Abstract
TrkB mediates the effects of brain-derived neurotrophic factor (BDNF) in neuronal and nonnneuronal cells. Based on recent reports that TrkB can also be transactivated through epidermal growth-factor receptor (EGFR) signaling and thus regulates migration of early neurons, we investigated the role of TrkB in migration of lung tumor cells. Early metastasis remains a major challenge in the clinical management of non-small cell lung cancer (NSCLC). TrkB receptor signaling is associated with metastasis and poor patient prognosis in NSCLC. Expression of this receptor in A549 cells and in another adenocarcinoma cell line, NCI-H441, promoted enhanced migratory capacity in wound healing assays in the presence of the TrkB ligand BDNF. Furthermore, TrkB expression in A549 cells potentiated the stimulatory effect of EGF in wound healing and in Boyden chamber migration experiments. Consistent with a potential loss of cell polarity upon TrkB expression, cell dispersal and de-clustering was induced in A549 cells independently of exogeneous BDNF. Morphological transformation involved extensive cytoskeletal changes, reduced E-cadherin expression and suppression of E-cadherin expression on the cell surface in TrkB expressing tumor cells. This function depended on MEK and Akt kinase activity but was independent of Src. These data indicate that TrkB expression in lung adenoma cells is an early step in tumor cell dissemination, and thus could represent a target for therapy development.
Highlights
Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer-related death among the malignant tumors [1]
We show here that forced expression of the TrkB receptor kinase in two human lung adenocarcinoma cell lines, A549 and NCI-H441, caused enhanced migratory capacity in the presence of the TrkB ligand brain-derived neurotrophic factor (BDNF)
TrkB expression in A549 cells potentiated the stimulatory effect of EGF in wound healing and in Boyden chamber migration experiments
Summary
Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer-related death among the malignant tumors [1]. More than a million deaths per year are due to lung cancer worldwide. NSCLC is initiated in lung cells by toxicity (e.g. from tobacco smoke) that causes genetic alterations. The primary reason for the low cure rate from NSCLC is that about 70% of patients present with advanced disease, after the formation of metastatic spreading, and that even early stage NSCLC have a low overall survival rate [5]. Whether the metastatic cells disseminated from an aggressive NSCLC primary tumor at around the time of advanced stage disease or by clonal outgrowth of dormant micrometastatic cells that had dislodged from an early primary tumor years before first disease symptoms is an unresolved question [6]. In cases of advanced disease (spread to contralateral and mediastinal lymph nodes or even distant metastases) systemic chemotherapy is the main treatment
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