Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1

• Published in: Cancer research (Chicago, Ill.) Vol. 67; no. 13; pp. 6007 - 6011
• Main Authors: TANAKA, Hisaaki, YANAGISAWA, Kiyoshi, MITSUDOMI, Tetsuya, SEKIDO, Yoshitaka, TANIMOTO, Mitsune, YATABE, Yasushi, TAKAHASHI, Takashi, SHINJO, Keiko, TAGUCHI, Ayumu, MAENO, Ken, TOMIDA, Shuta, SHIMADA, Yukako, OSADA, Hirotaka, KOSAKA, Takayuki, MATSUBARA, Hideo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2007
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Antineoplastic agents; Apoptosis; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Lineage; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung - pathology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical sciences; Nuclear Proteins - metabolism; Pharmacology. Drug treatments; Pneumology; RNA Interference; Stem Cells; Thyroid Nuclear Factor 1; Transcription Factors - metabolism; Tumors; Tumors of the respiratory system and mediastinum; Lung disease; Respiratory disease; Lung cancer; Bronchus disease; Malignant tumor; Regulator; Bronchopulmonary adenocarcinoma; Bronchopulmonary
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-06-4774

Emerging evidence, although currently very sparse, suggests the presence of "lineage-specific dependency" in the survival mechanisms of certain cancers. TTF-1 has a decisive role as a master regulatory transcription factor in lung development and in the maintenance of the functions of terminal respiratory unit (TRU) cells. We show that a subset of lung adenocarcinoma cell lines expressing TTF-1, which presumably represent those derived from the TRU lineage, exhibit marked dependence on the persistent expression of TTF-1. The inhibition of TTF-1 by RNA interference (RNAi) significantly and specifically induced growth inhibition and apoptosis in these adenocarcinoma cell lines. Furthermore, a fraction of TTF-1-expressing tumors and cell lines displayed an increase in the gene dosage of TTF-1 in the analysis of 214 patients with non-small-cell lung cancer, including 174 adenocarcinomas, showing a tendency of higher frequency of increased gene copies at metastatic sites than at primary sites (P=0.07, by two-sided Fisher's exact test). These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model.