Colony-stimulating factor 1 potentiates lung cancer bone metastasis

Abstract

Colony-stimulating factor 1 (CSF1) is essential for osteoclastogenesis that mediates osteolysis in metastatic tumors. Patients with lung cancer have increased CSF1 in serum and high levels are associated with poor survival. Adenocarcinomas metastasize rapidly and many patients suffer from bone metastasis. Lung cancer stem-like cells sustain tumor growth and potentiate metastasis. The purpose of this study was to determine the role of CSF1 in lung cancer bone metastasis and whether inhibition of CSF1 ameliorates the disease. Human lung adenocarcinoma A549 cells were examined in vitro for CSF1/CSF1R. A549-luc cells were injected intracardiac in NOD/SCID mice and metastasis was assessed. To determine the effect of CSF1 knockdown (KD) in A549 cells on bone metastasis, cells were stably transfected with a retroviral vector containing short-hairpin CSF1 (KD) or empty vector (CT). Results showed that A549 cells express CSF1/CSF1R; CSF1 increased their proliferation and invasion, whereas soluble CSF1R inhibited invasion. Mice injected with A549-luc cells showed osteolytic bone lesions 3.5 weeks after injection and lesions increased over 5 weeks. Tumors recapitulated adenocarcinoma morphology and showed osteoclasts along the tumor/bone interface, trabecular, and cortical bone loss. Analyses of KD cells showed decreased CSF1 protein levels, reduced colony formation in soft agar assay, and decreased fraction of stem-like cells. In CSF1KD mice, the incidence of tumor metastasis was similar to controls, although fewer CSF1KD mice had metastasis in both hind limbs. KD tumors showed reduced CSF1 expression, Ki-67 þ cells, and osteoclasts. Importantly, there was a low incidence of large tumors 40.1 mm 2 in CSF1KD mice compared with control mice (10% vs 62.5%). This study established a lung osteolytic bone metastasis model that resembles human disease and suggests that CSF1 is a key determinant of cancer stem cell survival and tumor growth. Results may lead to novel strategies to inhibit CSF1 in lung cancer and improve management of bone metastasis.Laboratory Investigation (2014) 94, 371-381; doi:10.1038/labinvest.2014.1; published online 27 January 2014 KEYWORDS: bone; cancer; CSF1; lung; metastasis Lung cancer is the leading cause of cancer deaths world wide. 1 The majority of lung cancers are non-small-cell type and, of those, adenocarcinoma is the most common. These tumors have a high mortality rate and metastasize rapidly, often within months of diagnosis, with 60-70% of patients developing bone metastasis. 2,3 Lesions are predominantly osteolytic, involving vertebrae, rib, pelvis, and femur that lead to significant morbidity from spinal cord compression, pathologic fractures, and intractable pain. Metastasis to bone is associated with a poor prognosis and a mean survival of 9.7 months. 2 Colony-stimulating factor 1 (CSF1) is essential for osteoclastogenesis that mediates osteolysis in metastatic tumors to bone. The effect of CSF1 is mediated via the c-fms tyrosine kinase receptor (CSF1R) that is expressed on mononuclear ph...

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