Presence of podoplanin-positive cancer-associated fibroblasts in surgically resected primary lung adenocarcinoma predicts a shorter progression-free survival period in patients with recurrences who received platinum-based chemotherapy

Abstract

Purpose: The influence of microenvironmental factors on the effectiveness of chemotherapy is being increasingly recognized. The purpose of this study was to investigate the relationships between cancer cell and stromal cell phenotypes in primary tumors and the progression-free survival (PFS) of recurrent lung cancer patients who received platinum-based chemotherapy.

Methods: We retrospectively analyzed 87 postoperative recurrent lung adenocarcinoma patients treated with platinum-based chemotherapy. The expressions of drug resistance-related proteins including BCRP, ezrin, and ALDH1 in cancer cells, the number of CD204-positive tumor-associated macrophages (TAMs), and the presence of podoplanin-positive cancer-associated fibroblasts (CAFs) in the primary tumor were examined. The relationships between the immunohistochemical staining results of primary tumors and the PFS after receiving chemotherapy were also analyzed.

Results: Among the clinicopathological factors of primary tumors, only an advanced pathological stage was significantly associated with a shorter PFS. As for immunohistochemical staining, no significant relationships were found between the PFS and the expression of BCRP, ezrin, or ALDH1. Although the number of CD204-positive TAMs was not associated with the PFS, the presence of podoplanin-positive CAFs was significantly associated with a shorter PFS (median PFS: 5.1 vs. 7.8 months, P = 0.028). A multivariate analysis revealed a tendency of podoplanin-positive CAFs to be correlated with a shorter PFS (P = 0.087).

Conclusions: The presence of podoplanin-positive CAFs in the primary tumor could be a predictor of a shorter PFS in recurrent lung adenocarcinoma patients who received chemotherapy. These findings suggest that stromal-cell-derived factors should be incorporated into predictions of the effectiveness of chemotherapy.

Fig. 1

Immunohistochemical staining of tumor tissue. a Case with BCRP-positive cancer cells, b case with BCRP-negative cancer cells, c case with ezrin-positive cancer cells, d case with ezrin-negative cancer cells, e case with ALDH1-positive cancer cells, f case with ALDH1-negative cancer cells, g case with a high number of CD204-positive TAMs, h case with a low number of CD204-positive TAMs, i case with podoplanin-positive CAFs, and j case with podoplanin-negative CAFs

Fig. 2

Kaplan–Meier analyses of progression-free survival according to the expressions of BCRP (a), ezrin (b), and ALDH1 (c) in cancer cells, the number of CD204-positive TAMs (d), and the presence of podoplanin-positive CAFs (e)

Fig. 3

Kaplan–Meier analysis of overall survival according to the presence of podoplanin-positive CAFs