title: 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: OBJECTIVE
  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.
authors.affiliation: Pathology Division, Department of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Koriyama
authors.forename: Genichiro
authors.initials: G
authors.lastname: Ishii
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Yoh
authors.forename: Shinya
authors.initials: S
authors.lastname: Neri
authors.forename: Masahiro
authors.initials: M
authors.lastname: Morise
authors.forename: Shigeki
authors.initials: S
authors.lastname: Umemura
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Niho
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ohmatsu
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuboi
authors.forename: Koichi
authors.initials: K
authors.lastname: Goto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000473:pathology; D017671:Platinum Compounds / Q000008:administration & dosage*; D011013:Pneumonectomy / Q000379:methods; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome; D000098853:Podoplanin
chemical_list: D014408:Biomarkers, Tumor; D008562:Membrane Glycoproteins; D017671:Platinum Compounds; C117468:PDPN protein, human; D000098853:Podoplanin