Abstract
Molecular targeted therapies against EGFR and ALK have improved the quality of life of lung adenocarcinoma patients. However, targetable driver mutations are mainly found in TTF‐1/NKX2‐1‐positive terminal respiratory unit (TRU) types and rarely in non‐TRU types.To elucidate the molecular characteristics of the major subtypes of non‐TRU‐type adenocarcinomas, we analyzed 19 lung adenocarcinoma cell lines (11 TRU types and 8 non‐TRU types). A characteristic of non‐TRU‐type cell lines was the strong expression of TFF‐1 (trefoil factor‐1), a gastric mucosal protective factor.
An immunohistochemical analysis of 238 primary lung adenocarcinomas resected at Jichi Medical University Hospital revealed that TFF‐1 was positive in 31 cases (13%). TFF‐1 expression was frequently detected in invasive mucinous(14/15,93%), enteric(2/2,100%), and colloid(1/1,100%) adenocarcinomas, less frequent in acinar(5/24,21%), papillary(7/120,6%), and solid(2/43,5%) adenocarcinomas, and negative in micropapillary(0/1,0%), lepidic(0/23,0%), and microinvasive adenocarcinomas or adenocarcinoma in situ(0/9,0%). TFF‐1 expression correlated with the expression of HNF4alpha and MUC5AC (p<0.0001, p<0.0001, respectively) and inversely correlated with that of TTF‐1/NKX2‐1 (p<0.0001). These results indicate that TFF‐1 is characteristically expressed in non‐TRU‐type adenocarcinomas with gastrointestinal features. TFF‐1‐positive cases harbored KRAS mutations at a high frequency, but no EGFR or ALK mutations. TFF‐1 expression correlated with tumor spread through air space (STAS), and a poor prognosis in advanced stages. Moreover, the knockdown of TFF‐1 inhibited cell proliferation and soft‐agar colony formation and induced apoptosis in a TFF‐1‐high and KRAS‐mutated lung adenocarcinoma cell line.
These results indicate that TFF‐1 is not only a biomarker, but also a potential molecular target for non‐TRU‐type lung adenocarcinomas.
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