TrkB/BDNF signaling pathway is a potential therapeutic target for pulmonary large cell neuroendocrine carcinoma

Abstract

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.