ECTS2016 Cancer and Bone Oral Communications Oral Communications (18 abstracts)
Blockade of C5aR impairs tumor-induced osteoclastogenesis preventing bone metastasis colonization in lung cancer
Daniel Ajona 1, , Carolina Zandueta 1, , Leticia Corrales 1, , Maria J. Pajares 1, , Elena Martinez-Terroba 1, , Naiara Perurena 1, , Luis M. Montuenga 1, , Ruben Pio 1, & Fernando Lecanda 1,
1Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), Pamplona, Spain; 2Navarra Institute for Health Research (IDISNA), Pamplona, Spain, Pamplona, Spain.
C5aR is a membrane-associated receptor for C5a, a potent immune mediator generated after complement activation. C5aR expressed in tumor infiltrating immune cells creates a favorable microenvironment for tumor progression. However, the expression of C5aR by cancer cells and its contribution to their malignant phenotype is poorly understood. Immunohistochemical analysis revealed that high levels of C5aR in human lung tumors were associated with poor survival (P=0.005) and recurrence-free survival (P<0.001) in a cohort of 76 patients. Lentiviral shRNA-mediated C5aR silencing in A549 lung adenocarcinoma cells showed unaltered growth kinetics in vitro and in vivo. However, intracardiac inoculation (i.c.) of C5aR-silenced cells led to a substantial reduction in skeletal metastatic burden (P<0.001), as assessed by bioluminescence imaging, and the presence of osteolytic lesions (P<0.001), evaluated by X-ray and μCT imaging and histological analysis. A decreased tumor cell growth was detected in vivo (Ki-67) (P<0.05). These findings were validated in H460 large-cell lung carcinoma cells using an identical approach. Similarly, pharmacological blockade using a specific inhibitor of C5a significantly reduced the osseous metastatic activity of A549 cells after i.c. inoculation. This effect was associated with decreased bone colonization, since intratibial injection of shC5aR cells showed a reduction in tumor burden as compared to control animals. Interestingly, a reduced TRAP+ osteoclast staining was detected in bones derived from shC5aR inoculated animals (P<0.05). These results were correlated with a marked reduction in osteoclastogenic activity (TRAP+) induced by conditioned medium from shC5aR cells cultured alone or co-cultured with ST-2 bone marrow-derived stromal cells (P<0.001). Furthermore, C5aR also enhanced metalloproteolytic activity, and migration and invasion capabilities in vitro. These data indicate that C5aR disruption abrogates osteoclatogenic activity, critically impairing osseous colonization. We suggest that C5aR could represent a clinically relevant factor in lung cancer prognosis and a potential therapeutic target.
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