Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis.

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.

• Authors: Kerstin W Sinkevicius, Christina Kriegel, Kelly J Bellaria, Jaewon Lee, Allison N Lau, Kristen T Leeman, Pengcheng Zhou, Alexander M Beede, Christine M Fillmore, Deborah Caswell, Juliana Barrios, Kwok-Kin Wong, Lynette M Sholl, Thorsten M Schlaeger, Roderick T Bronson, Lucian R Chirieac, Monte M Winslow, Marcia C Haigis, Carla F Kim
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 28 Pg. 10299-304 (Jul 15 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24982195 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1
• Membrane Glycoproteins
• Ntrk2 protein, mouse
• Protein-Tyrosine Kinases
• Receptor, trkB
• Proto-Oncogene Proteins c-akt

Topics

• Adenocarcinoma (drug therapy, enzymology, genetics, pathology)
• Animals
• Cell Line, Tumor
• Cell Movement
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Hypoxia-Inducible Factor 1 (genetics, metabolism)
• Lung Neoplasms (drug therapy, enzymology, genetics, pathology, secondary)
• Membrane Glycoproteins (biosynthesis, genetics)
• Mice, Mutant Strains
• Neoplasm Metastasis (genetics, pathology)
• Protein-Tyrosine Kinases (biosynthesis, genetics)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Receptor, trkB (biosynthesis, genetics)
• Signal Transduction (genetics)