-NET. In particular, LCNEC, a subtype of NET, exhibited significantly higher TrkB and
BDNF expressions than another NET type:
small cell lung cancer (SCLC), and a significant correlation between TrkB and
BDNF expressions was noted in LCNEC but not in SCLC. In vitro assay, exogenous
BDNF addition enhanced the invasion into matrigels of LCNEC cells, whereas inhibition of TrkB or
BDNF suppressed
matrix metalloproteinase-2 and -9 activities and the invasiveness. Exogenous
BDNF also increased anchor-independent colony formation on soft
agar gels for LCNEC, while inhibition of TrkB or
BDNF suppressed the anchorage-independency. In vivo experiments, implanted LCNEC cells pretreated with TrkB-
siRNA developed no subcutaneous
tumor in all six nude mice, although those with control-
siRNA formed
tumors in four of six nude mice. In conclusion,
BDNF/TrkB signal is involved in malignant progression of invasiveness and tumorigenicity for LCNEC, and may be a potential target for LCNEC without standard
therapy.