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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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NCI-H292 cells induced osteolytic lesions in tibia by activating osteoclasts through the interaction between osteoblasts/stromal cells and NCI-H292 cells. a Radiophotograph. Arrowheads indicate the osteolytic foci. Arrowheads indicate the osteolytic foci. b The total area of osteolytic foci. Each point represents the mean + SE of 20 determinations. c Histological pictures of non-tumor-bearing mouse and NCI-H292 tumor-bearing mouse double stained for TRAP/ALP on day 13. TRAP-positive activated osteoclasts (red, OC). ALP-positive osteoblasts/stromal cell layer (purple, ST). d Mouse RANKL expression in osteoblasts/stromal cells cocultured with NCI-H292 confluent cell monolayer, and with NCI-H292 cells in suspension. Each point represents the mean + SD of duplicates
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Fig1: NCI-H292 cells induced osteolytic lesions in tibia by activating osteoclasts through the interaction between osteoblasts/stromal cells and NCI-H292 cells. a Radiophotograph. Arrowheads indicate the osteolytic foci. Arrowheads indicate the osteolytic foci. b The total area of osteolytic foci. Each point represents the mean + SE of 20 determinations. c Histological pictures of non-tumor-bearing mouse and NCI-H292 tumor-bearing mouse double stained for TRAP/ALP on day 13. TRAP-positive activated osteoclasts (red, OC). ALP-positive osteoblasts/stromal cell layer (purple, ST). d Mouse RANKL expression in osteoblasts/stromal cells cocultured with NCI-H292 confluent cell monolayer, and with NCI-H292 cells in suspension. Each point represents the mean + SD of duplicates

Mentions: To examine the effects of erlotinib on bone metastasis of NSCLC, we established a novel in vivo intratibial osteolytic bone invasion model of the human NSCLC cell line NCI-H292. In mice injected with NCI-H292 cells into tibia, osteolytic bone lesions appeared from day 14 and expanded in a time-dependent manner (Fig. 1a, b). The tumor take rate in this model was 90% (osteolytic bone lesions were observed only in eighteen of twenty legs inoculated on day 28). ALP/TRAP double staining demonstrated that many TRAP-positive activated osteoclasts were present within the ALP-positive osteoblast/stromal cell layer covering the bone surfaces close to the metastatic tumor (Fig. 1c). In contrast, activated osteoclasts could hardly be seen in normal mouse (Fig. 1c). These findings indicate that direct contact between NCI-H292 tumor cells and osteoblasts/stromal cells induced the activation of osteoclastic precursors in the metastatic lesions.Fig. 1


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)

NCI-H292 cells induced osteolytic lesions in tibia by activating osteoclasts through the interaction between osteoblasts/stromal cells and NCI-H292 cells. a Radiophotograph. Arrowheads indicate the osteolytic foci. Arrowheads indicate the osteolytic foci. b The total area of osteolytic foci. Each point represents the mean + SE of 20 determinations. c Histological pictures of non-tumor-bearing mouse and NCI-H292 tumor-bearing mouse double stained for TRAP/ALP on day 13. TRAP-positive activated osteoclasts (red, OC). ALP-positive osteoblasts/stromal cell layer (purple, ST). d Mouse RANKL expression in osteoblasts/stromal cells cocultured with NCI-H292 confluent cell monolayer, and with NCI-H292 cells in suspension. Each point represents the mean + SD of duplicates
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Related In: Results  -  Collection

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

Fig1: NCI-H292 cells induced osteolytic lesions in tibia by activating osteoclasts through the interaction between osteoblasts/stromal cells and NCI-H292 cells. a Radiophotograph. Arrowheads indicate the osteolytic foci. Arrowheads indicate the osteolytic foci. b The total area of osteolytic foci. Each point represents the mean + SE of 20 determinations. c Histological pictures of non-tumor-bearing mouse and NCI-H292 tumor-bearing mouse double stained for TRAP/ALP on day 13. TRAP-positive activated osteoclasts (red, OC). ALP-positive osteoblasts/stromal cell layer (purple, ST). d Mouse RANKL expression in osteoblasts/stromal cells cocultured with NCI-H292 confluent cell monolayer, and with NCI-H292 cells in suspension. Each point represents the mean + SD of duplicates
Mentions: To examine the effects of erlotinib on bone metastasis of NSCLC, we established a novel in vivo intratibial osteolytic bone invasion model of the human NSCLC cell line NCI-H292. In mice injected with NCI-H292 cells into tibia, osteolytic bone lesions appeared from day 14 and expanded in a time-dependent manner (Fig. 1a, b). The tumor take rate in this model was 90% (osteolytic bone lesions were observed only in eighteen of twenty legs inoculated on day 28). ALP/TRAP double staining demonstrated that many TRAP-positive activated osteoclasts were present within the ALP-positive osteoblast/stromal cell layer covering the bone surfaces close to the metastatic tumor (Fig. 1c). In contrast, activated osteoclasts could hardly be seen in normal mouse (Fig. 1c). These findings indicate that direct contact between NCI-H292 tumor cells and osteoblasts/stromal cells induced the activation of osteoclastic precursors in the metastatic lesions.Fig. 1

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