Gefitinib inhibits the ability of human bone marrow stromal cells to induce osteoclast differentiation: implications for the pathogenesis and treatment of bone metastasis.
Significant relief of bone pain in patients with bone metastases was observed in a clinical trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in breast cancer. Osteoclast activation and differentiation are regulated by bone marrow stromal cells (BMSC), a heterogeneous cell compartment that comprehends undifferentiated mesenchymal stem cells (MSC) and their specialized progeny. In this regard, we found that human primary BMSCs express immunoreactive EGFR. Expression of EGFR mRNA and protein was also demonstrated in two human, continuous MSC-like cell lines, HDS-1 and HDS-2 cells. Treatment of HDS cells with EGF produced a significant increase in the levels of activated EGFR which was not observed in the presence of gefitinib. A significant reduction in the basal levels of activation of the EGFR and of Akt was observed in HDS cells following treatment with gefitinib. Treatment of HDS cells with gefitinib produced a significant reduction in the levels of secreted macrophage colony-stimulating factor (M-CSF) and cell-associated receptor activator of NF-kappaB ligand (RANKL) in both cell lines, as assessed by using specific ELISA and Western blotting techniques. Finally, the ability to sustain the differentiation of pre-osteoclasts of conditioned medium from gefitinib-treated HDS cells was reduced by approximately 45% as compared with untreated HDS cells. These data have demonstrated for the first time that the EGFR regulates the ability of BMSCs to induce osteoclast differentiation and strongly support clinical trials of gefitinib in breast cancer patients with bone disease.
Normanno
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Cell Biology and Preclinical Models, INT-Fondazione Pascale, Via Mariano Semmola, 80131 Naples, Italy. nicnorm@yahoo.com
De Luca
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A
Aldinucci
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D
Maiello
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MR
Mancino
M
M
D'Antonio
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De Filippi
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R
Pinto
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000737:chemistry / Q000187:drug effects*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D002454:Cell Differentiation / Q000187:drug effects; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D000077156:Gefitinib; D006801:Humans; D010010:Osteoclasts / Q000166:cytology* / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D017154:Stromal Cells / Q000737:chemistry / Q000187:drug effects
D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib