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

Abstract

Abstract Background Adenocarcinomas show a stepwise progression from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS) and finally to invasive adenocarcinoma (IA). The expression of immunoglobulin superfamily containing leucine-rich repeat (ISLR) is a marker of tumor-restraining cancer-associated fibroblasts (CAFs), which are distinct from the conventional, strongly α-smooth muscle actin (αSMA)-positive CAFs. Fibroblast-activation protein (FAP) is expressed in activated and profibrotic fibroblasts of tumors and fibrotic tissues and has recently been focused on as a potential therapeutic and diagnostic target of CAFs. Methods This study investigated the changes in protein expression during adenocarcinoma progression in pre-existing alveolar septa by assessing the ISLR, αSMA, and FAP expression in normal, AAH, AIS, and IA lung nodules. From January 2018 to December 2019, 14 AAH, 17 AIS, and 20 IA lesions were identified and randomly sampled at our institute. The immunohistochemical analysis evaluated the cancer-associated changes and FAP expression in pre-existing alveolar structures of normal, AAH, AIS, and IA tissues. Normal alveolar septa-expressed ISLR, and ISLR levels in alveolar septa decreased in AAH and AIS tissues compared with those in normal lung tissue. Results The αSMA-positive area significantly increased from that in the adjacent lung tissue (13.3 ± 15%) to that in AIS (87.7 ± 14%), through that in AAH (70.2 ± 21%). Moreover, the FAP-positive area significantly increased from that in AAH (1.69 ± 1.4%) to that in IA (11.8 ± 7.1%), through that in AIS (6.11 ± 5.3%). Protein expression changes are a feature of CAFs in pre-existing alveolar septa that begin in AAH. This change, including FAP expression, gradually progressed from AAH to IA through AIS. Conclusions Our findings suggest that FAP-positive fibroblasts may contribute to tumor stroma formation in early-stage lung adenocarcinoma, which could influence the development of therapeutic strategies targeting FAP-positive CAFs for disturbing extracellular matrix formation.