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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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Effects of erlotinib on osteolytic bone invasion model of NCI-H292 cells. NCI-H292 cell-induced osteolytic lesions in mice treated with or without 75 mg/kg of erlotinib. a Radiophotographs on day 28. Arrowheads indicate the osteolytic foci. The total area (b) and incidence (c) of osteolytic foci were measured. Each point represents the mean + SE of 20 determinations. *P < 0.05, by Wilcoxon test, compared with vehicle-treated group. d Histological pictures on day 14 stained with anti-mouse RANKL antibody. The stained area (brown) indicates the expression of RANKL in osteoblasts/stromal cells. e Histological pictures on day 14 stained with TRAP in mice treated with or without 75 mg/kg of erlotinib. Arrowheads indicate the activated osteoclasts. f The number of multinucleated (>4 nuclei) TRAP-positive osteoclasts were measured. Each point represents the mean + SE of sex tuplicates
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Fig2: Effects of erlotinib on osteolytic bone invasion model of NCI-H292 cells. NCI-H292 cell-induced osteolytic lesions in mice treated with or without 75 mg/kg of erlotinib. a Radiophotographs on day 28. Arrowheads indicate the osteolytic foci. The total area (b) and incidence (c) of osteolytic foci were measured. Each point represents the mean + SE of 20 determinations. *P < 0.05, by Wilcoxon test, compared with vehicle-treated group. d Histological pictures on day 14 stained with anti-mouse RANKL antibody. The stained area (brown) indicates the expression of RANKL in osteoblasts/stromal cells. e Histological pictures on day 14 stained with TRAP in mice treated with or without 75 mg/kg of erlotinib. Arrowheads indicate the activated osteoclasts. f The number of multinucleated (>4 nuclei) TRAP-positive osteoclasts were measured. Each point represents the mean + SE of sex tuplicates

Mentions: Administration of erlotinib significantly decreased the area and incidences of NCI-H292 cell-induced osteolytic lesions on days 21 and 28 (Fig. 2a, b, c). Administration of erlotinib starting from days 7 or 14 exerted almost the same inhibitory effects of osteolytic lesions on day 28 as starting from day 1 (data not shown). A difference in body weight loss was not observed in the erlotinib treatment group compared with the vehicle group on days 21 and 28 (data not shown). Furthermore, erlotinib completely suppressed the tumor induced-RANKL expression in osteoblasts/stromal cells (Fig. 2d). Erlotinib markedly suppressed the osteoclast activation to the basal level of non-tumor bearing mouse (P = 0.07) (Fig. 2e, f). These findings indicate that erlotinib inhibited osteolytic bone destruction of NCI-H292 cells in the tibia by inhibiting the accumulation of activated osteoclasts.Fig. 2


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)

Effects of erlotinib on osteolytic bone invasion model of NCI-H292 cells. NCI-H292 cell-induced osteolytic lesions in mice treated with or without 75 mg/kg of erlotinib. a Radiophotographs on day 28. Arrowheads indicate the osteolytic foci. The total area (b) and incidence (c) of osteolytic foci were measured. Each point represents the mean + SE of 20 determinations. *P < 0.05, by Wilcoxon test, compared with vehicle-treated group. d Histological pictures on day 14 stained with anti-mouse RANKL antibody. The stained area (brown) indicates the expression of RANKL in osteoblasts/stromal cells. e Histological pictures on day 14 stained with TRAP in mice treated with or without 75 mg/kg of erlotinib. Arrowheads indicate the activated osteoclasts. f The number of multinucleated (>4 nuclei) TRAP-positive osteoclasts were measured. Each point represents the mean + SE of sex tuplicates
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198194&req=5

Fig2: Effects of erlotinib on osteolytic bone invasion model of NCI-H292 cells. NCI-H292 cell-induced osteolytic lesions in mice treated with or without 75 mg/kg of erlotinib. a Radiophotographs on day 28. Arrowheads indicate the osteolytic foci. The total area (b) and incidence (c) of osteolytic foci were measured. Each point represents the mean + SE of 20 determinations. *P < 0.05, by Wilcoxon test, compared with vehicle-treated group. d Histological pictures on day 14 stained with anti-mouse RANKL antibody. The stained area (brown) indicates the expression of RANKL in osteoblasts/stromal cells. e Histological pictures on day 14 stained with TRAP in mice treated with or without 75 mg/kg of erlotinib. Arrowheads indicate the activated osteoclasts. f The number of multinucleated (>4 nuclei) TRAP-positive osteoclasts were measured. Each point represents the mean + SE of sex tuplicates
Mentions: Administration of erlotinib significantly decreased the area and incidences of NCI-H292 cell-induced osteolytic lesions on days 21 and 28 (Fig. 2a, b, c). Administration of erlotinib starting from days 7 or 14 exerted almost the same inhibitory effects of osteolytic lesions on day 28 as starting from day 1 (data not shown). A difference in body weight loss was not observed in the erlotinib treatment group compared with the vehicle group on days 21 and 28 (data not shown). Furthermore, erlotinib completely suppressed the tumor induced-RANKL expression in osteoblasts/stromal cells (Fig. 2d). Erlotinib markedly suppressed the osteoclast activation to the basal level of non-tumor bearing mouse (P = 0.07) (Fig. 2e, f). These findings indicate that erlotinib inhibited osteolytic bone destruction of NCI-H292 cells in the tibia by inhibiting the accumulation of activated osteoclasts.Fig. 2

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