Daniel Ajona1,2,3,4, Carolina Zandueta1,2,3, Leticia Corrales1, Haritz Moreno1,2, María J Pajares1,2,3,5, Sergio Ortiz-Espinosa1,3,4, Elena Martínez-Terroba1,5, Naiara Perurena1, Fernando J de Miguel1,4, Eloisa Jantus-Lewintre3,6,7, Carlos Camps3,6,8,9, Silvestre Vicent1,2,3,5, Jackeline Agorreta1,2,3,5, Luis M Montuenga1,2,3,5, Ruben Pio1,2,3,4, Fernando Lecanda1,2,3,5. 1. 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain. 2. 2 IdiSNA (Navarra Institute for Health Research), Pamplona, Spain. 3. 3 CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Spain. 4. 4 Department of Biochemistry and Genetics, School of Sciences, and. 5. 5 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain. 6. 6 Molecular Oncology Laboratory, Fundación Investigación, Hospital General Universitario de Valencia, Valencia, Spain. 7. 7 Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain. 8. 8 Department of Medical Oncology, Hospital General Universitario de Valencia, Valencia, Spain; and. 9. 9 Department of Medicine, Universitat de València, Valencia, Spain.
Abstract
RATIONALE: C5aR1 (CD88), a receptor for complement anaphylatoxin C5a, is a potent immune mediator. Its impact on malignant growth and dissemination of non-small cell lung cancer cells is poorly understood. OBJECTIVES: To investigate the contribution of the C5a/C5aR1 axis to the malignant phenotype of non-small cell lung cancer cells, particularly in skeletal colonization, a preferential lung metastasis site. METHODS: Association between C5aR1 expression and clinical outcome was assessed in silico and validated by immunohistochemistry. Functional significance was evaluated by lentiviral gene silencing and ligand l-aptamer inhibition in in vivo models of lung cancer bone metastasis. In vitro functional assays for signaling, migration, invasion, metalloprotease activity, and osteoclastogenesis were also performed. MEASUREMENTS AND MAIN RESULTS: High levels of C5aR1 in human lung tumors were significantly associated with shorter recurrence-free survival, overall survival, and bone metastasis. Silencing of C5aR1 in lung cancer cells led to a substantial reduction in skeletal metastatic burden and osteolysis in in vivo models. Furthermore, metalloproteolytic, migratory, and invasive tumor cell activities were modulated in vitro by C5aR1 stimulation or gene silencing. l-Aptamer blockade or C5aR1 silencing significantly reduced the osseous metastatic activity of lung cancer cells in vivo. This effect was associated with decreased osteoclastogenic activity in vitro and was rescued by the exogenous addition of the chemokine CXCL16. CONCLUSIONS: Disruption of C5aR1 signaling in lung cancer cells abrogates their tumor-associated osteoclastogenic activity, impairing osseous colonization. This study unveils the role played by the C5a/C5aR1 axis in lung cancer dissemination and supports its potential use as a novel therapeutic target.
RATIONALE: C5aR1 (CD88), a receptor for complement anaphylatoxin C5a, is a potent immune mediator. Its impact on malignant growth and dissemination of non-small cell lung cancer cells is poorly understood. OBJECTIVES: To investigate the contribution of the C5a/C5aR1 axis to the malignant phenotype of non-small cell lung cancer cells, particularly in skeletal colonization, a preferential lung metastasis site. METHODS: Association between C5aR1 expression and clinical outcome was assessed in silico and validated by immunohistochemistry. Functional significance was evaluated by lentiviral gene silencing and ligand l-aptamer inhibition in in vivo models of lung cancer bone metastasis. In vitro functional assays for signaling, migration, invasion, metalloprotease activity, and osteoclastogenesis were also performed. MEASUREMENTS AND MAIN RESULTS: High levels of C5aR1 in humanlung tumors were significantly associated with shorter recurrence-free survival, overall survival, and bone metastasis. Silencing of C5aR1 in lung cancer cells led to a substantial reduction in skeletal metastatic burden and osteolysis in in vivo models. Furthermore, metalloproteolytic, migratory, and invasive tumor cell activities were modulated in vitro by C5aR1 stimulation or gene silencing. l-Aptamer blockade or C5aR1 silencing significantly reduced the osseous metastatic activity of lung cancer cells in vivo. This effect was associated with decreased osteoclastogenic activity in vitro and was rescued by the exogenous addition of the chemokine CXCL16. CONCLUSIONS: Disruption of C5aR1 signaling in lung cancer cells abrogates their tumor-associated osteoclastogenic activity, impairing osseous colonization. This study unveils the role played by the C5a/C5aR1 axis in lung cancer dissemination and supports its potential use as a novel therapeutic target.
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