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Erlotinib prevents experimental metastases of human small cell lung cancer cells with no epidermal growth factor receptor expression

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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.

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Abbreviations

EGFR–TKI:

Epidermal growth factor receptor–tyrosine kinase inhibitor

NSCLC:

Non-small cell lung cancer

NK:

Natural killer

SCID:

Severe combined immunodeficient

SCLC:

Small cell lung cancer

PTHrP:

Parathyroid hormone-related protein

EGFR:

Epidermal growth factor receptor

HUVECs:

Human umbilical vein endothelial cells

IL:

Interleukin

Ab:

Antibody

VEGF:

Vascular endothelial growth factor

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium

BMMSCs:

Bone marrow mesenchymal stem cells

HGF:

Hepatocyte growth factor

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Acknowledgments

This work was supported in part by a Grant-in-aid for Cancer Research from the Ministry of Education, Science, Sports and Culture of Japan, and Ministry of Health and Welfare of Japan.

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Authors and Affiliations

  1. Department of Medical Oncology, Institute of Health Biosciences, The University of Tokushima Gradate School, Tokushima, Japan

    Adel Gomaa Mohammed Gabr, Takuya Kuramoto, Soji Kakiuchi, Van The Trung & Saburo Sone

  2. Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Hisatsugu Goto, Masaki Hanibuchi, Minako Suzuki, Atsuro Saijo, Satoshi Sakaguchi, Saburo Sone & Yasuhiko Nishioka

  3. Department of Molecular and Environmental Pathology, Institute of Health Biosciences, The University of Tokushima Gradate School, Tokushima, Japan

    Hirohisa Ogawa

  4. Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

    Yoichiro Moriya

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  1. Adel Gomaa Mohammed Gabr
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  2. Hisatsugu Goto
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Correspondence to Yasuhiko Nishioka.

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Gabr, A.G.M., Goto, H., Hanibuchi, M. et al. Erlotinib prevents experimental metastases of human small cell lung cancer cells with no epidermal growth factor receptor expression. Clin Exp Metastasis 29, 207–216 (2012). https://doi.org/10.1007/s10585-011-9443-3

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  • DOI: https://doi.org/10.1007/s10585-011-9443-3

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