1. Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis.
- Author
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Sinkevicius KW, Kriegel C, Bellaria KJ, Lee J, Lau AN, Leeman KT, Zhou P, Beede AM, Fillmore CM, Caswell D, Barrios J, Wong KK, Sholl LM, Schlaeger TM, Bronson RT, Chirieac LR, Winslow MM, Haigis MC, and Kim CF
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma genetics, Adenocarcinoma pathology, Animals, Cell Line, Tumor, Gene Knockdown Techniques, Humans, Hypoxia-Inducible Factor 1 genetics, Hypoxia-Inducible Factor 1 metabolism, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Lung Neoplasms secondary, Membrane Glycoproteins genetics, Mice, Mutant Strains, Neoplasm Metastasis genetics, Neoplasm Metastasis pathology, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Receptor, trkB genetics, Signal Transduction genetics, Adenocarcinoma enzymology, Cell Movement, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Lung Neoplasms enzymology, Membrane Glycoproteins biosynthesis, Protein-Tyrosine Kinases biosynthesis, Receptor, trkB biosynthesis
- Abstract
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 tropomyosin-related 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. Hypoxia-inducible 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.
- Published
- 2014
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