Prognostic significance of combining immunohistochemical markers for cancer-associated fibroblasts in lung adenocarcinoma tissue.

Abstract

Cancer-associated fibroblasts (CAFs), activated fibroblasts in a cancer microenvironment, exert various effects upon carcinoma cells including lung adenocarcinoma cells. Various markers identifying CAFs have been proposed, but the correlations among these markers proposed and their clinicopathological significance have remained largely unknown. Therefore, in this study, we immunohistochemically evaluated the expression of alpha-smooth muscle actin (α-SMA), podoplanin, and periostin among these proposed markers in 92 cases of lung adenocarcinoma. These three markers were weakly correlated, but the relative abundance of α-SMA was significantly associated with high Ki-67 labelling index (LI), lymph node metastasis, and low 5-year overall survival (OS) rate of the patients. That of podoplanin was significantly associated with high pT and Ki-67 LI, distant metastasis, and low 5-year OS rate and that of periostin with high pT and Ki-67 LI. We then tentatively subclassified these cases into four groups according to high or low status of each of paired markers: α-SMA/podoplanin, α-SMA/periostin, and periostin/podoplanin. The α-SMA high/podoplanin high group was associated with the lowest survival rate (53.3%) among the four groups with significance. However, there were no significant differences in overall survival when the patients were classified according to the combinations of α-SMA/periostin or periostin/podoplanin. Results of our study firstly revealed the heterogeneity of CAFs in human lung adenocarcinoma tissue, and the analysis employing multiple markers of CAFs is generally required to study the clinical significance of CAFs in clinical materials.