RRC ID 71658
Author Kinoshita K, Nakagawa K, Hamada J, Hida Y, Tada M, Kondo S, Moriuchi T.
Title Imatinib mesylate inhibits the proliferation-stimulating effect of human lung cancer-associated stromal fibroblasts on lung cancer cells.
Journal Int J Oncol
Abstract Platelet-derived growth factor (PDGF) is a significant mediator in the proliferation of cancer-associated stromal fibroblasts (CAFs). The inhibition of CAF proliferation by blocking PDGF signaling could lead to a development of novel cancer therapy. We analyzed whether inhibiting proliferation of lung CAFs by imatinib mesylate, which has inhibitory activity on PDGF-receptor tyrosine kinase, could suppress the proliferative activity of lung cancer cells which coexisted in the tumor tissue. First, we established primary cultured fibroblasts from human lung cancer tissues. RT-PCR analysis showed that PDGF-receptors (PDGFRalpha and beta) were more highly expressed in the fibroblasts, whereas PDGFs (PDGF-A, and -B) were more in lung cancer cell lines. Western blotting showed that imatinib treatment inhibited phosphorylation of PDGFRbeta, Akt, and Erk1/2 in the fibroblasts. The treatment also significantly inhibited the proliferative activity of the fibroblasts. The inhibitory effects were exerted more definitely in co-administering imatinib and PDGF-BB, a dimer of the polypeptide chains of B, than in administering imatinib alone. The conditioned media of the fibroblasts significantly increased the proliferative activity of human lung cancer cell line A549 compared to control culture medium. The proliferation-stimulating effect on A549 cells decreased significantly in the conditioned media of the primary cultured fibroblasts that had been treated with imatinib. Our results suggest that imatinib has antitumor activity which is exerted by reducing the proliferation-stimulating effect of CAFs on lung cancer cells, as well as inhibiting the proliferation of CAFs, by way of blocking PDGF signaling.
Volume 37(4)
Pages 869-77
Published 2010-10-1
DOI 10.3892/ijo_00000738
PMID 20811709
MeSH Actins / metabolism Antineoplastic Agents / pharmacology* Becaplermin Benzamides Blotting, Western Cell Line, Tumor Cell Proliferation / drug effects* Culture Media, Conditioned / metabolism Dose-Response Relationship, Drug Fibroblasts / drug effects* Fibroblasts / metabolism Humans Imatinib Mesylate Lung Neoplasms / metabolism Lung Neoplasms / pathology* Mitogen-Activated Protein Kinase 1 / metabolism Mitogen-Activated Protein Kinase 3 / metabolism Paracrine Communication / drug effects* Phosphorylation Piperazines / pharmacology* Platelet-Derived Growth Factor / metabolism Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins c-akt / metabolism Proto-Oncogene Proteins c-sis Pyrimidines / pharmacology* Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors Receptors, Platelet-Derived Growth Factor / metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects Stromal Cells / drug effects* Stromal Cells / metabolism
IF 3.899
Human and Animal Cells WI-38(RCB0702)