title: Imatinib mesylate inhibits the proliferation-stimulating effect of human lung cancer-associated stromal fibroblasts on lung cancer cells.
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.
authors.affiliation: Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Hokkaido 060-8638, Japan. mr-white@med.hokudai.ac.jp
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Koji
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Hamada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hida
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Tada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kondo
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Moriuchi
mesh_terms: D000199:Actins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077214:Becaplermin; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D017077:Culture Media, Conditioned / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019899:Paracrine Communication / Q000187:drug effects*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D001549:Benzamides; D017077:Culture Media, Conditioned; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000077214:Becaplermin; D000068877:Imatinib Mesylate; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3