Progressive Changes in the Protein Expression Profile of Alveolar Septa in Early-Stage Lung Adenocarcinoma

Abstract

Abstract Background Adenocarcinomas show a stepwise progression from atypical adenomatous hyperplasia (AAH) through adenocarcinoma in situ (AIS) to invasive adenocarcinoma (IA). Immunoglobulin superfamily containing leucine-rich repeat (ISLR) is a marker of tumor-restraining cancer-associated fibroblasts (CAFs), which are distinct from conventional, strongly α-smooth muscle actin (αSMA)-positive CAFs. Fibroblast-activation protein (FAP) has been focused on as a potential therapeutic and diagnostic target of CAFs. Methods We investigated the changes in protein expression during adenocarcinoma progression in pre-existing alveolar septa by assessing ISLR, αSMA, and FAP expression in normal, AAH, AIS, and IA lung nodules. Fourteen AAH, seventeen AIS, and twenty IA lesions were identified and randomly sampled. Immunohistochemical analysis was performed to evaluate cancer-associated changes and FAP expression in pre-existing alveolar structures. Results Normal alveolar septa expressed ISLR. The ISLR level in the alveolar septa decreased in AAH and AIS tissues compared with that in normal lung tissue. The αSMA-positive area gradually increased from the adjacent lung tissue (13.3% ± 15%) to AIS (87.7% ± 14%), through AAH (70.2% ± 21%). Moreover, the FAP-positive area gradually increased from AAH (1.69% ± 1.4%) to IA (11.8% ± 7.1%), through AIS (6.11% ± 5.3%). Protein expression changes are a feature of CAFs in pre-existing alveolar septa that begin in AAH. These changes gradually progressed from AAH to IA through AIS. Conclusions FAP-positive fibroblasts may contribute to tumor stroma formation in early-stage lung adenocarcinoma, and this could influence the development of therapeutic strategies targeting FAP-positive CAFs for disrupting extracellular matrix formation.