RRC ID 47979
Author Ishibashi M, Neri S, Hashimoto H, Miyashita T, Yoshida T, Nakamura Y, Udagawa H, Kirita K, Matsumoto S, Umemura S, Yoh K, Niho S, Tsuboi M, Masutomi K, Goto K, Ochiai A, Ishii G.
Title CD200-positive cancer associated fibroblasts augment the sensitivity of Epidermal Growth Factor Receptor mutation-positive lung adenocarcinomas to EGFR Tyrosine kinase inhibitors.
Journal Sci Rep
Abstract Cancer associated fibroblasts (CAFs) play important roles in the chemotherapeutic process, especially through influencing the resistance of tumor cells to molecular targeted therapy. Here we report the existence of a special subpopulation of patient-specific-CAFs that augment the sensitivity of EGFR gene mutation-positive lung cancer to the EGFR-tyrosine kinase inhibitor (EGFR-TKI), gefitinib. When cocultured with EGFR mutation positive lung cancer cells, these CAFs increased the apoptic effect of gefitinib on cancer cells, whereas, in the absence of gefitinib, they did not affect cancer cell viability. The assay using different single cell-derived clones demonstrated that the aforementioned sensitizing ability is clone-specific. Microarray analysis revealed that CD200 was expressed at much higher levels in this CAFs. Knocking down of CD200 expression deprived CAFs of their sensitizing potential, suggesting that CD200 is the functional molecule responsible for the effect. Immunohistochemical analysis of samples from patients receiving postoperative gefitinib treatment revealed that the individuals whose resected lung adenocarcinomas contained CD200-positive CAFs tended to have longer progression free survival of gefitinib when they recurred after surgery. These results suggest that CD200-positive CAFs can augment the sensitivity to EGFR-TKIs and may possess far reaching applications in the therapeutic use of EGFR-TKIs.
Volume 7
Pages 46662
Published 2017-4-21
DOI 10.1038/srep46662
PII srep46662
PMID 28429795
PMC PMC5399371
MeSH Adenocarcinoma of Lung / drug therapy* Adenocarcinoma of Lung / metabolism Adenocarcinoma of Lung / surgery Adult Aged Aged, 80 and over Antigens, CD / genetics Antigens, CD / metabolism* Cancer-Associated Fibroblasts / metabolism* Cancer-Associated Fibroblasts / pathology Cell Line, Tumor Cell Survival / drug effects Cell Survival / genetics Coculture Techniques ErbB Receptors / genetics ErbB Receptors / metabolism Female Gefitinib / pharmacology Gefitinib / therapeutic use* Gene Expression Profiling / methods Humans Kaplan-Meier Estimate Lung Neoplasms / drug therapy* Lung Neoplasms / metabolism Lung Neoplasms / surgery Male Middle Aged Mutation Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use RNA Interference
IF 4.011
Times Cited 10
WOS Category ONCOLOGY
Resource
DNA material pENTR4-H1 (RDB04395) CS-RfA-EG (RDB04391) CSII-CMV-RfA-IRES2-Venus (RDB04388) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394).