title: Erlotinib prevents experimental metastases of human small cell lung cancer cells with no epidermal growth factor receptor expression.
abstract: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show dramatic antitumor activity in a subset of patients with non-small cell lung cancer who have an active mutation in the epidermal growth factor receptor (EGFR) gene. On the other hand, some lung cancer patients with wild type EGFR also respond to EGFR-TKIs, suggesting that EGFR-TKIs have an effect on host cells as well as tumor cells. However, the effect of EGFR-TKIs on host microenvironments is largely unknown. A multiple organ metastasis model was previously established in natural killer cell-depleted severe combined immunodeficient mice using human lung cancer cells. This model was used to investigate the therapeutic efficacy of erlotinib, an EGFR-TKI, on multiple organ metastases induced by human small cell lung cancer cells (SBC-5 cells) that did not express EGFR. Although erlotinib did not have any effect on the proliferation of SBC-5 cells in vitro, it significantly suppressed bone and lung metastases in vivo, but not liver metastases. An immunohistochemical analysis revealed that, erlotinib significantly suppressed the number of osteoclasts in bone metastases, whereas no difference was seen in microvessel density. Moreover, erlotinib inhibited EGF-induced receptor activator of nuclear factor kappa-B expression in an osteoblastic cell line (MC3T3-E1 cells). These results strongly suggested that erlotinib prevented bone metastases by affecting host microenvironments irrespective of its direct effect on tumor cells.
authors.affiliation: Department of Medical Oncology, Institute of Health Biosciences, The University of Tokushima Gradate School, Tokushima, Japan.
authors.forename: Adel Gomaa Mohammed
authors.initials: AG
authors.lastname: Gabr
authors.forename: Hisatsugu
authors.initials: H
authors.lastname: Goto
authors.forename: Masaki
authors.initials: M
authors.lastname: Hanibuchi
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Ogawa
authors.forename: Takuya
authors.initials: T
authors.lastname: Kuramoto
authors.forename: Minako
authors.initials: M
authors.lastname: Suzuki
authors.forename: Atsuro
authors.initials: A
authors.lastname: Saijo
authors.forename: Soji
authors.initials: S
authors.lastname: Kakiuchi
authors.forename: Van The
authors.initials: VT
authors.lastname: Trung
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Moriya
authors.forename: Saburo
authors.initials: S
authors.lastname: Sone
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000517:prevention & control / Q000556:secondary; D018288:Carcinoma, Small Cell / Q000737:chemistry / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000737:chemistry / Q000473:pathology*; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D053245:RANK Ligand / Q000032:analysis
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D053245:RANK Ligand; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors