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Erlotinib inhibits osteolytic bone invasion of human non-small-cell lung cancer cell line NCI-H292.

Furugaki K, Moriya Y, Iwai T, Yorozu K, Yanagisawa M, Kondoh K, Fujimoto-Ohuchi K, Mori K - Clin. Exp. Metastasis (2011)

Bottom Line: In this model, NCI-H292 cells markedly activated osteoclasts in tibia, which resulted in osteolytic bone destruction.Furthermore, erlotinib also inhibited osteoblast/stromal cell proliferation in vitro and the development of osteoclasts induced by RANKL in vitro.In conclusion, erlotinib inhibits tumor-induced osteolytic invasion in bone metastasis by suppressing osteoclast activation through inhibiting tumor growth at the bone metastatic sites, osteolytic factor production in tumor cells, osteoblast/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells.

View Article: PubMed Central - PubMed

Affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kajiwara, Kamakura, Kanagawa, Japan.

ABSTRACT
Previous preclinical and clinical findings have suggested a potential role of epidermal growth factor receptor (EGFR) in osteoclast differentiation and the pathogenesis of bone metastasis in cancer. In this study, we investigated the effect of erlotinib, an orally active EGFR tyrosine kinase inhibitor (TKI), on the bone invasion of human non-small-cell lung cancer (NSCLC) cell line NCI-H292. First, we established a novel osteolytic bone invasion model of NCI-H292 cells which was made by inoculating cancer cells into the tibia of scid mice. In this model, NCI-H292 cells markedly activated osteoclasts in tibia, which resulted in osteolytic bone destruction. Erlotinib treatment suppressed osteoclast activation to the basal level through suppressing receptor activator of NF-κB ligand (RANKL) expression in osteoblast/stromal cell at the bone metastatic sites, which leads to inhibition of osteolytic bone destruction caused by NCI-H292 cells. Erlotinib inhibited the proliferation of NCI-H292 cells in in vitro. Erlotinib suppressed the production of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), IL-8, IL-11 and vascular endothelial growth factor (VEGF) in NCI-H292 cells. Furthermore, erlotinib also inhibited osteoblast/stromal cell proliferation in vitro and the development of osteoclasts induced by RANKL in vitro. In conclusion, erlotinib inhibits tumor-induced osteolytic invasion in bone metastasis by suppressing osteoclast activation through inhibiting tumor growth at the bone metastatic sites, osteolytic factor production in tumor cells, osteoblast/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells.

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A schematic diagram of the mechanism of erlotinib in a NCI-H292 osteolytic bone invasion model. Erlotinib suppressed NCI-H292 cell-induced osteoclast activation by suppressing metastatic tumor growth, osteolytic factor production in tumor cells, osteoblasts/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells. Abbreviations: OB/ST osteoblast/stromal, OC osteoclast
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Fig6: A schematic diagram of the mechanism of erlotinib in a NCI-H292 osteolytic bone invasion model. Erlotinib suppressed NCI-H292 cell-induced osteoclast activation by suppressing metastatic tumor growth, osteolytic factor production in tumor cells, osteoblasts/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells. Abbreviations: OB/ST osteoblast/stromal, OC osteoclast

Mentions: In the present study, erlotinib treatment suppressed osteoclast activation, which led to inhibit osteolytic bone destruction caused by NCI-H292 cells (Fig. 2). To clarify the bone metastasis inhibitory mechanism of erlotinib would be a useful approach to clinically select NSCLC patients with bone metastases who could benefit from erlotinib treatment. We demonstrated that erlotinib affects the vicious circle of NCI-H292 osteolytic bone invasion which results in inhibition of osteoclast activation. The effects of erlotinib appear to be related to four different mechanisms: the suppression of (1) tumor growth at the bone metastatic sites, (2) osteolytic factor production, such as PTHrP, IL-6, IL-8, IL-11 and VEGF in tumor cells, (3) osteoblasts/stromal cell proliferation and (4) osteoclast differentiation from mouse bone marrow cells (Fig. 6).Fig. 6


Erlotinib inhibits osteolytic bone invasion of human non-small-cell lung cancer cell line NCI-H292.

Furugaki K, Moriya Y, Iwai T, Yorozu K, Yanagisawa M, Kondoh K, Fujimoto-Ohuchi K, Mori K - Clin. Exp. Metastasis (2011)

A schematic diagram of the mechanism of erlotinib in a NCI-H292 osteolytic bone invasion model. Erlotinib suppressed NCI-H292 cell-induced osteoclast activation by suppressing metastatic tumor growth, osteolytic factor production in tumor cells, osteoblasts/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells. Abbreviations: OB/ST osteoblast/stromal, OC osteoclast
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198194&req=5

Fig6: A schematic diagram of the mechanism of erlotinib in a NCI-H292 osteolytic bone invasion model. Erlotinib suppressed NCI-H292 cell-induced osteoclast activation by suppressing metastatic tumor growth, osteolytic factor production in tumor cells, osteoblasts/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells. Abbreviations: OB/ST osteoblast/stromal, OC osteoclast
Mentions: In the present study, erlotinib treatment suppressed osteoclast activation, which led to inhibit osteolytic bone destruction caused by NCI-H292 cells (Fig. 2). To clarify the bone metastasis inhibitory mechanism of erlotinib would be a useful approach to clinically select NSCLC patients with bone metastases who could benefit from erlotinib treatment. We demonstrated that erlotinib affects the vicious circle of NCI-H292 osteolytic bone invasion which results in inhibition of osteoclast activation. The effects of erlotinib appear to be related to four different mechanisms: the suppression of (1) tumor growth at the bone metastatic sites, (2) osteolytic factor production, such as PTHrP, IL-6, IL-8, IL-11 and VEGF in tumor cells, (3) osteoblasts/stromal cell proliferation and (4) osteoclast differentiation from mouse bone marrow cells (Fig. 6).Fig. 6

Bottom Line: In this model, NCI-H292 cells markedly activated osteoclasts in tibia, which resulted in osteolytic bone destruction.Furthermore, erlotinib also inhibited osteoblast/stromal cell proliferation in vitro and the development of osteoclasts induced by RANKL in vitro.In conclusion, erlotinib inhibits tumor-induced osteolytic invasion in bone metastasis by suppressing osteoclast activation through inhibiting tumor growth at the bone metastatic sites, osteolytic factor production in tumor cells, osteoblast/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells.

View Article: PubMed Central - PubMed

Affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kajiwara, Kamakura, Kanagawa, Japan.

ABSTRACT
Previous preclinical and clinical findings have suggested a potential role of epidermal growth factor receptor (EGFR) in osteoclast differentiation and the pathogenesis of bone metastasis in cancer. In this study, we investigated the effect of erlotinib, an orally active EGFR tyrosine kinase inhibitor (TKI), on the bone invasion of human non-small-cell lung cancer (NSCLC) cell line NCI-H292. First, we established a novel osteolytic bone invasion model of NCI-H292 cells which was made by inoculating cancer cells into the tibia of scid mice. In this model, NCI-H292 cells markedly activated osteoclasts in tibia, which resulted in osteolytic bone destruction. Erlotinib treatment suppressed osteoclast activation to the basal level through suppressing receptor activator of NF-κB ligand (RANKL) expression in osteoblast/stromal cell at the bone metastatic sites, which leads to inhibition of osteolytic bone destruction caused by NCI-H292 cells. Erlotinib inhibited the proliferation of NCI-H292 cells in in vitro. Erlotinib suppressed the production of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), IL-8, IL-11 and vascular endothelial growth factor (VEGF) in NCI-H292 cells. Furthermore, erlotinib also inhibited osteoblast/stromal cell proliferation in vitro and the development of osteoclasts induced by RANKL in vitro. In conclusion, erlotinib inhibits tumor-induced osteolytic invasion in bone metastasis by suppressing osteoclast activation through inhibiting tumor growth at the bone metastatic sites, osteolytic factor production in tumor cells, osteoblast/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells.

Show MeSH
Related in: MedlinePlus