Lung cancer is notorious for its ability to metastasize, but the pathways regulating lung cancer metastasis are largely unknown. An in vitro system designed to discover factors critical for lung cancer cell migration identified brain-derived neurotrophic factor, which stimulates cell migration through activation of tropomyosinrelated kinase B (TrkB; also called NTRK2). Knockdown of TrkB in human lung cancer cell lines significantly decreased their migratory and metastatic ability in vitro and in vivo. In an autochthonous lung adenocarcinoma model driven by activated oncogenic Kras and p53 loss, TrkB deficiency significantly reduced metastasis. Hypoxiainducible factor-1 directly regulated TrkB expression, and, in turn, TrkB activated Akt signaling in metastatic lung cancer cells. Finally, TrkB expression was correlated with metastasis in patient samples, and TrkB was detected more often in tumors that did not have Kras or epidermal growth factor receptor mutations. These studies demonstrate that TrkB is an important therapeutic target in metastatic lung adenocarcinoma.TrkB/NTRK2 | NSCLC L ung cancer remains the major cause of death from cancer worldwide. The two types of lung cancer are non-small-cell lung cancers (NSCLCs; 80% of all lung cancers), which include adenocarcinomas, squamous cell carcinomas, and large cell carcinomas, and small-cell lung cancers (20%, exhibiting neuroendocrine features). The average 5-y survival rate for NSCLC is only 16% (1). Most NSCLC patients have advanced disease at diagnosis; 22% have regional lymph node metastases, and 56% have distant metastases in the brain, bone, liver, or adrenal glands (1). Surgery or therapies that treat primary lung tumors rarely prevent metastases (1). Understanding the mechanisms of NSCLC metastasis is crucial for the development of new therapies to improve survival for lung cancer patients.Tropomyosin-related kinase B (TrkB; also called NTRK2), a neurotrophin receptor, is important for neural development and is an independent prognostic marker in many tumor types (2). TrkB-expressing neural precursors migrate from their proliferative zone toward a gradient of the TrkB ligand, brainderived neurotrophic factor (BDNF), which is made near the site of residence of the mature neurons (3). High levels of TrkB are correlated with poor patient prognosis in neuroblastomas and ovarian, pancreatic, colon, prostate, and gastric cancers (2). TrkB was overexpressed in ovarian adenocarcinoma metastases compared with primary lesions (4). TrkB is also a supressor of anoikis in cell lines (5). Finally, overexpression of TrkB and BDNF in nonmalignant rat intestinal epithelial cells promoted metastasis from s.c. injection sites to the lungs (6).Despite these clues that TrkB regulates parts of the metastatic cascade in other tumor types, the role of TrkB in NSCLC metastasis remains unclear. TrkB immunoreactivity was correlated with advanced stage disease in lung squamous cell carcinomas, yet was also correlated with better survival (7). In contrast, TrkB expression was as...
Metastatic disease is the primary cause of death of patients with lung cancer, but the mouse models of lung adenocarcinoma do not accurately recapitulate the tumor microenvironment or metastatic disease observed in patients. In this study, we conditionally deleted E-cadherin in an autochthonous lung adenocarcinoma mouse model driven by activated oncogenic Kras and p53 loss. Loss of E-cadherin significantly accelerated lung adenocarcinoma progression and decreased survival of the mice. Kras;p53;E-cadherin mice had a 41% lung tumor burden, invasive grade 4 tumors, and a desmoplastic stroma just 8 weeks after tumor initiation. One hundred percent of the mice developed local metastases to the lymph nodes or chest wall, and 38% developed distant metastases to the liver or kidney. Lung adenocarcinoma cancer cell lines derived from these tumors also had high migratory rates. These studies demonstrate that the Kras;p53;E-cadherin mouse model better emulates the tumor microenvironment and metastases observed in patients with lung adenocarcinoma than previous models and may therefore be useful for studying metastasis and testing new lung cancer treatments in vivo.
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