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. 2007 Jul 1;67(13):6007-11.
doi: 10.1158/0008-5472.CAN-06-4774.

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

Hisaaki Tanaka  1 , Kiyoshi Yanagisawa, Keiko Shinjo, Ayumu Taguchi, Ken Maeno, Shuta Tomida, Yukako Shimada, Hirotaka Osada, Takayuki Kosaka, Hideo Matsubara, Tetsuya Mitsudomi, Yoshitaka Sekido, Mitsune Tanimoto, Yasushi Yatabe, Takashi Takahashi
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Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1

Hisaaki Tanaka et al. Cancer Res. .

Abstract

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.

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